Publications by authors named "Jaume Lillo"
Epigenetic alterations are key contributors to Alzheimer's disease (AD), driving age-related cognitive decline. This study explores the combined neuroprotective effects of G9a histone methyltransferase inhibition (via UNC0642) and cannabinoid receptor activation (CB1R: ACEA; CB2R: JWH133) in AD models. We used HEK-293T cells and hippocampal neurons to demonstrate that G9a inhibition selectively enhances CB1R-mediated ERK/cAMP signaling.
View Article and Find Full Text PDFBackground: Cannabidiol (CBD), the second most abundant phytocannabinoid in Cannabis sativa, has garnered significant interest due to its non-psychoactive nature and diverse receptor interactions.
Methods: This study employs in vitro and in vivo methodologies to validate CBD's potential as a treatment for Alzheimer's disease (AD) by addressing key hallmarks of the condition and promoting neuroprotective effects on spatial memory.
Results: Our findings demonstrate CBD's ability to decrease pTau and Aβ aggregation and to mitigate their axonal transport between cortical and hippocampal neurons.
Novel protocol for metabolomics data normalization and biomarker discovery in human tears.
Clin Chem Lab Med
July 2025
Objectives: Human tear analysis holds promise for biomarker discovery, but its clinical utility is hindered by the lack of standardized reference values, limiting interindividual comparisons. This study aimed at developing a protocol for normalizing metabolomic data from human tears, enhancing its potential for biomarker identification.
Methods: Tear metabolomic profiling was conducted on 103 donors (64 females, 39 males, aged 18-82 years) without ocular pathology, using the AbsoluteIDQ™ p180 Kit for targeted metabolomics.
Neurodegenerative diseases such as Alzheimer's and Parkinson's diseases are among the leading causes of physical and cognitive disability across the globe. Fifty million people worldwide suffer these diseases, and that number is expected to rise as the population ages. Ictus is another pathology that also courses with neurodegeneration and is a leading cause of mortality and long-term disability in developed countries.
View Article and Find Full Text PDFArticle Synopsis
- GPR88 is an orphan G protein-coupled receptor primarily found in the striatum, and its function is not well understood despite changes in its expression seen in Parkinson's disease models.
- GPR88 was found to interact with the kappa-opioid receptor (KOR), and this interaction inhibits KOR-mediated signaling, as evidenced by experiments showing that GPR88 can modulate effects of KOR agonists in both cultured cells and primary striatal neurons.
- The GPR88-KOR complexes were more common in specific neurons related to dopamine pathways, suggesting that understanding their relationship could have implications for conditions like neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.
Cannabinoid regulation of angiotensin II-induced calcium signaling in striatal neurons.
NPJ Parkinsons Dis
November 2024
Article Synopsis
- - Calcium ion (Ca) homeostasis is essential for proper neuron function, and this study investigated how the CB receptor (CBR) interacts with the ATR receptor to regulate cytoplasmic Ca levels in CNS neurons.
- - A specific type of interaction called AT-CB receptor heteromers (ATCBHets) was identified using bioluminescence resonance energy transfer (BRET) in lab cells and in the context of Parkinson's disease (PD).
- - The study found that activation of ATR reduces Ca levels in the presence of cannabinoids, and in a rat model of PD, lower levels of ATCBHets were linked to lesioned neurons, suggesting that cannabinoids might help mitigate calcium imbalance related to levodopa-induced
Olfactory receptors in neural regeneration in the central nervous system.
Neural Regen Res
September 2025
Article Synopsis
- Olfactory receptors are essential for our sense of smell and influence behaviors like food preferences and emotional memories.
- They have unique regenerative abilities that can provide insights into neural regeneration, which is crucial for addressing central nervous system injuries.
- Exploring the ectopic expression of these receptors may lead to new therapeutic approaches for repairing neural damage and treating neurodegenerative diseases.
Article Synopsis
- The text discusses the need for better tools to measure neuroprotection in Alzheimer's and Parkinson's diseases, emphasizing that current methods lack specific markers.
- It outlines the main outcome measures used in clinical trials for these neurodegenerative diseases since 2018, noting that they do not specifically assess neuroprotection.
- Finally, the text highlights the potential of metabolomics, utilizing body fluids to discover new biomarkers related to neuroprotection, thanks to recent advancements in technology that allow for better detection of relevant metabolites.
Article Synopsis
- Allosterism is a regulatory mechanism for G protein-coupled receptors (GPCRs) that can be affected by ligand binding or interactions between different GPCRs; the study focuses on the allosteric properties of A receptor and CB receptor when they form a heteromer.
- Experimental techniques used include measuring cAMP levels, analyzing phosphorylation of kinases, and using dynamic mass redistribution methods, showing how disrupting the heteromer affects receptor activation.
- Key findings reveal that the A receptor can inhibit signaling in the CB receptor by blocking essential structural components, and that certain antagonists can change the interaction dynamics to allow for receptor activation, highlighting a unique allosteric mechanism in GPCR signaling.
Potential of CBD Acting on Cannabinoid Receptors CB and CB in Ischemic Stroke.
Int J Mol Sci
June 2024
Article Synopsis
- Stroke is a major global health issue, affecting 15 million people annually and leaving millions dead or disabled, highlighting the need for new treatments to prevent cognitive decline and neuronal death.
- Phytocannabinoids are traditional compounds known for their neuroprotective benefits, but their psychoactive effects have limited their use in medicine, prompting research for non-psychoactive alternatives.
- Advances in cannabinoid receptor research, including the development of heteromers and the approval of certain CBD and Δ-THC combinations for specific conditions, represent promising new therapeutic avenues for neurodegenerative diseases and other disorders.
Article Synopsis
- Alzheimer's disease (AD) is increasingly prevalent and presents a major health challenge, prompting research into its underlying mechanisms and potential treatments.
- G protein-coupled receptors (GPCRs), specifically orexin and cannabinoid receptors, play important roles in AD progression; orexin is linked to sleep disruption and Aβ peptide buildup, while cannabinoids may offer neuroprotection.
- Research findings suggest that targeting the interactions between cannabinoid and orexin systems, particularly though the CBR-OXR complex, could be a promising new approach to developing therapies for AD.
Dual Role of NMDAR Containing NR2A and NR2B Subunits in Alzheimer's Disease.
Int J Mol Sci
April 2024
Article Synopsis
- Alzheimer's disease (AD) is the leading cause of dementia, and NMDA receptors (NMDARs) play a crucial role in the disease's development by affecting learning and memory through calcium influx in neurons.* -
- NMDARs consist of two GluN1 subunits and either NR2A or NR2B subunits; NR2A promotes cell survival while NR2B is linked to neurodegeneration.* -
- Research indicates that Aβ increases calcium signaling and MAPK phosphorylation in NR2B, leading to higher neurotoxicity, while NR2A activation supports neuronal survival, highlighting their distinct roles in potential AD therapies.*
Alterations in olfactory functions are proposed as possible early biomarkers of neurodegenerative diseases. Parkinson's and Alzheimer's diseases manifest olfactory dysfunction as a symptom, which is worth mentioning. The alterations do not occur in all patients, but they can serve to rule out neurodegenerative pathologies that are not associated with small deficits.
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- Parkinson's disease (PD) involves changes in NMDA receptor (NMDAR) and cannabinoid receptor 1 (CBR) functions, with CBR-NMDAR complexes being identified in neurons.
- The study found that α-synuclein, a protein linked to PD, alters the organization of these receptor complexes and decreases important signaling pathways in both lab cells and primary neurons.
- These findings suggest that targeting CBR-NMDAR complexes could be a potential new approach for treating Parkinson's disease.
Article Synopsis
- - CBD is a phytocannabinoid that shows potential for treating various diseases and operates through cannabinoid and other receptors, including the adenosine A receptor.
- - In lab experiments using CHO cells, CBD could not bind to the A receptor in the same way as a certain fluorescent probe but did influence the receptor’s response to a known agonist.
- - The findings imply that CBD acts as a negative allosteric modulator of the adenosine A receptor, meaning it can inhibit the receptor’s function without directly competing for the binding site.
Article Synopsis
- Microglial activation is linked to brain changes in neurodegenerative diseases, and A adenosine receptors are explored as possible treatment targets.
- RNA sequencing of activated microglia treated with selective A receptor antagonists and agonists showed no significant changes in classic microglial polarization genes, but many immune system-related genes were downregulated.
- Researchers identified AC122413.1 and Olfr56 as potentially important genes affected by the treatments, suggesting their products could serve as biomarkers for microglial activation phenotypes.
Article Synopsis
- THC acts as a psychoactive compound by binding to cannabinoid receptors CB1 and CB2, influencing various cellular processes.
- Molecular dynamics simulations indicated that THC's structure allows it to engage effectively with the CB1 receptor, but not with the CB2 receptor due to differences in their amino acid structures.
- The findings highlight that the amino acid at position 6.51 is crucial for the activation of GPCRs by lipid-derived signaling molecules, suggesting a specific role in receptor functionality.
Heteromer formation is unknown for the olfactory family of G protein-coupled receptors (GPCRs). We here identified, in a heterologous system, heteromers formed by the adenosine A receptor (AR), which is a target for neuroprotection, and an olfactory receptor. AR interacts with the receptor family 51, subfamily E, member 2 (OR51E2), the human ortholog of the mouse Olfr-78, whose mRNA is differentially expressed in activated microglia treated with adenosine receptor ligands.
View Article and Find Full Text PDFGene regulation in activated microglia by adenosine A receptor agonists: a transcriptomics study.
Purinergic Signal
June 2024
Article Synopsis
- Neurodegenerative disorders like Alzheimer's and Parkinson's involve activated microglia, which are immune cells in the brain that can contribute to disease progression.
- The study used RNA sequencing to analyze how a specific adenosine receptor agonist, 2-Cl-IB-MECA, affects gene expression in activated microglia and found that it negatively affected more genes than it positively regulated.
- Gene analysis revealed that while the agonist influenced various immune-related genes, it did not shift the microglia towards a neuroprotective state typically associated with M2-type cells.
Article Synopsis
- The potential of cannabinoid (CB) and angiotensin (AT) receptors as therapeutic targets for Parkinson's disease (PD) is highlighted, particularly their interaction in brain circuits.
- Research has shown that CB receptors can directly interact with AT receptors, leading to increased G-signaling, and this interaction is present in both lab systems and in primary neurons.
- In a rodent model of PD, increased levels of CB-AT receptor complexes were observed in the striatum of rats that developed dyskinesia after levodopa treatment, suggesting that targeting CB receptors may have implications for both addictive behaviors and neurodegenerative diseases.
Article Synopsis
- The study suggests that orexin may influence amyloid beta peptide levels in a model of Alzheimer's disease, indicating a link between orexin and CBR in microglial regulation.
- The research highlights the formation of CB-OX receptor complexes in microglia, which may enhance neuroprotection when activated.
- Findings indicate that using OXR antagonists can amplify the effects of CBR activation, presenting a potential therapeutic strategy for Alzheimer's disease treatment.
Cannabidiol (CBD) is a phytocannabinoid with potential in one of the most prevalent syndromes occurring at birth, the hypoxia of the neonate. CBD targets a variety of proteins, cannabinoid CB and serotonin 5HT receptors included. These two receptors may interact to form heteromers (CB-5HT-Hets) that are also a target of CBD.
View Article and Find Full Text PDFAdenosine (Ado) receptors have been instrumental in the detection of heteromers and other higher-order receptor structures, mainly via interactions with other cell surface G-protein-coupled receptors. Apart from the first report of the A Ado receptor interacting with the A Ado receptor, there has been more recent data on the possibility that every Ado receptor type, A, A, A, and A, may interact with each other. The aim of this paper was to look for the expression and function of the A/A receptor heteromer (AAHet) in neurons and microglia.
View Article and Find Full Text PDFThere is evidence of ghrelinergic-cannabinoidergic interactions in the central nervous system (CNS) that may impact on the plasticity of reward circuits. The aim of this article was to look for molecular and/or functional interactions between cannabinoid CB and ghrelin GHS-R1a receptors. In a heterologous system and using the bioluminescence resonance energy transfer technique we show that human versions of cannabinoid CB and ghrelin GHS-R1a receptors may form macromolecular complexes.
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- The study compared the effects of Δ-THCA and Δ-THCV with Δ-THC by examining their binding to human cannabinoid receptors CB1, CB2, and heteromers in living cells.
- Differential signaling outcomes were found, indicating that the effects of these cannabinoids vary based on the specific receptor and the structure of the compound used, showing variability in how they activate different pathways.
- Results suggest that cannabinoids can bind in various ways, leading to different physiological effects depending on the receptor type and which signaling pathways are activated.