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Emerging evidence has implicated nicotinamide adenine dinucleotide (NAD+) metabolism in various inflammatory diseases. In the study, the role of NAD+ metabolism in Complete Freund's Adjuvant (CFA)‐evoked inflammatory pain and the underlying mechanisms are investigated. The study demonstrated that CFA induced upregulation of nicotinamide phosphoribosyltransferase (NAMPT) in dorsal root ganglia (DRG) without significant changes in the spinal cord. Inhibition of NAMPT expression by intrathecal injection of NAMPT siRNA alleviated CFA‐induced pain‐like behavior, decreased NAD+ contents in DRG, and lowered poly‐(ADP‐ribose) polymerase 1 (PARP1) activity levels. These effects are all reversed by the supplement of nicotinamide mononucleotide (NMN). Inhibition of PARP1 expression by intrathecal injection of PARP1 siRNA alleviated CFA‐induced pain‐like behavior, while elevated NAD+ levels of DRG. The analgesic effect of inhibiting NAMPT/NAD+/PARP1 axis can be attributed to the downregulation of the NF‐κB/IL‐1β inflammatory pathway. Double immunofluorescence staining showed that the expression of NAMPT/NAD+/PARP1 axis is restricted to DRG neurons. In conclusion, PARP1 activation in response to CFA stimulation, fueled by NAMPT‐derived NAD+, mediates CFA‐induced inflammatory pain through NF‐κB/IL‐1β inflammatory pathway. [ABSTRACT FROM AUTHOR]

Herein, I5+ with stereochemically active lone pairs (SCALP) was introduced into the selenate system, and two novel iodate-selenates were successfully obtained, Na7(SeO4)3(IO3) and K2(SeO4)[IO2(OH)]. Innovatively, both the title compounds are potential short-wave ultraviolet (UV) birefringent materials that possess large optical band gaps (4.57 eV and 4.27 eV, respectively) and large birefringence (0.087@546 nm and 0.101@546 nm, respectively). Simultaneously, the powder second harmonic generation (SHG) measurement reveals that Na7(SeO4)3(IO3) exhibits SHG responses of 0.6 × KDP (KH2PO4) with type-I phase matching. Detailed structural analysis and theoretical calculations confirm the excellent optical performance originating from the cooperative effect of [SeO4] and [IO3]/[IO2(OH)] functional units. This work indicates that the iodate-selenate system offers additional candidates for designing short-wave UV optical materials. [ABSTRACT FROM AUTHOR]

When processing sensing signals under low signal-to-noise ratio environment, the sensing performance cannot be guaranteed in existing algorithms. To ensure sensing performance, we propose a novel spectrum sensing algorithm based on soft low-rank subspace clustering (SLRSC) in this brief. Firstly, the lowest rank coefficient matrix of signal vectors is calculated by low-rank representation, and the adjacency matrix is built to make coefficient matrix balance. Secondly, the eigenvalue of the adjacency covariance matrix is extracted as a feature. Finally, variable weighting $k$ -means method is used to cluster, which avoids complicated threshold derivation and improves cluster accuracy. Simulation results prove that the proposed SLRSC algorithm has excellent sensing performance under high noise case. [ABSTRACT FROM AUTHOR]

The bioactive lipid lysophosphatidylcholine (LPC), a major phospholipid component of oxidized low-density lipoprotein (Ox-LDL), originates from the cleavage of phosphatidylcholine by phospholipase A2 (PLA2) and is catabolized to other substances by different enzymatic pathways. LPC exerts pleiotropic effects mediated by its receptors, G protein-coupled signaling receptors, Toll-like receptors, and ion channels to activate several second messengers. Lysophosphatidylcholine (LPC) is increasingly considered a key marker/factor positively in pathological states, especially inflammation and atherosclerosis development. Current studies have indicated that the injury of nervous tissues promotes oxidative stress and lipid peroxidation, as well as excessive accumulation of LPC, enhancing the membrane hyperexcitability to induce chronic pain, which may be recognized as one of the hallmarks of chronic pain. However, findings from lipidomic studies of LPC have been lacking in the context of chronic pain. In this review, we focus in some detail on LPC sources, biochemical pathways, and the signal-transduction system. Moreover, we outline the detection methods of LPC for accurate analysis of each individual LPC species and reveal the pathophysiological implication of LPC in chronic pain, which makes it an interesting target for biomarkers and the development of medicine regarding chronic pain. [ABSTRACT FROM AUTHOR]

Background: Ischemic heart diseases is one of the leading causes of death worldwide. Although revascularization timely is an effective therapeutic intervention to salvage the ischemic myocardium, reperfusion itself causes additional myocardial injury called ischemia/reperfusion (I/R) injury. Bone marrow-derived mesenchymal stem cells (MSCs) is one of the promising cells to alleviate ischemic myocardial injury. However, this cell therapy is limited by poor MSCs survival after transplantation. Here, we investigated whether sevoflurane preconditioning could promote MSCs to attenuate myocardial I/R injury via transient receptor potential canonical channel 6 (TRPC6)-induced angiogenesis. Methods: The anti-apoptotic effect of sevoflurane preconditioning on MSCs was determined by Annexin V-FITC/propidium iodide staining. TRPC6, hypoxia-inducible factor-1α (HIF-1α), Chemokine receptor 4 (CXCR4) and vascular endothelial growth factor (VEGF) protein expressions and VEGF release from MSCs were determined after hypoxia and reoxygenation (H/R). Small interfering RNA (siRNA) was used to knock down TRPC6 gene expression in MSCs. The angiogenesis of human umbilical vein endothelial cells (HUVECs) co-cultured with MSCs was determined by Matrigel tube formation. Myocardial I/R mouse model was induced by occluding left anterior descending coronary artery for 30 min and then reperfusion. MSCs or sevoflurane preconditioned MSCs were injected around the ligature border zone 5 min before reperfusion. Left ventricle systolic function, infarction size, serum LDH, cTnI and inflammatory cytokines were determined after reperfusion. Results: Sevoflurane preconditioning up-regulated TRPC6, HIF-1α, CXCR4 and VEGF expressions in MSCs and VEGF release from MSCs under H/R, which were reversed by knockdown of TRPC6 gene using siRNA in MSCs. Furthermore, sevoflurane preconditioning promoted the angiogenic and anti-inflammatory effect of HUVECs co-cultured with MSCs. Sevoflurane preconditioned MSCs improved left ventricle systolic function and alleviated myocardial infarction and inflammation in mice subjected to I/R insult. Conclusion: The current findings reveal that sevoflurane preconditioned MSCs boost angiogenesis in HUVECs subjected to H/R insult and attenuate myocardial I/R injury, which may be mediated by TRPC6 up-regulated HIF-1α, CXCR4 and VEGF. [ABSTRACT FROM AUTHOR]

Opioids are the last option for the pharmacological treatment of neuropathic pain, but their antinociceptive effects are limited. Decreased mu opioid receptor (MOR) expression in the peripheral nervous system may contribute to this. Here, we showed that nerve injury induced hypermethylation of the Oprm1 gene promoter and an increased expression of methyl-CpG binding protein 2 (MeCP2) in injured dorsal root ganglion (DRG). The downregulation of MOR in the DRG is closely related to the augmentation of MeCP2, an epigenetic repressor, which could recruit HDAC1 and bind to the methylated regions of the Oprm1 gene promoter. MeCP2 knockdown restored the expression of MOR in injured DRG and enhanced the analgesic effect of morphine, while the mimicking of this increase via the intrathecal infusion of viral vector-mediated MeCP2 was sufficient to reduce MOR in the DRG. Moreover, HDAC1 inhibition with suberoylanilide hydroxamic acid, an HDAC inhibitor, also prevented MOR reduction in the DRG of neuropathic pain mice, contributing to the augmentation of morphine analgesia effects. Mechanistically, upregulated MeCP2 promotes the binding of a high level of HDCA1 to hypermethylated regions of the Oprm1 gene promoter, reduces the acetylation of histone H3 (acH3) levels of the Oprm1 gene promoter, and attenuates Oprm1 transcription in injured DRG. Thus, upregulated MeCP2 and HDAC1 in Oprm1 gene promoter sites, negatively regulates MOR expression in injured DRG, mitigating the analgesic effect of the opioids. Targeting MeCP2/HDAC1 may thus provide a new solution for improving the therapeutic effect of opioids in a clinical setting. [ABSTRACT FROM AUTHOR]

General anesthesia is a drug-induced reversible state comprised of altered states of consciousness, amnesia, analgesia, and immobility. The medial frontal cortex (mPFC) has been discovered to modulate the level of consciousness through cholinergic and glutamatergic pathways. The optogenetic tools combined with in vivo electrophysiological recording were used to study the neural oscillatory modulation mechanisms in mPFC underlying the loss of consciousness (LOC) and emergence. We found that optogenetic activation of both cholinergic and glutamatergic neurons in the basal forebrain (BF) reversed the hypnotic effect of propofol and accelerated the emergence from propofol-induced unconsciousness. The cholinergic light-activation during propofol anesthesia increased the power in the β (12–20 Hz) and low γ (20–30 Hz) bands. Conversely, glutamatergic activation increased the power at less specific broad (1–150 Hz) bands. The cholinergic-induced alteration to specific power bands after LOC had opposite effects to that of propofol. These results suggested that the cholinergic system might act on more specific cortical neural circuits related to propofol anesthesia. [ABSTRACT FROM AUTHOR]

Mesenchymal stem cells have cannabinoid (CB) receptors type 1 and type 2 and can alleviate a variety of neuropathic pains, including chronic constriction injury (CCI). A selective CB2 receptor agonist is AM1241. In the present study, it was found that mice with CCI displayed a longer duration of mechanical and thermal analgesia when intrathecally (i.t.) injected with AM1241-treated mesenchymal stem cells, compared to those injected with untreated mesenchymal stem cells or AM1241 alone. Moreover, CCI-induced upregulation of the phosphorylated extracellular signal-regulated kinase (ERK) 1/2 (p-ERK1/2) was inhibited following i.t. injection of AM1241-treated mesenchymal stem cells and this inhibition was noticeably higher compared to injection with untreated mesenchymal stem cells. The expression of transforming growth factor-β1 (TGF-β1) was also analyzed in the dorsal root ganglion (DRGs) and spinal cord of CCI mice. In untreated CCI mice, expression of TGF-β1 was increased, whereas pretreatment with AM1241-treated mesenchymal stem cells regulated the expression of TGF-β1 on 10 days and 19 days after surgery. In addition, i.t. injection of exogenous TGF-β1 slightly alleviated neuropathic pain whilst neutralization of TGF-β1 potently blocked the effect of AM1241-treated mesenchymal stem cells on thermal hyperalgesia and mechanical allodynia of CCI mice. In an in vitro experiment, AM1241 could enhance the release of TGF-β1 in the supernatant of BMSCs after lipopolysaccharide (LPS) simulation. Taken together, the findings of the current study show that i.t. administration of AM1241-treated mesenchymal stem cells has a positive effect on analgesia and that TGF-β1 and p-ERK1/2 may be the molecular signaling pathway involved in this process. [ABSTRACT FROM AUTHOR]

Neuropathic pain (NP) is a type of chronic pain that is different from the common type of pain. The mechanisms of NP are still poorly understood. Exploring the key genes and neurobiological changes in NP could provide important diagnostic and treatment tools for clinicians. GSE24982 is an mRNA-seq dataset that we downloaded from the Gene Expression Omnibus database to identify key genes in NP. Differentially expressed genes (DEGs) were identified using the BRB-ArrayTools software and R. Functional and pathway enrichment analyses of the DEGs were performed using Metascape. A protein–protein interaction network was created and visualized using Cytoscape. A total of 123 upregulated DEGs were obtained. Among these genes, p53 was the node with the highest degree; hence, we validated it experimentally using a chronic constriction injury mouse model. Our results showed that overexpression of the p53 gene, and the subsequent increase in caspase-3 expression, in dorsal root ganglion neurons led to increased apoptotic changes in these neurons. p53 may therefore be partly responsible for the development of chronic constriction injury-induced NP. [ABSTRACT FROM AUTHOR]

The metabolite itaconate has both anti-inflammatory and immunomodulatory effects. However, its influence on chronic pain is unclear. Here, we demonstrated that intraperitoneal injection of the itaconate derivative dimethyl itaconate (DI) alleviated chronic pain symptoms, such as allodynia and hyperalgesia, in spinal nerve ligation (SNL) and inflammatory pain models. Moreover, intraperitoneal DI reduced the secretion of inflammatory cytokines (i.e., interleukin-1β, tumour necrosis factor-alpha) in dorsal root ganglion (DRG), spinal cord and hind paw tissues, suppressed the activation of macrophages in the DRG and glial cells in the spinal dorsal horn and decreased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in the DRG and spinal cord. DI boosted nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) levels in the DRG and spinal cord of SNL mice. Intraperitoneal administration of the Nrf2 inhibitor ML385 abolished the analgesic effect of DI and decreased the expression of Nrf2 in the DRG and spinal cord. Similarly, administration of DI potently reversed the lipopolysaccharide (LPS)-induced inflammatory effect in microglia. Reduction of endogenous itaconate levels by pretreatment with immune-responsive gene 1 (IRG1) siRNA blocked Nrf2 expression, which impaired the analgesic and anti-inflammatory effects of DI in vitro. Therefore, our findings revealed for the first time that intraperitoneal DI elicited anti-inflammatory effect and sustained chronic pain relief, which may be regarded as a promising therapeutic agent for chronic pain treatment. • DI alleviated SNL-induced neuropathic pain and inhibited neuroinflammation. • Nrf2 may act as a downstream regulator of DI to exert analgesic effects. • DI also relieved CFA-induced inflammatory pain and inflammatory response. [ABSTRACT FROM AUTHOR]

Nerve injury-induced gene expression change in the spinal cord is critical for neuropathic pain genesis. RNA N6-methyladenosine (m6A) modification represents an additional layer of gene regulation. We showed that spinal nerve ligation (SNL) upregulated the expression of matrix metallopeptidase 24 (MMP24) protein, but not Mmp24 mRNA, in the spinal cord neurons. Blocking the SNL-induced upregulation of spinal MMP24 attenuated local neuron sensitization, neuropathic pain development and maintenance. Conversely, mimicking MMP24 increase promoted the spinal ERK activation and produced evoked nociceptive hypersensitivity. Methylated RNA Immunoprecipitation Sequencing (MeRIP-seq) and RNA Immunoprecipitation (RIP) assay indicated the decreased m6A enrichment in the Mmp24 mRNA under neuropathic pain condition. Moreover, fat-mass and obesity-associated protein (FTO) was colocalized with MMP24 in spinal neurons and shown increased binding to the Mmp24 mRNA in the spinal cord after SNL. Overexpression or suppression of FTO correlates with promotion or inhibition of MMP24 expression in cultured spinal cord neurons. In conclusion, SNL promoted the m6A eraser FTO binding to the Mmp24 mRNA, which subsequently facilitated the translation of MMP24 in the spinal cord, and ultimately contributed to neuropathic pain genesis. [ABSTRACT FROM AUTHOR]