Purinergic P2X7 receptor involves in anti-retinal photodamage effects of berberine.

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-1ß). 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.

Association of the ADORA2A receptor and CD73 polymorphisms with epilepsy.

Single-nucleotide polymorphisms are connected with the risk of epilepsy on occurrence, progress, and the individual response to drugs. Progress in genomic technology is exposing the complex genetic architecture of epilepsy. Compelling evidence has demonstrated that purines and adenosine are key mediators in the epileptic process. Our previous study found the interconnection of P2Y12 receptor single-nucleotide polymorphisms and epilepsy. However, little is known about the interaction between the purine nucleoside A2A receptor and rate-limiting enzyme ecto-5'-nucleotidase/CD73 and epilepsy from the genetic polymorphism aspect. The aim of the study is to evaluate the impact of A2AR and CD73 polymorphisms on epilepsy cases. The study group encompassed 181 patients with epilepsy and 55 healthy volunteers. A significant correlation was confirmed between CD73 rs4431401 and epilepsy (p < 0.001), with TT genotype frequency being higher and C allele being lower among epilepsy patients in comparison with healthy individuals, indicating that the presence of the TT genotype is related to an increased risk of epilepsy (OR = 2.742, p = 0.006) while carriers of the C allele demonstrated a decreased risk of epilepsy (OR = 0.304, p < 0.001). According to analysis based on gender, the allele and genotype of rs4431401 in CD73 were associated with both male and female cases (p < 0.0001, p = 0.026, respectively). Of note, we found that A2AR genetic variants rs2267076 T>C (p = 0.031), rs2298383 C>T (p = 0.045), rs4822492 T>G (p = 0.034), and rs4822489 T>G (p = 0.029) were only associated with epilepsy in female subjects instead of male. It is evident that the TT genotype and T allele of rs4431401 in CD73 were genetic risk factors for epilepsy, whereas rs2267076, rs2298383, rs4822492, and rs4822489 polymorphisms of the A2AR were mainly associated with female subjects.

CD73: Friend or Foe in Lung Injury.

Ecto-5'-nucleotidase (CD73) plays a strategic role in calibrating the magnitude and chemical nature of purinergic signals that are delivered to immune cells. Its primary function is to convert extracellular ATP to adenosine in concert with ectonucleoside triphosphate diphosphohydrolase-1 (CD39) in normal tissues to limit an excessive immune response in many pathophysiological events, such as lung injury induced by a variety of contributing factors. Multiple lines of evidence suggest that the location of CD73, in proximity to adenosine receptor subtypes, indirectly determines its positive or negative effect in a variety of organs and tissues and that its action is affected by the transfer of nucleoside to subtype-specific adenosine receptors. Nonetheless, the bidirectional nature of CD73 as an emerging immune checkpoint in the pathogenesis of lung injury is still unknown. In this review, we explore the relationship between CD73 and the onset and progression of lung injury, highlighting the potential value of this molecule as a drug target for the treatment of pulmonary disease.

The circadian regulation of extracellular ATP.

Extracellular ATP is a potent signaling molecule released from various cells throughout the body and is intimately involved in the pathophysiological functions of the nervous system and immune system by activating P2 purinergic receptors. Recent increasingly studies showed that extracellular ATP exhibits circadian oscillation with an approximately 24-h periodicity, which participates in regulatory pathways of central oscillator suprachiasmatic nucleus and peripheral oscillator bladder, respectively. Oscillators modulate the protein expression of ATP release channels and ectonucleotidase activity through clock genes; indeed, real-time alterations of ATP release and degradation determine outcomes of temporal character on extracellular ATP rhythm. The regulatory pathways on extracellular ATP rhythm are different in central and peripheral systems. In this review, we summarize the circadian rhythm of extracellular ATP and discuss several circadian regulatory pathways in different organs via ATP release and degradation, to provide a new understanding for purinergic signaling in the regulatory mechanism of circadian rhythm and a potential target to research the circadian regulation of extracellular ATP in other circadian oscillators.

P2Y12 receptor gene polymorphisms are associated with epilepsy.

The basic research indicated that microglial P2Y12 receptors (P2Y12Rs) are involved in the pathophysiology of epilepsy through regulated microglial-neuronal interactions, aberrant neurogenesis, or immature neuronal projections. However, whether the clinic case of epilepsy would be associated with P2Y12 receptor gene polymorphisms is presented with few data. In our study, a total of 176 patients with epilepsy and 50 healthy controls were enrolled. Two single-nucleotide polymorphisms, namely rs1491974 and rs6798347, were selected for analysis. The results revealed that carriers of the G allele of rs1491974 G>A or rs6798347 G>A may be associated with an increased risk of epilepsy (OR = 0.576, 95% CI = 0.368-0.901, p = 0.015; OR = 0.603, 95% CI = 0.367-0.988, p = 0.043). Interestingly, we found that the rs1491974 G>A genotype and allele frequencies have only a significant difference in female instead of male case (p = 0.004 for genotype; p = 0.001 for allele). The subgroup analysis demonstrated that individuals with the rs1491974 G>A genotype might have more frequent seizure (OR = 0.476, 95% CI = 0.255-0.890; p = 0.019). These data implied that both rs1491974 and rs6798347 polymorphisms of P2Y12R would be able to play import roles in epilepsy susceptibility, whereas the rs1491974 polymorphism may be specifically related to seizure frequency.

Aberrant NF-κB activation in odontoblasts orchestrates inflammatory matrix degradation and mineral resorption.

Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction. As a specialized inflammatory pathological process, dental internal resorption (IR) includes both soft and hard tissues deconstruction within the dentin-pulp complex, which has been one of the main reasons for inflammatory tooth loss. Mechanisms of inflammatory matrix degradation and tissue resorption in IR are largely unclear. In this study, we used a combination of Cre-loxP reporter, flow cytometry, cell transplantation, and enzyme activities assay to mechanistically investigate the role of regenerative cells, odontoblasts (ODs), in inflammatory mineral resorption and matrices degradation. We report that inflamed ODs have strong capabilities of matrix degradation and tissue resorption. Traditionally, ODs are regarded as hard-tissue regenerative cells; however, our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue deconstruction. Specifically, we uncovered that nuclear factor-kappa b (NF-κB) signaling orchestrated Tumor necrosis factor α (TNF-α)-induced matrix metalloproteinases (Mmps) and Cathepsin K (Ctsk) functions in ODs to enhance matrix degradation and tissue resorption. Furthermore, TNF-α increases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level, which utterly makes ODs cell line 17IIA11 (A11) become Trap+ and Ctsk+ multinucleated cells to perform resorptive actions. Blocking of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and Ctsk. Utterly, via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in vivo. Our data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.

Wnt/ß-catenin signaling in cancers and targeted therapies.

Wnt/ß-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals. Aberrant activation of Wnt/ß-catenin signaling is tightly linked with the increment of prevalence, advancement of malignant progression, development of poor prognostics, and even ascendence of the cancer-associated mortality. Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers. Up to date, many therapies targeting Wnt/ß-catenin signaling in cancers have been developed, which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/ß-catenin signaling. However, current facts indicate that the clinical translations of Wnt/ß-catenin signaling-dependent targeted therapies have faced un-neglectable crises and challenges. Therefore, in this study, we systematically reviewed the most updated knowledge of Wnt/ß-catenin signaling in cancers and relatively targeted therapies to generate a clearer and more accurate awareness of both the developmental stage and underlying limitations of Wnt/ß-catenin-targeted therapies in cancers. Insights of this study will help readers better understand the roles of Wnt/ß-catenin signaling in cancers and provide insights to acknowledge the current opportunities and challenges of targeting this signaling in cancers.

DNA damage response manages cell cycle restriction of senile multipotent mesenchymal stromal cells.

Multipotent mesenchymal stromal cells (MMSCs) are promising to treat a variety of traumatic and degenerative diseases. However, in vitro-passage aging induces cell cycle arrest and a series of genetic and biological changes, which greatly limits ex vivo cell number expansion and further clinical application of MMSCs. In most cases, DNA damage and DNA damage response (DDR) act as the main cause and executor of cellular senescence respectively. Mechanistically, DNA damage signals induce cell cycle arrest and DNA damage repair via DDR. If the DNA damage is indelible, MMSCs would entry into a permanent cell cycle arrest. It should be noted that apart from DDR signaling, certain proliferation or metabolism pathways are also occupied in DNA damage related cell cycle arrest. New findings of these aspects will also be summarized in this study. In summary, we aim to provide a comprehensive review of DDR associated cell cycle regulation and other major molecular signaling in the senescence of MMSCs. Above knowledge could contribute to improve the limited capacity of in vitro expansion of MMSCs, and then promote their clinical applications.