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Diabetes is the largest global epidemic of the 21st century, and the cost of diabetes and its complications comprise about 12% of global health expenditure. Diabetic neuropathy is the most common complication of diabetes, affecting up to 50% of patients over the course of their disease. Among them, 30%–50% develop neuropathic pain, which has typical symptoms that originate from the toes and progress to foot ulcers and seriously influence quality of life. The pathogenesis of diabetic neuropathic pain (DNP) is complicated and incompletely understood and there is no effective treatment except supportive treatment. Long noncoding RNAs (lncRNAs), a class of noncoding RNAs exceeding 200 nucleotides in length, have been shown to play key roles in fundamental cellular processes, and are considered to be potential targets for treatment. Recent research indicates that lncRNA is involved in the pathogenesis of DNP. Certain overexpressed lncRNAs can enhance the purinergic receptor‐mediated neuropathic pain in peripheral ganglia and inflammatory cytokines are released due to receptors activated by adenosine triphosphate. In recent years, our laboratory also has been exploring the relationship and pathogenesis between lncRNAs and DNP. In this review, we focus on the recent progress in functional lncRNAs associated with DNP and investigate their roles related to respective receptors. [ABSTRACT FROM AUTHOR]

The adenosine triphosphate (ATP)‐gated P2X receptor cation channel family consists of permeable ligand‐gated ion channels that expand on the binding of extracellular adenosine 5'‐ATP. ATP‐gated P2X receptors are trimer ion channels that assemble homo or isomer from seven cloned subunits. P2X receptors are discovered mostly in mammalian and are being found in an increasing number of non‐vertebrates, such as zebrafish, bullfrog, and ameba. P2X receptors are involved in many physiological processes, including regulation of heart rhythm and contractility, and regulation of pain, especially chronic pain and glia integration. This review summarizes the current studies on the regulation of P2X receptors in abnormal neuronal‐glial interaction and the pathological changes in viscera, especially in myocardial ischemia. [ABSTRACT FROM AUTHOR]

Pyroptosis is a type of programmed cell death, displaying caspase‐1‐dependent and pro‐inflammatory features. Purinergic 2X4 (P2X4) receptor activation in response to high‐adenosine triphosphate release can induce inflammation. Envelope glycoprotein 120 (gp120) of human immunodeficiency virus type 1 is considered one of the primary pathogens leading to neuronal injury. In this study, we investigated the possible role of P2X4 receptor activation in gp120‐triggered pyroptosis in cultured satellite glial cells (SGCs) of rat dorsal root ganglia (DRG). MTS assay, TdT‐mediated dUTP Nick‐end labeling assay, real‐time RT‐PCR, and western blotting et al. methods were used. The results indicated that the expression of P2X4 receptor in SGCs of DRG was up‐regulated upon cultured with gp120 for 24 h. The highest decrease in viability of SGCs due to gp120 treatment was accompanied by marked increases of positive pyroptosis cells and cellular lactate dehydrogenase release, elevated levels of interleukin‐1β, interleukin‐18, active caspase‐1 and NOD‐like receptor family, pyrin domain containing 1, and enhanced phosphorylation of p38MAPK. These abnormal changes because of gp120 were significantly inhibited and cell viability was markedly improved when SGCs of DRG were treated with short hairpin RNAs targeting P2X4 receptor. Our data suggest that silencing of P2X4 receptor may act effectively against gp120‐induced pyroptosis mediated by the activation of NOD‐like receptor family, pyrin domain containing 1 inflammasome and caspase‐1 signaling in SGCs of DRG. [ABSTRACT FROM AUTHOR]

Increasing evidence has suggested high‐fat diet (HFD) is an independent risk factor for myocardial ischemia/reperfusion (MI/R) injury. Long noncoding RNAs (lncRNAs) recently attracted much attraction in the study of MI/R injury. However, the functional questions of specific lncRNAs in HFD‐induced MI/R injury have not been well elucidated. Uc.48+ is a lncRNA from a transcribed ultraconserved region (T‐UCR) of human, mouse, and rat genomes. Here, we explored the aggravating role of uc.48+and identified purinergic P2X7 receptor (P2X7R) as a downstream regulator of uc.48+ in HFD‐induced MI/R vulnerability. We demonstrated uc.48+ expression was upregulated, accompanied by the corresponding upregulation of P2X7R in HFD I/R myocardium and HFD‐induced MI/R vulnerability. Overexpression of uc.48+enhanced, whereas silencing of uc.48 + decreased the expression of P2X7R, cardiomyocyte apoptosis, and MI/R injury. The functional relevance of uc.48+ regulated P2X7R expression and the subsequent NF‐κB signaling to promote cardiomyocyte apoptosis was supported by inhibition of P2X7R with its specific antagonist (A438079) as well as the inhibitor of NF‐κB signaling (pyrrolidine dithiocarbamate, PDTC) in H9c2 hypoxia/reoxygenation (H/R) cells transfected with pcDNA3.0‐uc.48 + plasmid, and RNA immunoprecipitation (RIP) suggested uc.48+ could interact with transcription factor Sp1. Importantly, Sp1 inhibitor (mithramycin, MIT) was found to suppress uc.48+ ‐induced P2X7R expression and the NF‐κB signaling and cardiomyocyte apoptosis. Our findings provide a potential novel mechanism through which uc.48+ boosts cardiomyocyte apoptosis and MI/R vulnerability to HFD. Thus, uc.48+ is a novel regulator of HFD‐induced MI/R injury; targeting uc.48+ may be a novel therapeutic approach of MI/R vulnerability to HFD. High‐fat diet (HFD) is an independent risk factor for myocardial ischemia/reperfusion (MI/R) injury. Uc.48+ is a long noncoding RNA (lncRNA) from a transcribed ultraconserved region (T‐UCR) of human, mouse, and rat genomes. Here, we explored the aggravating role of uc.48+ and identified purinergic P2X7 receptor (P2X7R) as a downstream regulator of uc.48+ in HFD‐induced MI/R vulnerability. Targeting uc.48+ may be a novel therapeutic approach of MI/R vulnerability to HFD. [ABSTRACT FROM AUTHOR]

The upregulation of nociceptive ion channels expressed in dorsal root ganglia (DRG) contributes to the development and retaining of diabetic pain symptoms. The flavonoid quercetin (3,3′,4′,5,7‐pentahydroxyflavone) is a component extracted from various fruits and vegetables and exerts anti‐inflammatory, analgesic, anticarcinogenic, antiulcer, and antihypertensive effects. However, the exact mechanism underlying quercetin's analgesic action remains poorly understood. The aim of this study was to investigate the effects of quercetin on diabetic neuropathic pain related to the P2X4 receptor in the DRG of type 2 diabetic rat model. Our data showed that both mechanical withdrawal threshold and thermal withdrawal latency in diabetic rats treated with quercetin were higher compared with those in untreated diabetic rats. The expression levels of P2X4 messenger RNA and protein in the DRG of diabetic rats were increased compared with the control rats, while quercetin treatment significantly inhibited such enhanced P2X4 expression in diabetic rats. The satellite glial cells (SGCs) enwrap the neuronal soma in the DRG. Quercetin treatment also lowered the elevated coexpression of P2X4 and glial fibrillary acidic protein (a marker of SGCs) and decreased the upregulation of phosphorylated p38 mitogen‐activated protein kinase (p38MAPK) in the DRG of diabetic rats. Quercetin significantly reduced the P2X4 agonist adenosine triphosphate‐activated currents in HEK293 cells transfected with P2X4 receptors. Thus, our data demonstrate that quercetin may decrease the upregulation of the P2X4 receptor in DRG SGCs, and consequently inhibit P2X4 receptor‐mediated p38MAPK activation to relieve the mechanical and thermal hyperalgesia in diabetic rats. The expression levels of P2X4 receptor in the dorsal root ganglia (DRG) satellite glial cells (SGCs) of diabetic rats were increased to relate to hyperalgesia. Quercetin decreased the upregulation of the P2X4 receptor in DRG SGCs. Consequently, quercetin relieved the mechanical and thermal hyperalgesia in diabetic rats. [ABSTRACT FROM AUTHOR]

Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin‐1β (IL‐1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL‐1β, and tumor necrosis factor‐receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p‐P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats. Upregulated P2Y12 in satellite glial cells (SGCs) of dorsal root ganglia (DRG) was involved in diabetic neuropathic pain. Targeting the P2Y12 receptor by short hairpin RNA decreased the upregulated expression of the P2Y12 receptor in DRG SGCs and relieved mechanical and thermal hyperalgesia in type 2 DM rats. [ABSTRACT FROM AUTHOR]

Abstract: Chronic lead exposure causes peripheral sympathetic nerve stimulation, including increased blood pressure and heart rate. Purinergic receptors are involved in the sympathoexcitatory response induced by myocardial ischemia injury. However, whether P2X4 receptor participates in sympathoexcitatory response induced by chronic lead exposure and the possible mechanisms are still unknown. The aim of this study was to explore the change of the sympathoexcitatory response induced by chronic lead exposure via the P2X4 receptor in the stellate ganglion (SG). Rats were given lead acetate through drinking water freely at doses of 0 g/L (control group), 0.5 g/L (low lead group), and 2 g/L (high lead group) for 1 year. Our results demonstrated that lead exposure caused autonomic nervous dysfunction, including blood pressure and heart rate increased and heart rate variability (HRV) decreased. Western blotting results indicated that after lead exposure, the protein expression levels in the SG of P2X4 receptor, IL‐1β and Cx43 were up‐regulated, the phosphorylation of p38 mitogen‐activated protein kinase (MAPK) was activated. Real‐time PCR results showed that the mRNA expression of P2X4 receptor in the SG was higher in lead exposure group than that in the control group. Double‐labeled immunofluorescence results showed that P2X4 receptor was co‐expressed with glutamine synthetase (GS), the marker of satellite glial cells (SGCs). These changes were positively correlated with the dose of lead exposure. The up‐regulated expression of P2X4 receptor in SGCs of the SG maybe enhance the sympathoexcitatory response induced by chronic lead exposure. [ABSTRACT FROM AUTHOR]

Superior cervical ganglia (SCG) innervate the myocardium and participate in sympathoexcitatory transmission. P2Y12 receptor is expressed in satellite glial cells (SGCs). This study seeks to clarify whether the P2Y12 receptor is involved in the sympathoexcitation reflex after myocardial ischemia (MI). MI model was induced by occlusion of the left coronary artery. P2Y12 were assayed by real time PCR and Western blotting. Our results showed that expression levels of P2Y12 mRNA and protein were significantly higher in the MI group than in the sham group. Administration of P2Y12 short hairpin RNA (shRNA) caused downregulation of the P2Y12 receptor in the SCG. In MI rats plus P2Y12 shRNA treatment group, the abnormal changes in diastolic blood pressure (DBP), systolic blood pressure (SBP), heart rate (HR), electrocardiograms (ECGs), and cardiac tissue structures were alleviated. When the treatment of P2Y12shRNA in MI rats, upregulated coexpression values of P2Y12 and glial fibrillary acidic protein (GFAP), the upregulation of tumor necrosis factor α (TNF-α) and phosphorylated P38 mitogen activated protein kinase (p-P38 MAPK) in the SCG were decreased. Downregulation of the P2Y12 receptor in the SCG after MI may improve cardiac function by alleviating the sympathoexcitatory reflex. [ABSTRACT FROM AUTHOR]

Neuropathic pain is a very common complication in diabetes mellitus ( DM), and treatment for it is limited. As DM is becoming a global epidemic it is important to understand and treat this problem. The mechanisms of diabetic neuropathic pain are largely obscure. Recent studies have shown that glial cells are important for a variety of neuropathic pain types, and we investigated what are the changes that satellite glial cells ( SGCs) in dorsal root ganglia undergo in a DM type 1 model, induced by streptozotocin ( STZ) in mice and rats. We carried out immunohistochemical studies to learn about changes in the activation marker glial fibrillary acidic protein ( GFAP) in SGCs. We found that after STZ-treatment the number of neurons surrounded with GFAP-positive SGCs in dorsal root ganglia increased 4-fold in mice and 5-fold in rats. Western blotting for GFAP, which was done only on rats because of the larger size of the ganglia, showed an increase of about 2-fold in STZ-treated rats, supporting the immunohistochemical results. These results indicate for the first time that SGCs are activated in rodent models of DM1. As SGC activation appears to contribute to chronic pain, these results suggest that SGCs may participate in the generation and maintenance of diabetic neuropathic pain, and can serve as a potential therapeutic target. [ABSTRACT FROM AUTHOR]