Search Results (587)

Cannabinoids can bind to several cannabinoid receptors and modulate cellular signaling and gene expression relevant to inflammation and lipid homeostasis. Likewise, several vitamin E analogs can modulate inflammatory signaling and foam cell formation in macrophages by antioxidant and non-antioxidant mechanisms. We analyzed the regulatory effects on the expression of genes involved in cellular lipid homeostasis (e.g., CD36/FAT cluster of differentiation/fatty acid transporter and scavenger receptor SR-B1) and inflammation (e.g., inflammatory cytokines, TNFα, IL1β) by cannabinoids (cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC)) in human THP-1 macrophages with/without co-treatment with natural alpha-tocopherol (RRR-αT), natural RRR-αTA (αTAn), and synthetic racemic all-rac-αTA (αTAr). In general, αTAr inhibited both lipid accumulation and the inflammatory response (TNFα, IL6, IL1β) more efficiently compared to αTAn. Our results suggest that induction of CD36/FAT mRNA expression after treatment with THC can be prevented, albeit incompletely, by αTA (either αTAn or αTAr) or CBD. A similar response pattern was observed with genes involved in lipid efflux (ABCA1, less with SR-B1), suggesting an imbalance between uptake, metabolism, and efflux of lipids/αTA, increasing macrophage foam cell formation. THC increased reactive oxygen species (ROS), and co-treatment with αTAn or αTAr only partially prevented this. To study the mechanisms by which inflammatory and lipid-related genes are modulated, HEK293 cells overexpressing cannabinoid receptors (CB1 or TRPV-1) were transfected with luciferase reporter plasmids containing the human CD36 promoter or response elements for transcription factors involved in its regulation (e.g., LXR and NFκB). In cells overexpressing CB1, we observed activation of NFκB by THC that was inhibited by αTAr. Full article

Autophagy is a well-preserved biological mechanism that is essential for sustaining homeostasis by degradation and recycling damaged organelles, misfolded proteins, and other cytoplasmic detritus. Cannabinoid signaling has emerged as a prospective regulator of diverse cellular functions, including immunological modulation, oxidative stress response, apoptosis, and autophagy. Dysregulation of autophagy contributes to pathogenesis and treatment resistance of several oral diseases, including oral squamous cell carcinoma (OSCC), periodontitis, and gingival inflammation. This review delineates the molecular crosstalk between cannabinoid receptor type I (CB1) and type II (CB2) activation and autophagic pathways across oral tissues. Cannabinoids, including cannabidiol (CBD) and tetrahydrocannabinol (THC), modulate key regulators like mTOR, AMPK, and Beclin-1, thereby influencing autophagic flux, inflammation, and apoptosis. Experimental studies indicate that cannabinoids inhibit the PI3K/AKT/mTOR pathway, promote reactive oxygen species (ROS)-induced autophagy, and modulate cytokine secretion, mechanisms that underline their dual anti-inflammatory and anti-cancer capabilities. In addition, cannabinoid-induced autophagy has been shown to enhance stem cell survival and differentiation, offering promise for dental pulp regeneration. Despite these promising prospects, several challenges remain, including receptor selectivity, dose-dependent variability, limited oral bioavailability, and ongoing regulatory constraints. A deeper understanding of the context-dependent regulation of autophagy by cannabinoid signaling could pave the way for innovative therapeutic interventions in dentistry. Tailored cannabinoid-based formulations, engineered for receptor specificity, tissue selectivity, and optimized delivery, hold significant potential to revolutionize oral healthcare by modulating autophagy-related molecular pathways involved in disease resolution and tissue regeneration. Full article

The cannabinoid 1-receptor (CB1R) is found in particularly high levels in the hippocampus (HPC). Increased CB1R density and binding are observed in patients with schizophrenia, and epidemiological studies suggest that regular cannabis use during adolescence is a risk factor for the disease. CB1R was shown to interfere with neuronal network oscillations and to impair sensory gating and memory function. Neuronal oscillations are essential in multiple cognitive functions, and their impairment was documented in neurological and psychiatric diseases. The aim of this study was to investigate how adolescent pre-treatment with the CB1R-selective agonist CP-55940 may lead to abnormalities in theta synchronization in adulthood. Rats were pre-treated with CP-55940 or vehicle during adolescence (daily injections in PND 32–36 or PND 42–46). They were then tested in adulthood (PND over 70) under urethane anesthesia. Hippocampal theta rhythm was elicited by brainstem stimulation at five intensity levels 1 hour before and up to 5 h after injection. We found a significant decrease in elicited theta power after CP-55940 in adult rats, which was aggravated further in rats pre-treated in adolescence with the CB1R agonist. The effect was significantly larger in rats pre-treated during early adolescence (PND 32–36) compared to the group pre-treated during late adolescence (PND 42–46). We conclude that (1) exposure to cannabis during adolescence leads to increased sensitivity to CB1R agonist in adulthood, and (2) early adolescence, a critical period for development of HPC networks generating theta rhythms, is particularly prone to this sensitivity. 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

The cannabinoid receptor type 2 (CB₂) is increasingly recognized as a crucial regulator of neuroimmune balance in the brain. In addition to its well-established role in immunity, the CB₂ receptor has been identified in specific populations of neurons and glial cells throughout various brain regions, and its expression is dynamically increased during inflammatory and neuropathological conditions, positioning it as a potential non-psychoactive target for modifying neurological diseases. The expression of the CB₂ gene (CNR2) is finely tuned by epigenetic processes, including promoter CpG methylation, histone modifications, and non-coding RNAs, which regulate receptor availability and signaling preferences in response to stress, inflammation, and environmental factors. CB₂ signaling interacts with TRP channels (such as TRPV1), nuclear receptors (PPARγ), and orphan G Protein-Coupled Receptors (GPCRs, including GPR55 and GPR18) within the endocannabinoidome (eCBome), influencing microglial characteristics, cytokine production, and synaptic activity. We review how these interconnected mechanisms affect neurodegenerative and neuropsychiatric disorders, underscore the species- and cell-type-specificities that pose challenges for translation, and explore emerging strategies, including selective agonists, positive allosteric modulators, and biased ligands, that leverage the signaling adaptability of the CB₂ receptor while reducing central effects mediated by the CB₁ receptor. This focus on the neuro-centric perspective repositions the CB₂ receptor as an epigenetically informed, context-dependent hub within the eCBome, making it a promising candidate for precision therapies in conditions featuring neuroinflammation. Full article

Cannabinoid receptor (CB1), a G protein coupled receptor (GPCR), is a known pharmacological target in several diseases and modulates key physiological processes through Gi protein-mediated signaling. However, recent evidence suggests that CB1 can also activate other G proteins, including the stimulatory Gs protein, a phenomenon with unclear structural determinants. Here, we use a computational approach to elucidate the structural basis of the CB1-Gs interaction. Protein–protein docking and extensive molecular dynamics simulations yield a model for the CB1-Gs complex that agrees well with both existing experimental data and available GPCR-Gs structures, supporting its validity. This work provides new insights into the structural basis of CB1’s ability to couple with different G-proteins. The model provides a basis for future studies dissecting the functional consequences of CB1-Gs signaling and the development of improved therapeutics targeting the CB1 receptor and the wider endocannabinoid system. 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 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

Cannabinoids, compounds that interact with the endocannabinoid system, have shown promising neuroprotective effects in various neurodegenerative diseases, including those affecting the retina. This review evaluates evidence for the presence and action of cannabinoids in the retina, their function in protecting against oxidative stress and modulating neuroinflammation, and the outcomes observed in animal models of retinal diseases such as glaucoma and age-related macular degeneration (AMD), the most common causes of vision loss. Cannabinoids have proven effective in reducing the neurodegeneration seen in these eye diseases, acting via the CB1 and CB2 cannabinoid receptors. The cannabinoid neuroprotective effect is often of a similar magnitude to the other proven therapy of medical dosage of vitamins, though it confers a greater risk due to neurotoxicity with high THC:CBD ratios, making the vitamin therapy of greater efficacy when time is available. Given the increased ratio of THC:CBD in commercial cannabis strains, rising from 10:1 at the beginning of this century to 100:1 now, the risk of neurotoxicity has increased, reducing the neuroprotective benefit. The proven safety and efficacy of vitamin therapy may be a more viable neuroprotective method than cannabinoid use for chronic conditions, with cannabinoids proving their utility in more acute conditions. This review evaluates both the method of action of cannabinoids and the receptor pathway utilized and compares the suggested therapeutic applicability of cannabinoids with proven vitamin therapy. Full article

Although antiviral therapy has improved quality of life, around 50% of people with HIV (PWH) experience neurodegeneration and cognitive decline. This is prompted in part by the migration of HIV-infected monocyte-derived macrophages (MDMs) to the brain, leading to neuronal death. Previous studies in our lab have shown that HIV-infected MDMs secrete cathepsin B (CATB), which is a pro-inflammatory neurotoxic enzyme that is reduced by the addition of cannabinoid receptor-2 (CB2R) agonist JWH-133 to cell cultures. In this study, we aimed to identify the proteins secreted (secretome) by HIV-infected macrophages exposed to JWH-133 and quantify them using tandem mass tag (TMT) mass spectrometry. Frozen 13-day MDM supernatants from (1) an MDM negative control; (2) HIV+MDM, and (3) HIV+MDM-JWH-133 were compared in triplicate by mass spectrometry (LC/MS/MS) and analyzed for protein identification. Subsequently, the same samples were labeled by TMT labeling and quantified by LC/MS/MS. After a database search, 528 proteins were identified from all groups. Thereafter, proteins with more than three unique peptides and more than 10% coverage were selected for protein identification. Venn diagrams revealed one unique protein secreted by MDM-HIV, 10 unique proteins in HIV+MDM-JWH-133, and 15 common proteins in the three groups. CATB was unique to HIV+MDM. HIV+MDM exposed to JWH-133 showed proteins related to metabolism, cell organization, antiviral activity, and stress response. TMT analysis revealed 1454 proteins with abundance for statistical analysis based on FC ≥ |1.5| and p-value ≤ 0.05, of which Ruvb-like 1 and Hornerin decreased significantly with JWH-133 treatment. Both proteins stimulate HIV replication. In addition, HIV infection upregulated proteins associated with pathways of viral latency that were inhibited by JWH-133. In conclusion, JWH-133 treatment in HIV-infected macrophages leads to the secretion of antiviral host factors and decreases the secretion of proviral, inflammatory, and neurotoxic host factors. Full article

Background: The interaction between the endocannabinoid system (ECS), specifically the CB1 and CB2 cannabinoid receptors, and neuropathy has aroused great research interest due to the possible implications for treatment. Complications following type 1 diabetes, due to impaired glucose metabolism and chronic inflammation, may benefit from targeted therapeutic strategies involving the ECS. This study explores the effects of photobiomodulation therapy (PBMT) on streptozotocin (STZ)-induced diabetic peripheral neuropathy (DPN) in rats. The study assessed body mass, hyperglycemia, mechanical hyperalgesia, and the influence of PBMT on these conditions over four weeks. Results showed that while PBMT did not alter the metabolic aspects of type I diabetes, it significantly reduced mechanical hyperalgesia compared to untreated diabetic neuropathic rats. Notably, cannabinoid receptor antagonists for CB1 and CB2 elicited a transient reversal of this antihyperalgesic effect, indicating a potential role of these receptors in PBMT’s mechanism. However, CB2 modulation was not statistically significant, whereas changes in CB1 receptor expression were observed in the dorsal root ganglia, suggesting its involvement in PBMT’s effects. These findings highlight the importance of CB1 and CB2 receptors in DPN and suggest that PBMT may offer a therapeutic benefit by mitigating mechanical hyperalgesia. Further investigation into cannabinoid receptor dynamics in diabetes could help in new therapeutic strategies for managing diabetic complications. Full article

Background/Objectives: Cannabis is the most widely used illicit substance worldwide, particularly among young adults, with growing acceptance following medical and recreational legalization. Although generally perceived as a drug with low acute toxicity, an expanding body of evidence indicates that cannabinoids can exert relevant cardiovascular effects, including arrhythmias, myocardial ischemia, and sudden cardiac death (SCD). These mechanisms are mediated through complex, dose-dependent interactions among CB1 and CB2 receptors, autonomic imbalance, and endothelial dysfunction. Nevertheless, cannabis-related fatalities remain underestimated in both clinical and forensic settings. Case presentation: Three cases of sudden unexpected death in previously healthy men aged 28, 37, and 37 years are described. All were found deceased at home under non-suspicious circumstances. Forensic autopsies ruled out trauma, coronary atherosclerosis, congenital malformations, or cardiomyopathy. Histological analyses consistently revealed polymorphic myocardial alterations, including interstitial edema, fiber disruption, and focal myocytolysis, without inflammatory infiltrates or necrosis. Toxicological examinations demonstrated the presence of Δ9-tetrahydrocannabinol (THC) and metabolites in peripheral blood and urine, while alcohol and other illicit drugs tested negative. In each case, the cause of death was attributed to arrhythmic sudden cardiac death in temporal association with cannabis use. Conclusions: This case series, integrated with a narrative review of current literature, supports the hypothesis that cannabis consumption can contribute to fatal arrhythmias even in young adults without conventional cardiovascular risk factors. The convergence of autopsy, histopathological, and toxicological findings suggests a potential causal link between THC exposure and sudden unexpected death. These results highlight the importance of systematic postmortem investigations in suspected drug-related fatalities and underscore the need for greater awareness among clinicians, forensic pathologists, and policymakers regarding the underestimated cardiovascular toxicity of cannabis. Full article

Sepsis is a life-threatening syndrome marked by a dysregulated host response to infection, resulting in systemic inflammation, organ dysfunction, and high mortality globally. Despite advancements in supportive care, effective immunomodulatory therapies remain elusive, necessitating exploration of novel biological pathways and subsequent therapeutic development. The endocannabinoid system (ECS), which regulates immune function and homeostasis, has emerged as a key modulator of immunological and metabolic pathways central to sepsis pathophysiology. The ECS mediates its effects through endogenous ligands, G-protein-coupled cannabinoid receptors (CB1 and CB1), and regulatory enzymes that control its synthesis and degradation. Following PRISMA-ScR guidelines, this scoping review synthesizes current evidence on the mechanistic roles of ECS components in experimental and clinical models of sepsis, identifies knowledge gaps, and delineates future areas of work. A comprehensive literature search across multiple databases without restrictions on date or publication type was executed to ensure broad coverage of original studies investigating ECS mechanisms and their intersection with sepsis and septic shock. Across 53 studies, CB2 receptor activation was consistently associated with anti-inflammatory process, organ-protective outcomes, and increased survival rates against septic challenges in preclinical rodent models. CB1 receptor activation trends, however, showed context dependent outcomes. Central antagonism improved hemodynamics and survival rate, but peripheral effects varied with cell type and timing. Non-canonical ECS components (TRPV1, GPR55, PPAR-α, FAAH, MAGL) also contributed to neuroimmune and metabolic regulation. Limited clinical data linked ECS lipid profiles and gene expression with sepsis severity and outcomes. Collectively, ECS modulation, particularly CB2 agonism, TRPV1 activation, and FAAH/MAGL inhibition, shows promise in mitigating sepsis-induced inflammation and organ dysfunction. However, complex, context-dependent effects, especially involving CB1, highlight the need for precision-targeted therapeutic approaches. Further preclinical research is needed to expand generalizable trends to allow translational research to refine ECS-based interventions for sepsis management. Full article

Background: Chronic inflammatory skin disorders, including atopic dermatitis, psoriasis, acne, and chronic wounds, affect nearly two billion people worldwide, impose substantial morbidity and economic burden, and remain only partially controlled by existing therapies. The cutaneous endocannabinoid system (ECS), comprising cannabinoid receptors, endocannabinoids, and their metabolic enzymes, regulates inflammation, pruritus, barrier integrity, and tissue repair; cannabinoid receptor type 2 (CB₂) has emerged as a particularly relevant target. β-Caryophyllene (BCP), a dietary sesquiterpene and highly selective CB₂ agonist with favorable safety and pharmacokinetic attributes, has attracted attention as a promising topical candidate. Methods: We systematically searched PubMed, Embase, and Web of Science (inception–30 July 2025) for studies on “β-caryophyllene” and dermatological outcomes, prioritizing purified BCP and analytically characterized BCP-rich fractions. Quantitative parameters, including tested concentration ranges (0.5 µM–10%) and principal mechanistic outcomes, were extracted to provide a translational context. Results: BCP penetrates the stratum corneum, suppresses NF-κB/MAPK and IL-4/TSLP pathways, enhances Nrf2-driven antioxidant defenses, and accelerates re-epithelialization and collagen remodeling. Across in vitro, in vivo, and formulation studies, BCP produced consistent anti-inflammatory and barrier-restorative effects within this concentration range. CB₂ antagonism attenuated these responses, confirming receptor specificity. BCP’s volatility and autoxidation to β-caryophyllene oxide (BCPO) necessitate stability-by-design strategies using antioxidants, low-oxygen processing, and protective packaging. Human evidence, limited to BCP-rich botanicals such as Copaifera oleoresins, suggests benefits for scars, wounds, and acne but lacks compound-specific validation. Conclusions: BCP exhibits coherent CB₂-mediated anti-inflammatory, antipruritic, antioxidant, and reparative actions with a favorable safety profile. Dose-defined, oxidation-controlled clinical trials of purified BCP are warranted to establish its potential as a steroid-sparing topical therapy. Full article

Background/Objectives: The cannabinoid type 2 receptor (CB₂ receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant psychoactive effects. Herein, we report the design, synthesis, characterization, biological assays, and molecular modelling analyses of novel (5/6-chloro-2-aryl-1H-benzo [d]imidazol-1-yl)(4-methoxyphenyl)methanone and 5/6-chloro-1-(4-methoxybenzyl)-2-aryl-1H-benzo [d]imidazole regioisomers as potential cannabinoid type 2 receptor ligands. Methods: The compounds were evaluated for their presumed CB₂ agonist activity using an indirect receptor-dependent apoptotic cell death assay exerted by cannabinoids, using the cell lines HEK293 (low CB₁/CB₂ expression), U-87 MG (high CB₁ expression), and HL-60 (exclusive CB₂ expression), and including the known cannabinoid ligands WIN-55,212-2 and AM630 as reference ligands. Flow cytometry was performed to assess apoptosis. Molecular docking and molecular dynamics simulations were used to explore ligand-receptor interactions at the CB₂ active site. Results: Compounds 3a, 3b’, 3c, and 4b selectively reduced HL-60 cell viability, similar to WIN-55,212-2, while showing no toxicity toward HEK293 or U-87 MG cells. Flow cytometry indicated that compounds 3a and 3c induced apoptosis in HL-60 cells comparable to WIN-55,212-2. Computational studies suggested that both compounds bind within the CB₂ receptor active site predominantly through π–π and hydrophobic interactions involving their benzo [d]imidazole cores, 2-aryl moieties, and 4-methoxybenzoyl scaffolds, resembling the binding patterns of established CB₂ ligands. Conclusions: Compounds 3a and 3c exert selective cytotoxicity against HL-60 cells, likely via a CB₂ agonist-mediated apoptotic mechanism. The applied combined experimental and computational approach provides a rapid, informative strategy for preliminary evaluation of CB₂ ligands and guides subsequent detailed pharmacological studies. Full article