No abstract

In mammals, the neural control of airway smooth muscle is dominated by a subset of airway vagal preganglionic neurons in the ventrolateral medulla. These neurons are physiologically modulated by adrenergic/noradrenergic projections, and weakened α₂-adrenergic inhibition of them is indicated to participate in the pathogenesis and exacerbation of asthma. This study tests whether these neurons are modulated by α₁-adrenoceptors, and if so, how. In anesthetized adult rats, microinjection of the α₁A-adrenoceptor agonist A61603 (1 pmol) unilaterally into the medullary region containing these neurons caused a significant increase in airway resistance, which was prevented by intraperitoneal atropine (0.5 mg/kg). In rhythmically firing medullary slices of newborn rats, A61603 (10 nM) caused depolarization in both the inspiratory-activated and inspiratory-inhibited airway vagal preganglionic neurons that were retrogradely labeled, and a significant increase in the spontaneous firing rate. Under voltage clamp, A61603 significantly enhanced the spontaneous excitatory inputs to both types of neurons and caused a tonic inward current in the inspiratory-activated neurons along with significantly increased peak amplitude of the inspiratory inward currents. The responses in vitro were prevented by α₁A-adrenoceptor antagonist RS100329 (1 μM), which alone significantly inhibited the spontaneous excitatory inputs to both types of the neurons. After pretreatment with tetrodotoxin (1 μM), A61603 (10 or 100 nM) had no effect on either type of neuron. We conclude that in rats, activation of α₁-adrenoceptors in the medullary region containing airway vagal preganglionic neurons increases airway vagal tone, and that this effect is primarily mediated by facilitation of the excitatory inputs to the preganglionic neurons.

The airway vagal preganglionic neurons (AVPNs) in the external formation of the nucleus ambiguus (eNA) play a major role in the vagal control of tracheobronchial smooth muscle tone and maintenance of airway resistance. The eNA receives vasopressinergic projection from the hypothalamic paraventricular nucleus (PVN), the key node for the genesis of psychological stress. Since airway vagal excitation is reportedly to be associated with the psychological stress-induced/exacerbated airway hyperresponsiveness in asthmatics, arginine vasopressin (AVP) might be involved in stress-related airway vagal excitation. However, this possibility has not been validated. This study aimed to test whether and how AVP regulates AVPNs. In rhythmically active medullary slices of newborn rats, retrogradely labeled AVPNs were identified as inspiratory-activated and inspiratory-inhibited AVPNs (IA- and II-AVPNs) using patch-clamp techniques according to their inspiratory-related firing behavior and synaptic activities. The results show that under current clamp, AVP depolarized both IA- and II-AVPNs, and significantly increased their spontaneous firing rate. Under voltage clamp, AVP elicited a slow inward current, and significantly increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in both types of AVPNs. In addition, AVP significantly enhanced the phase-locked excitatory inspiratory inward current in inspiratory-activated airway vagal preganglionic neurons (IA-AVPNs), but significantly suppressed the phase-locked inhibitory inspiratory outward current in II-AVPNs. In both types AVPNs, AVP significantly increased the frequency and amplitude of pharmacologically isolated spontaneous GABAergic and glycinergic inhibitory postsynaptic currents (IPSCs). All of the AVP-induced effects were prevented by SR49059, an antagonist of V1a receptors, but unaffected by SSR149415, an antagonist of V1b receptors. AVP did not cause significant changes in the miniature excitatory postsynaptic currents (mEPSCs), miniature inhibitory postsynaptic currents (mIPSCs) and membrane input resistance of either type of AVPNs. These results demonstrate that AVP, via activation of V1a receptors, enhanced the spontaneous excitatory and inhibitory inputs similarly in the two types of AVPNs, but differentially altered their phase-locked inspiratory excitatory and inhibitory inputs. The overall effects of AVP are excitatory in both types AVPNs. These results suggest that increased central AVP release may be involved in the stress-induced augmentation of airway vagal activity, and, consequently, the induction or exacerbation of some airway diseases.

The severity of asthma is closely related to the intensity of airway vagal activity; however, it is unclear how airway vagal activity is centrally augmented in asthma. Here we report that in an asthma model of male Sprague−Dawley rats, the expression and activity of ecto-5′-nucleotidase (CD73) were decreased in airway vagal centers, ATP concentration in cerebral spinal fluid was increased, and the inhibitory and excitatory airway vagal responses to intracisternally injected ATP (5 μmol) and CD73 inhibitor AMPCP (5 μmol), respectively, were attenuated. In airway vagal preganglionic neurons (AVPNs) identified in medullary slices of neonatal Sprague−Dawley rats, AMPCP (100 μmol•L −1 ) caused excitatory effects, as are shown in patchclamp by depolarization, increased neuronal discharge, and facilitated spontaneous excitatory postsynaptic currents (sEPSCs). In contrast, exogenous ATP (100 μmol•L −1 , 1 mmol•L −1 ) primarily caused inhibitory effects, which are similar to those induced by exogenous adenosine (100 μmol•L −1 ). Adenosine A 1 receptor antagonist CPT (5 μmol•L −1 ) blocked the inhibition of sEPSCs induced by 100 μmol•L −1 exogenous ATP and that by 100 μmol•L −1 exogenous adenosine, whereas 50 μmol•L −1 CPT converted the inhibition of sEPSCs induced by 1 mmol•L −1 ATP to facilitation that was blocked by addition of P2X receptor antagonist PPADS (20 μmol•L −1 ). These results demonstrate that in rat, the sEPSCs of AVPNs are facilitated by extracellular ATP via activation of P2X receptors and inhibited by extracellular adenosine via activation of A 1 receptors; in experimental asthma, decreased CD73 expression and activity in airway vagal centers contribute to the augmentation of airway vagal activity through imbalanced ATP/ADO modulation of AVPNs.

Although N6-methyladenosine (m6A) has been implicated in various biological functions in human cancers, its role in predicting the prognosis of glioma remains unclear. In this study, the transcriptome expression profiles and the clinical data of 961 patients were derived from the Chinese Glioma Genome Atlas (CGGA). We comprehensively evaluated the association between the expression of m6A regulators and the prognosis of glioma and established a 3-gene (YTHDF2, FTO, and ALKBH5) risk signature using least absolute shrinkage and selection operator (LASSO) analysis. Patients with a high-risk signature had significantly adverse prognoses. Gene set enrichment analysis (GSEA) analysis revealed that the G2M checkpoint, MTORC1 signaling, epithelial mesenchymal transition, and PI3K-AKT-mTOR signaling were significantly enriched in the high-risk group. Univariate and multivariate Cox regression analyses confirmed the independent prognostic value of this risk signature. We then constructed a nomogram for individualized prediction of overall survival (OS) by integrating clinicopathological features (age, World Health Organization [WHO] grade), treatment information (radiotherapy, temozolomide therapy), and m6A risk signature. The calibration curves showed excellent agreement between the predicted and actual probabilities for the 1-, 3-, and 5-year OS, with a C-index of 0.780 in the training cohort and 0.717 in the validation cohort. Altogether, our study elucidated the important role of m6A regulators in glioma prognosis, which is valuable for the selection of therapeutic methods and clinical management of patients with glioma.

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Objective: To evaluate the blink reflex (BR) in estimating the potential injury of trigeminal nerve following percutaneous balloon compression (PBC) surgery, and to determine the association between BR alterations and early surgical outcomes. Methods:In this single-center, prospective before-and-after study, a total of 74 patients who had primary trigeminal neuralgia and scheduled for PBC between October 2020 and June 2021 were prospectively included. BR testing and facial sensory assessment were performed pre-and post-PBC. The latency and the area under the curve (AUC) of pre-and postoperative R1 (R1 pre /R1 post ) and R2 (R2 pre /R2 post ) were measured. Results:The BR components were noticeably delayed or diminished following PBC.R1 post was elicited in only 26 patients, and absent in 48 patients. The residual R1 post had markedly reduced AUC (median difference [Hodges-Lehmann]: −59.5, 95% confidence interval [CI]: −217.5 to −6.9, p = 0.023). Compared with R2 pre , the latency of R2 post was considerably delayed (mean difference: 4.3, 95% CI: 2.9 to 5.7, p < 0.001) and the AUC was greatly suppressed (median difference [Hodges-Lehmann]: −388.4, 95% CI: −548.4 to −259.5, p < 0.001). After PBC, 58 patients had immediate total pain relief, and 16 had partial relief. The absence of R1 post was found in 46 of 58 (79.3%) patients with complete remission, whereas in only 2 of 16 (12.5%) patients with partial relief. Association analysis showed that the absence of R1 post was strongly associated with total pain relief (46/58 [79.3%] vs. 2/16 [12.5%], odds ratio [OR]: 26.8, 95% CI: 5.4 to 134.5, Cramér's V: 0.6, p < 0.001). The latency of R2 post in patients with total relief was significantly delayed (mean difference: 2.5, 95% CI: 0.3 to 4.6, p = 0.028).Patients experienced graded facial numbness after PBC, of whom 31 reported mild numbness (Grades I-II) and 43 reported more severe numbness (Grades III-IV). The absence of R1 post was significantly associated with facial numbness severity, 33/43

Airway vagal nerves play a predominant role in the neural control of the airway, and augmented airway vagal activity is known to play important roles in the pathogenesis of some chronic inflammatory airway diseases. Several lines of evidence indicate that dysfunctional central orexinergic system is closely related to the severity of airway diseases, however, whether orexins affect airway vagal activity is unknown. This study investigates whether and how orexin-A regulates the activity of medullary airway vagal preganglionic neurons (AVPNs). The expression of orexin receptor type 1 (OX1R) and type 2 (OX2R) was examined using immunofluorescent staining. The effects of orexin-A on functionally identified inspiratory-activated AVPNs (IA-AVPNs), which are critical in the control of airway smooth muscle, were examined using patch-clamp in medullary slices of neonatal rats. Airway vagal response to injection of orexin-A into the magna cisterna was examined using plethysmography in juvenile rats. The results show that retrogradely labeled AVPNs were immunoreactive to anti-OX1R antibody and anti-OX2R antibody. Orexin-A dose-dependently depolarized IA-AVPNs and increased their firing rate. In synaptically isolated IA-AVPNs, the depolarization induced by orexin-A was blocked partially by OX1R antagonist SB-334867 or OX2R antagonist TCS OX2 29 alone, and completely by co-application of both antagonists. The orexin-A-induced depolarization was also mostly blocked by Na+/Ca2+ exchanger inhibitor KB-R7943. Orexin-A facilitated the glutamatergic, glycinergic and GABAergic inputs to IA-AVPNs, and the facilitation of each type of input was blocked partially by SB-334867 or TCS OX2 29 alone, and completely by co-application of both antagonists. Injection of orexin-A into the magna cisterna of juvenile rats significantly increased the inspiratory and expiratory resistance of the airway and consequently decreased the dynamic compliance of the lungs, all of which were prevented by atropine sulfate or bilateral vagotomy. These results demonstrate that orexin-A excites IA-AVPNs via activation of both OX1R and OX2R, and suggest that increased central synthesis/release of orexins might participate in the pathogenesis of airway diseases via over-activation of AVPNs.