-
International Journal of Molecular... Jul 2023Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules... (Review)
Review
Migraine is a debilitating neurological condition affecting millions of people worldwide. Until a few years ago, preventive migraine treatments were based on molecules with pleiotropic targets, developed for other indications, and discovered by serendipity to be effective in migraine prevention, although often burdened by tolerability issues leading to low adherence. However, the progresses in unravelling the migraine pathophysiology allowed identifying novel putative targets as calcitonin gene-related peptide (CGRP). Nevertheless, despite the revolution brought by CGRP monoclonal antibodies and gepants, a significant percentage of patients still remains burdened by an unsatisfactory response, suggesting that other pathways may play a critical role, with an extent of involvement varying among different migraine patients. Specifically, neuropeptides of the CGRP family, such as adrenomedullin and amylin; molecules of the secretin family, such as pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP); receptors, such as transient receptor potential (TRP) channels; intracellular downstream determinants, such as potassium channels, but also the opioid system and the purinergic pathway, have been suggested to be involved in migraine pathophysiology. The present review provides an overview of these pathways, highlighting, based on preclinical and clinical evidence, as well as provocative studies, their potential role as future targets for migraine preventive treatment.
Topics: Humans; Animals; Migraine Disorders; Signal Transduction; Vasoactive Intestinal Peptide; Potassium Channels; Analgesics, Opioid
PubMed: 37569648
DOI: 10.3390/ijms241512268 -
European Heart Journal Jan 2024Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a...
Macrophage P2Y6 receptor deletion attenuates atherosclerosis by limiting foam cell formation through phospholipase Cβ/store-operated calcium entry/calreticulin/scavenger receptor A pathways.
BACKGROUND AND AIMS
Macrophage-derived foam cells play a causal role during the pathogenesis of atherosclerosis. P2Y6 receptor (P2Y6R) highly expressed has been considered as a disease-causing factor in atherogenesis, but the detailed mechanism remains unknown. This study aims to explore P2Y6R in regulation of macrophage foaming, atherogenesis, and its downstream pathways. Furthermore, the present study sought to find a potent P2Y6R antagonist and investigate the feasibility of P2Y6R-targeting therapy for atherosclerosis.
METHODS
The P2Y6R expression was examined in human atherosclerotic plaques and mouse artery. Atherosclerosis animal models were established in whole-body P2Y6R or macrophage-specific P2Y6R knockout mice to evaluate the role of P2Y6R. RNA sequencing, DNA pull-down experiments, and proteomic approaches were performed to investigate the downstream mechanisms. High-throughput Glide docking pipeline from repurposing drug library was performed to find potent P2Y6R antagonists.
RESULTS
The P2Y6R deficiency alleviated atherogenesis characterized by decreasing plaque formation and lipid deposition of the aorta. Mechanically, deletion of macrophage P2Y6R significantly inhibited uptake of oxidized low-density lipoprotein through decreasing scavenger receptor A expression mediated by phospholipase Cβ/store-operated calcium entry pathways. More importantly, P2Y6R deficiency reduced the binding of scavenger receptor A to CALR, accompanied by dissociation of calreticulin and STIM1. Interestingly, thiamine pyrophosphate was found as a potent P2Y6R antagonist with excellent P2Y6R antagonistic activity and binding affinity, of which the pharmacodynamic effect and mechanism on atherosclerosis were verified.
CONCLUSIONS
Macrophage P2Y6R regulates phospholipase Cβ/store-operated calcium entry/calreticulin signalling pathway to increase scavenger receptor A protein level, thereby improving foam cell formation and atherosclerosis, indicating that the P2Y6R may be a potential therapeutic target for intervention of atherosclerotic diseases using P2Y6R antagonists including thiamine pyrophosphate.
Topics: Humans; Mice; Animals; Foam Cells; Calcium; Calreticulin; Proteomics; Thiamine Pyrophosphate; Atherosclerosis; Macrophages; Lipoproteins, LDL; Receptors, Scavenger; Mice, Knockout; Phospholipases; Receptors, Purinergic P2
PubMed: 38036416
DOI: 10.1093/eurheartj/ehad796 -
Neurobiology of Disease Sep 2023Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal... (Review)
Review
Purinergic receptors (Rs) of the ATP/ADP, UTP/UDP (P2X, P2Y) and adenosine (A1, A2A)-sensitive classes broadly interfere with cognitive processes both under quasi normal and disease conditions. During neurodegenerative illnesses, high concentrations of ATP are released from the damaged neuronal and non-neuronal cells of the brain; then, this ATP is enzymatically degraded to adenosine. Thus, the primary injury in neurodegenerative diseases appears to be caused by various protein aggregates on which a superimposed damage mediated by especially P2X7 and A2AR activation develops; this can be efficiently prevented by small molecular antagonists in animal models of the above diseases, or are mitigated in the respective knockout mice. Dementia is a leading symptom in Alzheimer's disease (AD), and accompanies Parkinson's disease (PD) and Huntington's disease (HD), especially in the advanced states of these illnesses. Animal experimentation suggests that P2X7 and A2ARs are also involved in a number of psychiatric diseases, such as major depressive disorder (MDD), obsessive compulsive behavior, and attention deficit hyperactivity disorder. In conclusion, small molecular antagonists of purinergic receptors are expected to supply us in the future with pharmaceuticals which are able to combat in a range of neurological/psychiatric diseases the accompanying cognitive deterioration.
Topics: Animals; Mice; Depressive Disorder, Major; Receptors, Purinergic; Adenosine; Adenosine Triphosphate; Nervous System Diseases; Cognition
PubMed: 37453562
DOI: 10.1016/j.nbd.2023.106229 -
European Heart Journal Aug 2023Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are...
AIMS
Excess dietary sodium intake and retention lead to hypertension. Impaired dermal lymphangiogenesis and lymphatic dysfunction-mediated sodium and fluid imbalance are pathological mechanisms. The adenosine A2A receptor (A2AR) is expressed in lymphatic endothelial cells (LECs), while the roles and mechanisms of LEC-A2AR in skin lymphangiogenesis during salt-induced hypertension are not clear.
METHODS AND RESULTS
The expression of LEC-A2AR correlated with lymphatic vessel density in both high-salt diet (HSD)-induced hypertensive mice and hypertensive patients. Lymphatic endothelial cell-specific A2AR knockout mice fed HSD exhibited 17 ± 2% increase in blood pressure and 17 ± 3% increase in Na+ content associated with decreased lymphatic density (-19 ± 2%) compared with HSD-WT mice. A2AR activation by agonist CGS21680 increased lymphatic capillary density and decreased blood pressure in HSD-WT mice. Furthermore, this A2AR agonist activated MSK1 directly to promote VEGFR2 activation and endocytosis independently of VEGF as assessed by phosphoprotein profiling and immunoprecipitation assays in LECs. VEGFR2 kinase activity inhibitor fruquintinib or VEGFR2 knockout in LECs but not VEGF-neutralizing antibody bevacizumab suppressed A2AR activation-mediated decrease in blood pressure. Immunostaining revealed phosphorylated VEGFR2 and MSK1 expression in the LECs were positively correlated with skin lymphatic vessel density and A2AR level in hypertensive patients.
CONCLUSION
The study highlights a novel A2AR-mediated VEGF-independent activation of VEGFR2 signaling in dermal lymphangiogenesis and sodium balance, which might be a potential therapeutic target in salt-sensitive hypertension.
Topics: Mice; Animals; Lymphangiogenesis; Receptor, Adenosine A2A; Endothelial Cells; Hypertension; Protein Kinase Inhibitors; Sodium
PubMed: 37377160
DOI: 10.1093/eurheartj/ehad377 -
Immunity Mar 2024Na/K-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a...
Na/K-ATPase (NKA) plays an important role in the central nervous system. However, little is known about its function in the microglia. Here, we found that NKAα1 forms a complex with the purinergic P2X7 receptor (P2X7R), an adenosine 5'-triphosphate (ATP)-gated ion channel, under physiological conditions. Chronic stress or treatment with lipopolysaccharide plus ATP decreased the membrane expression of NKAα1 in microglia, facilitated P2X7R function, and promoted microglia inflammatory activation via activation of the NLRP3 inflammasome. Accordingly, global deletion or conditional deletion of NKAα1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability. DR5-12D, a monoclonal antibody that stabilizes membrane NKAα1, improved stress-induced anxiety-like behavior and ameliorated neuronal hyperexcitability and neurogenesis deficits in the ventral hippocampus of mice. Our results reveal that NKAα1 limits microglia inflammation and may provide a target for the treatment of stress-related neuroinflammation and diseases.
Topics: Animals; Mice; Adenosine Triphosphatases; Adenosine Triphosphate; Anxiety; Microglia; Receptors, Purinergic P2X7
PubMed: 38395698
DOI: 10.1016/j.immuni.2024.01.018 -
Current Opinion in Pharmacology Aug 2023Increasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular diseases, such as hypertension, myocardial infarct,... (Review)
Review
Increasing evidence demonstrated the relevance of adenosine system in the onset and development of cardiovascular diseases, such as hypertension, myocardial infarct, ischemia, hypertension, heart failure, and atherosclerosis. In this regard, intense research efforts are being focused on the characterization of the pathophysiological significance of adenosine, acting at its membrane receptors named A, A, A, and A receptors, in cardiovascular diseases. The present review article provides an integrated and comprehensive overview about current clinical and pre-clinical evidence about the role of adenosine in the pathophysiology of cardiovascular diseases. Particular attention has been focused on current scientific evidence about the pharmacological ligands acting on adenosine pathway as useful tools to manage cardiovascular diseases.
Topics: Humans; Adenosine; Cardiovascular Diseases; Hypertension; Receptor, Adenosine A2A; Receptor, Adenosine A2B
PubMed: 37450948
DOI: 10.1016/j.coph.2023.102393 -
Frontiers in Immunology 2023While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central... (Review)
Review
While P2X7 receptor expression on tumour cells has been characterized as a promotor of cancer growth and metastasis, its expression by the host immune system is central for orchestration of both innate and adaptive immune responses against cancer. The role of P2X7R in anti-tumour immunity is complex and preclinical studies have described opposing roles of the P2X7R in regulating immune responses against tumours. Therefore, few P2X7R modulators have reached clinical testing in cancer patients. Here, we review the prognostic value of P2X7R in cancer, how P2X7R have been targeted to date in tumour models, and we discuss four aspects of how tumours skew immune responses to promote immune escape via the P2X7R; non-pore functional P2X7Rs, mono-ADP-ribosyltransferases, ectonucleotidases, and immunoregulatory cells. Lastly, we discuss alternative approaches to offset tumour immune escape via P2X7R to enhance immunotherapeutic strategies in cancer patients.
Topics: Humans; Tumor Escape; Receptors, Purinergic P2X7; Signal Transduction; Neoplasms
PubMed: 38022596
DOI: 10.3389/fimmu.2023.1287310 -
Nature Feb 2024Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone...
Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.
Topics: Animals; Mice; Adenosine Triphosphate; Autoantibodies; Autoimmunity; Bone Marrow Cells; Cell Lineage; Connexins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Mutation; Osteoblasts; Plasma Cells; Receptors, Purinergic P2X4; Signal Transduction
PubMed: 38355795
DOI: 10.1038/s41586-024-07047-2 -
Biomolecules Dec 2023OA is a common and debilitating condition that restricts mobility and diminishes the quality of life. Recent work indicates that the generation of adenosine at the cell... (Review)
Review
OA is a common and debilitating condition that restricts mobility and diminishes the quality of life. Recent work indicates that the generation of adenosine at the cell surface is an important mediator of chondrocyte homeostasis, and topical application of adenosine in a slow-release form (liposomes) can halt the progression of OA and diminish the pain associated with OA. Here, we review the evidence indicating that adenosine, acting at A receptors, plays a critical role in endogenous and exogenous treatment and reversal of OA.
Topics: Humans; Quality of Life; Purines; Osteoarthritis; Receptors, Purinergic P1; Adenosine
PubMed: 38136631
DOI: 10.3390/biom13121760