Purinergic Signalling最新文献

Electroacupuncture (EA), as a combination of traditional acupuncture and modern electrotherapy, and has analgesic effects on various acute and chronic pain. It has been proved to ameliorate chronic visceral pain, but its specific role in rectal visceral pain remains underexplored. A capsaicin (CAP)-induced visceral pain rat model was established, and behavioral pain responses were observed and recorded. Measurement of mechanical pain threshold was performed using electronic Von Frey system. Rectal tissues, and the activity of microglia cells were detected by Hematoxylin/eosin staining and immunofluorescence, respectively. Contents of interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were determined by enzyme-linked immunosorbent assay. Western blot was performed to determine the expressions of P2X4 receptor (P2X4R), p38 mitogen-activated protein kinase (p38), phosphorylated p38 (p-p38), transient receptor potential vanilloid-1 (TRPV1) and ionized calcium binding adapter molecule 1 (Iba-1). Transfection efficiency of TRPV1 overexpression plasmids was examined by quantitative real-time polymerase chain reaction. EA abrogated CAP-induced upregulation of behavioral pain responses and mechanical threshold, damage on rectal tissue, activation of microglia, stimulation of inflammatory response and promotion of P2X4R-p38-TRPV1 pathway expressions in rats, while P2X4R activation reversed the effect of EA. P2X4R antagonist weakened CAP-induced upregulation of P2X4R-p38-TRPV1 pathway expressions, microglia activation as well as increase of IL-1β in HMO6 cells, which was reversed by TRPV1 overexpression. Collectively, EA improves CAP-induced rectal visceral pain via inhibiting TRPV1 expression by blocking the P2X4R-activated p38 pathway in microglia. However, the specificity role of P2X4R needs to be confirmed by more experiment.

Berberine (BBR) is a Chinese herb with antioxidant and anti-inflammatory properties. In a previous study, we found that BBR had a protective effect against light-induced retinal degeneration in BALB/c mice. The purinergic P2X7 receptor (P2X7R) plays a key role in retinal degeneration via inducing oxidative stress, inflammatory changes, and cell death. The aim of this study was to investigate whether BBR can induce protective effects in light damage experiments and whether P2X7R can get involved in these effects. C57BL/6 J mice and P2X7 knockout (KO) mice on the C57BL/6 J background were used. We found that BBR preserved the outer nuclear layer (ONL) thickness and retinal ganglion cells following light stimulation. Furthermore, BBR significantly suppressed photoreceptor apoptosis, pro-apoptotic c-fos expression, pro-inflammatory responses of Mϋller cells, and inflammatory factors (TNF-α, IL-1β). In addition, protein levels of P2X7R were downregulated in BBR-treated mice. Double immunofluorescence showed that BBR reduced overexpression of P2X7R in retinal ganglion cells and Mϋller cells. Furthermore, BBR combined with the P2X7R agonist BzATP blocked the effects of BBR on retinal morphology and photoreceptor apoptosis. However, in P2X7 KO mice, BBR had an additive effect resulting in thicker ONL and more photoreceptors. The data suggest that the P2X7 receptor is involved in retinal light damage, and BBR inhibits this process by reducing histological impairment, cell death, and inflammatory responses.

Numerous studies have revealed that the ATP-gated ion channel purinergic 2X7 receptor (P2X7R) plays an important role in tumor progression and the pathogenesis of cancer pain. P2X7R requires activation by extracellular ATP to perform its regulatory role functions. During tumor development or cancer-induced pain, ATP is released from tumor cells or other cells in the tumor microenvironment (such as tumor-associated immune cells), which activates P2X7R, opens ion channels on the cell membrane, affects intracellular molecular metabolism, and regulates the activity of tumor cells. Furthermore, peripheral organs and receptors can be damaged during tumor progression, and P2X7R expression in nerve cells (such as microglia) is significantly upregulated, enhancing sensory afferent information, sensitizing the central nervous system, and inducing or exacerbating pain. These findings reveal that the ATP-P2X7R signaling axis plays a key regulatory role in the pathogenesis of tumors and cancer pain and also has a therapeutic role. Accordingly, in this study, we explored the role of P2X7R in tumors and cancer pain, discussed the pharmacological properties of inhibiting P2X7R activity (such as the use of antagonists) or blocking its expression in the treatment of tumor and cancer pain, and provided an important evidence for the treatment of both in the future.

Attention deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental condition characterized by persistent inattention, hyperactivity, and impulsivity. Although its precise etiology remains unclear, current evidence suggests that dysregulation within the neurotransmitter system plays a key role in the pathogenesis of ADHD. Adenosine, an endogenous nucleoside widely distributed throughout the body, modulates various physiological processes, including neurotransmitter release, sleep regulation, and cognitive functions through its receptors. This review critically examines the role of the adenosine system in ADHD, focusing on the links between adenosine receptor function and ADHD-related symptoms. Additionally, it explores how adenosine interacts with dopamine and other neurotransmitter pathways, shedding light on its involvement in ADHD pathophysiology. This review aims to provide insights into the potential therapeutic implications of targeting the adenosine system for ADHD management.

In a recent article published in Neuron, Li et al. (Neuron 112(22):3734-3749.e5, 2024) accomplished a major scientific advance by reporting that ATP-sensitive P2X3 receptor-channels (P2X3Rs) in the paraventricular hypothalamus (PVH) specifically regulate visceral pain without affecting somatic pain. On the other hand, vasoactive intestinal polypeptide-sensing receptors (VIPR2) selectively process somatic pain without altering visceral pain. Function-dependent laser capture microdissection sequencing (fLCM-Seq) and immunohistochemistry demonstrated that P2X3Rs and VIPR2 have different transcriptional profiles and belong to the colorectal distension (CRD) and von Frey filament (VFF)-stimulated subgroups of PVH neurons, respectively. An anterograde tracing strategy, in which green fluorescent protein (GFP) was selectively expressed in CRD-labeled or VFF-labeled PVH neurons, showed that PVH^P2X3R+ neuronal projections terminated exclusively at the ventral part of the lateral septal nucleus (LSV) while the PVH^VIPR2+ neuronal projections terminated at the caudal part of the zona incerta (ZIC). The PVH^P2X3R+ circuit selectively responded to visceral pain while remaining unresponsive to somatic pain. By contrast, the PVH^VIPR2+ circuit selectively responded to somatic pain, while it did not react to visceral pain. Knockdown of P2X3R expression in PVH neurons enhanced the visceral pain threshold without affecting somatic nociception, and the reverse findings were true for the knockdown of the VIPR2 expressing PVH neurons. All these results provide possible new strategies based on central-targeted therapies for the future treatment of visceral and somatic pain, respectively.

Cardiovascular diseases (CVDs), including hypertension, atherosclerosis, myocardial ischemia, and myocardial infarction, constitute the primary cause of mortality worldwide. Transcription factors play critical roles in the development of CVDs and contribute to the pathophysiology of these diseases by coordinating the transcription of many genes involved in inflammation, oxidative stress, angiogenesis, and glycolytic metabolism. One important regulator of hemostasis in both healthy and pathological settings has been identified as a purinergic signalling pathway. Research has demonstrated that several signalling networks implicated in the pathophysiology of CVDs are formed by transcription factors that are regulated by purinergic substances. Here, we briefly summarize the roles and mechanisms of the transcription factors regulated by purinergic pathways in various types of CVD. This information will be essential for discovering novel approaches for CVD treatment and prevention.

P2 purinergic receptor expression is dysregulated in multiple cancer subtypes and is associated with worse outcomes. Studies identify roles for P2 purinergic receptors in tumor cells that drive disease aggressiveness. There is also sufficient evidence that P2 purinergic receptor expression within the tumor microenvironment (TME) is critical for disease initiation and progression. Immune cells constitute a significant component of the TME and display both tumorigenic and anti-tumorigenic potential. Studies pre-dating the investigation of P2 purinergic receptors in cancer identify P2 receptor expression on multiple immune cells including macrophages, neutrophils, T-cells, and dendritic cells; all of which are implicated in tumor initiation, tumor promotion, or response to treatment. Herein, we discuss P2 purinergic receptor expression and function in tumor-related immune cells. We provide a rationale for further investigations of P2 purinergic receptors within the TME to better define the mechanistic pathways of inflammation-mediate tumorigenesis and explore P2 purinergic receptors as potential targets for novel immunotherapeutic approaches.

The glymphatic system is critical for brain homeostasis by eliminating metabolic waste, whose disturbance contributes to the accumulation of pathogenic proteins in neurodegenerative diseases. Promoting glymphatic clearance is a potential and attractive strategy for several brain disorders, including neurodegenerative diseases. Previous studies have uncovered that 40 Hz flickering augmented glymphatic flow and facilitated sleep (Zhou et al. in Cell Res 34:214-231, 2024) since sleep drives waste clearance via glymphatic flow (Xie et al. in Science 342:373-377, 2013). However, it remains unclear whether 40 Hz light flickering directly increased glymphatic flow or indirectly by promoting sleep. A recent article published in Cell Discovery by Chen et al. (Sun et al. in Cell Discov 10:81, 2024) revealed that 40 Hz light flickering facilitated glymphatic flow, by promoting the polarization of astrocytic aquaporin-4 (AQP4) and vasomotion through upregulated adenosine-A_2A receptor (A_2AR) signaling, independent of sleep. These findings suggest that 40 Hz light flickering may be used as a non-invasive approach to control the function of the glymphatic-lymphatic system, to help remove metabolic waste in the brain, thereby presenting a potential strategy for neurodegenerative disease treatment.

Purine nucleotides and nucleosides play critical roles in various pathological conditions, including tumor cell growth. Adenosine triphosphate (ATP) activates pro-tumor receptors, while adenosine (ADO) is a potent immunosuppressant and modulator of cell growth. This study aims to analyze the purinergic actions of ATP and its metabolites, associated enzymes, and P1 or P2 class receptors in primary central nervous system tumors. Additionally, we sought to correlate the levels of nucleosides and the density of P1, P2X, and P2Y receptors in cells with tumor progression. The results indicate that purinergic signaling depends on the receptor concentration and signaling molecules specific to each cell type, tissue, and tumor histology. The purinergic system may function as either a tumor-promoting agent or an antitumor factor, depending on the microenvironmental conditions and the concentrations of receptors and their respective activators. Notably, ATP emerges as the most significant extracellular signal, capable of being converted into other cellular stimulators pertinent to neoplasms, such as adenosine diphosphate, adenosine monophosphate, adenosine, and inosine. Consequently, a cascade of responses to these stimuli promotes tumor development, cell division, and metastasis. Purine nucleotides in central nervous system tumors are pivotal in cellular responses in glioblastoma multiforme, vestibular schwannoma, medulloblastoma, adenomas, gliomas, meningiomas, and pineal tumors. These findings hold the potential for developing novel therapeutic strategies and aiding in therapeutic management.