Purinergic Signalling最新文献

Atherosclerosis, a chronic inflammatory disease driven by lipid deposition and immune cell activation, remains a leading cause of cardiovascular morbidity and mortality. Emerging evidence highlights the role of purinergic signalling in atherogenesis, particularly the P2Y₆ receptor in macrophages [1]. Using RNA sequencing, proteomics, expression and functional validation in cells, mouse models and human materials, this study provides comprehensive mechanistic insights into how macrophage P2Y₆ receptors contribute to foam cell formation and plaque development through the phospholipase Cβ (PLCβ)/store-operated Ca²⁺ entry/calreticulin/scavenger receptor A (SR-A) pathway. Furthermore, the study identifies thiamine pyrophosphate (TPP) as a potent P2Y₆ receptor antagonist, effectively inhibiting foam cell formation and reducing plaque burden in atherosclerotic mice, without inducing toxicity. These findings establish P2Y₆ receptors as promising therapeutic targets in atherosclerosis and introduce TPP as a potential clinical candidate for intervention.

Breast cancer (BC) is a multifactorial disease characterized by cell cycle disorder and immune evasion. Studies reveal that the purinergic system (PS) is a mediator of the immune system and actively participates in the inflammatory process in cancer. Also, there is growing debate about the role of oxidative stress (OS) markers and interleukins as predictors of BC progression and invasion. Thus, PS and OS markers, in addition to the expression of interleukins and quantification of extracellular ATP, were evaluated in 39 BC patients, before the beginning of surgical or pharmacological treatment, and in 35 control participants, matched by sex and age. The results show reduced ATP and ADP hydrolysis in platelets, apart from increased extracellular ATP in the BC group. Increased AMP hydrolysis was observed in BC patients' peripheral blood mononuclear cells (PBMCs). BC patients presented elevated oxidative parameters (MDA) and reduced antioxidant parameters (SOD and ascorbic acid), and reduction in interleukins TNF, IL-4, and IL-2. In PBMC from the BC group, the expression of P2X7 gene was significantly higher in relation to the expression of CD39 gene. Also, the expression of CD39 was 1.71 fold higher in tumor samples compared to PBMC from the BC group, and it was 0.11 fold lower in PBMC from the BC group compared to the controls. We conclude that ectoenzymes that hydrolyze ATP and ADP, mainly CD39, present reduced activity in the BC group, promoting an increase in extracellular ATP and culminating in a pro-inflammatory environment, favoring cancer progression. The increase in active oxidants and the reduction in antioxidants contributed to the progression of BC in patients. Finally, TNF and IL-4 demonstrated to be promising prognostic markers in BC patients.

Epilepsy is one of the most common chronic brain diseases affecting up to 70 million people worldwide. Major challenges of epilepsy treatment include the high pharmacoresistance in patients and the lack of disease-modification. Extracellular adenosine 3'triphosphate (ATP), a key neurotransmitter in the activation of the purinergic signalling system, is increasingly recognized to contribute to pathological brain hyperexcitability in epilepsy. Consequently, targeting ATP-release mechanisms may constitute a new therapeutic strategy for seizure control and epilepsy. The calcium channel, Calcium Homeostasis Modulator 1 (CALHM1), a voltage-gated, non-selective ion channel that permits the passage of various cations and small molecules, is expressed in neurons and plays an essential role during neuronal excitability and neurotransmission. In addition to ions, CALHM1 also allows the passage of ATP into the extracellular space, activating thereby purinergic receptors. Here, we tested if the pharmacological blocking of CALHM1 via CGP37157 (7-chloro-5-(2-chlorophenyl)-3,5-dihydro-4,1-benzothiazepin-2-(1H)-one) alters the severity of intra-amygdala kainic acid-induced status epilepticus. Our results show that CGP37157 increased the severity of seizures during status epilepticus. In addition, CALHM1 protein levels are down-regulated in the hippocampus in epileptic mice and Temporal Lobe Epilepsy (TLE) patients. In summary, our results identify CALHM1 as a new contributor to seizures and suggest targeting of CALHM1 as new treatment strategy for epilepsy.

We have previously reported that adenine at high doses interferes with the vasopressin signaling pathway, causes massive diuresis and volume depletion, and ultimately leads to renal failure. In the present study, we examined the effects of adenine on renal salt and water handling in a time course and dose-response study in rats housed in metabolic cages and fed control or adenine-containing diet at 1500, 2000, 2500 mg/kg and euthanized after 1, 3, and 7 weeks. Adenine at 2000 and 2500 mg/kg caused early and significant polyuria, polydipsia, and decreased urine osmolality in a dose-dependent manner without significantly affecting food intake, blood volume, blood electrolyte levels, or acid-base composition. The impaired water balance resulted from the downregulation of apical water channel AQP2 in the outer and inner medulla but not in the cortex. Adenine did not alter electrolytes (Na⁺, K⁺, Cl^-) excretion at these doses for up to 3 weeks. However, a slight but significant increase in salt excretion was observed in adenine-fed rats for 7 weeks, which correlates with a significant downregulation of NKCC2, mostly in rats fed 2500 mg/kg adenine. Adenine-fed rats exhibited a substantial resistance to vasopressin in response to water deprivation or vasopressin treatment. Lastly, 2500 mg/kg adenine prevented the development of hyponatremia in a rat experimental model of the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). In conclusion, adenine acts as an aquaretic agent in the kidney at lower doses and during a short feeding period. It can be used as a vasopressin antagonist in conditions associated with hyponatremia.

This Journal Club article reviews a 2025 study by Qiu et al. that reports the development of a novel iodine-125 radioligand targeting the purinergic P2X7 receptor (P2X7R). The researchers created a small library of structurally modified P2X7R antagonists and identified compound 1c as a lead due to its high affinity and selectivity. Radiolabeling with iodine-125 produced [¹²⁵I]1c with high yield and purity. Binding studies confirmed its strong nanomolar affinity, supporting its use in radioligand screening and potential applications in imaging P2X7R in inflammatory and neurodegenerative diseases. The study demonstrates the value of radiolabeled probes in drug discovery and purinergic signaling research.

Periodontitis is a highly prevalent immunoinflammatory disease that compromises the supporting tissues of the teeth, especially the periodontal ligament and alveolar bone. During disease progression, inflammatory responses lead to the release of ATP, which interacts with purinergic receptors such as P2X7R, potentially influencing bone remodeling. Although P2X7R has been studied in bone cells, its specific role in periodontitis remains poorly characterized. This study aimed to evaluate the effects of P2X7R modulation on osteoblastic activity and experimental bone loss. In vitro, P2X7R expression was confirmed in OFCOL II osteoblastic cells. Receptor activation using BzATP significantly reduced cell viability, altered cell morphology, and decreased alkaline phosphatase (ALP) activity (p < 0.05). In vivo, periodontitis was induced in Wistar rats via ligature. Animals were allocated into four groups: (1) Naïve; (2) Periodontitis (saline-treated); (3) BzATP-treated (P2X7R agonist); and (4) BBG-treated (P2X7R antagonist). BzATP aggravated periodontal damage, with increased inflammation, loss of osteoblasts, and disorganization of periodontal ligament fibers. In contrast, BBG improved tissue architecture, reduced inflammatory infiltrate, and increased osteoblast numbers and ALP activity, possibly via the Wnt signaling pathway. These results suggest that P2X7R activation contributes to inflammation-driven bone loss, impairing osteoblast viability and function. Therefore, P2X7R inhibition may serve as a promising pharmacological strategy to preserve bone and periodontal integrity in the context of periodontitis.

The P2X7 receptor is a trimeric ion channel purinergic receptor. It plays a crucial part in the pathophysiology of cancers and a variety of inflammatory diseases and is widely expressed in different cell types. Leukemia represents a type of malignant clonal disorder that impacts the hematopoietic stem cells. Chemotherapy is one of the main treatment methods for leukemia, but there are also many side effects. In recent years, targeted therapy is a new treatment method. Research has shown that the progression and occurrence of leukemia is significantly related to the P2X7 receptor. The P2X7 receptor is also involved in the migration and invasion of leukemia cells. Furthermore, the polymorphism of the P2X7 receptor gene also takes on a significant function in the occurrence, development and clinical course of leukemia patients. The P2X7 receptor inhibitors have been found to work better in combination with existing therapeutics. Therefore, the P2X7 receptor may serve as a potential therapeutic target.

Adenosine is a key modulator in the pathophysiology of acute kidney injury (AKI), particularly through its influence on inflammatory pathways and renal hemodynamics. This nucleoside exerts its effects via four G protein-coupled receptors-A1, A2A, A2B, and A3-each displaying distinct roles during renal injury. The A1 receptor primarily protects renal tissue under ischemic conditions by reducing metabolic demand, while the A2A receptor promotes anti-inflammatory and vasodilatory effects, improving renal perfusion and attenuating leukocyte infiltration. The A2B receptor, upregulated under hypoxic or injury conditions, is involved in anti-inflammatory actions and vascular integrity, especially in renal tubular and endothelial cells. Conversely, activation of the A3 receptor is generally linked to adverse outcomes, including increased apoptosis and greater tissue damage. Therapeutic strategies targeting adenosine receptors are being actively explored: selective A1 and A2A agonists show potential for promoting renal recovery, while A3 antagonists helped counteract the harmful effects of A3 activation. The review also discusses advances from recent studies (2022-2024), including insights on COVID-19-associated AKI and the nuanced roles of A1 and A3 receptors in different pathological contexts. Additionally, the therapeutic promise of inhibiting adenosine-degrading enzymes, such as ADA and adenosine kinase (ADK), is highlighted. Novel mechanistic insights and recent literature are integrated, providing a comprehensive overview that expands upon previous reviews. Although adenosine receptor modulation holds significant promise as a therapeutic strategy for AKI, further clinical research is necessary to validate efficacy and safety in human populations.

Over the past few years, transcriptomics has emerged as a pillar for modern scientific research, enabling the comprehensive profiling of gene expression. The availability of large-scale public datasets, such as NCBI Gene Expression Omnibus, International Cancer Genome Consortium, and The Cancer Genome Atlas, has significantly boosted many scientific discoveries. However, to analyze and interpret these vast datasets, sophisticated bioinformatic tools are often necessary. Phantasus is a user-friendly web application designed to streamline gene expression analysis. By integrating data loading, normalization, filtering, enrichment pathways analysis, and principal component analysis, Phantasus enables researchers to promptly investigate and evaluate complex gene expression patterns. This tool simplifies the identification of differentially expressed genes and the discovery of novel biological insights. Here, we demonstrate how Phantasus can be utilized for gene expression analysis in glioblastoma (GBM), the most common primary malignant brain tumour in adults. Specifically, we focus on the role of purinergic signaling, with particular emphasis on the P2RX7 mRNA coding for the P2X7 receptor (P2RX7). To illustrate our proposal, we analyzed the expression of genes related to purinergic signaling in GBM patients stratified by high and low levels of P2RX7 expression. By harnessing Phantasus, researchers can further explore and navigate the nuances of gene regulation and its impact on human health and diseases.