Knockdown of circMYOF inhibits cell growth, metastasis, and glycolysis through miR-145-5p/OTX1 regulatory axis in laryngeal squamous cell carcinoma.

New evidence suggests that abnormal expression of circular RNA (circRNA) is associated with the development of human cancers. This study aims to reveal circMYOF roles in the malignant phenotype of laryngeal squamous cell carcinoma (LSCC). The expression of circMYOF, microRNA (miR)-145-5p, and orthodenticle homeobox 1 (OTX1) was detected by quantitative real-time PCR. Cell proliferation, migration, invasion, and apoptosis were determined using colony formation assay and EdU assay, wound healing assay, transwell assay, and flow cytometry, respectively. Protein expression was examined by western blot analysis. Cell glycolysis was assessed by detecting glucose consumption and lactate production. Mice xenograft models were constructed to evaluate the regulation of circMYOF on LSCC tumorigenesis. The regulatory relationships among circMYOF, miR-145-5p, and OTX1 were identified using dual-luciferase reporter assay and RIP assay. Serum exosomes were isolated to confirm the existence of circMYOF in LSCC patients. CircMYOF was upregulated in LSCC tissues and cells, and its knockdown suppressed LSCC cell growth, metastasis, and glycolysis, as well as inhibited LSCC tumor growth. MiR-145-5p had decreased expression in LSCC, and it could be sponged by circMYOF. The inhibition effect of circMYOF lentivirus short hairpin RNA (sh-circMYOF) on LSCC progression was restored by the inhibitor of miR-145-5p (in-miR-145-5p). Also, OTX1 was targeted by miR-145-5p and was positively regulated by circMYOF. MiR-145-5p could repress LSCC progression, and OTX1 overexpression also eliminated this effect. In addition, we found that circMYOF was significantly overexpressed in the serum exosomes of LSCC patients. Our data revealed that circMYOF contributed to LSCC progression by promoting cell growth, metastasis, and glycolysis through miR-145-5p/OTX1 axis.

Haemodynamic and renal sympathetic responses to V1b vasopressin receptor activation within the paraventricular nucleus.

NEW FINDINGS: What is the central question of this study? Does antagonism of V1b receptors prevent the haemodynamic and renal sympathetic nerve responses that occur with application of exogenous vasopressin into the paraventricular nucleus (PVN) of conscious, chronically instrumented rats? What is the main finding and its importance? Microinjection of vasopressin into the PVN increased mean arterial pressure, heart rate and renal sympathetic nerve activity, all of which were inhibited by pre-injection of the PVN with the V1b antagonist, nelivaptan. The administered vasopressin did not enter the peripheral circulation or increase plasma vasopressin. Ganglionic blockade prevented each of the responses, consistent with mediation by enhanced sympathetic output rather than an increase in circulating vasopressin. Vasopressin (VP) participates in regulation of haemodynamics and volume. Besides more classical actions as a circulating hormone, VP may act via release from axons and dendrites within the CNS. The paraventricular nucleus (PVN) possesses vasopressinergic neurons and a dense complement of VP receptors, including the V1b receptor, which has been implicated in several types of stress responses. We tested the hypothesis that antagonism of V1b receptors will prevent VP-induced increases in mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA). Studies were performed in conscious male Sprague-Dawley rats chronically instrumented with vascular catheters, renal nerve electrodes and a cannula stereotaxically directed into the PVN. Unilateral microinjection of VP into the PVN significantly increased MAP, HR and RSNA, peaking at 10 min. Pre-injection of the PVN with the selective V1b receptor antagonist, nelivaptan, did not alter baseline values but blocked the responses to VP. Ganglionic blockade with chlorisondamine decreased MAP and HR and abolished their increase in response to subsequent PVN application of VP. Injection of VP into the PVN did not alter plasma VP levels. Paraventricular nucleus injection with radiolabelled VP resulted in negligible radiolabelled VP in peripheral blood. These findings support the concept that, in basal conditions, PVN V1b receptor activation (rather than VP release into the periphery) may be implicated in the increases in MAP, HR and RSNA due to increased sympathetic outflow. While the role of V1a and oxytocin receptors cannot be excluded, these data suggest that further studies of the role of V1b receptor activation by endogenous VP during stress to effect neuroexcitation are warranted.

Severe hemorrhage attenuates cardiopulmonary chemoreflex control of regional sympathetic outputs via NTS adenosine receptors.

Selective stimulation of inhibitory A1 and facilitatory A2a adenosine receptor subtypes located in the nucleus of the solitary tract (NTS) powerfully inhibits cardiopulmonary chemoreflex (CCR) control of regional sympathetic outputs via different mechanisms: direct inhibition of glutamate release and facilitation of an inhibitory neurotransmitter release, respectively. However, it remains unknown whether adenosine naturally released into the NTS has similar inhibitory effects on the CCR as the exogenous agonists do. Our previous study showed that adenosine is released into the NTS during severe hemorrhage and contributes to reciprocal changes of renal (decreases) and adrenal (increases) sympathetic nerve activity observed in this setting. Both A1 and A2a adenosine receptors are involved. Therefore, we tested the hypothesis that, during severe hemorrhage, CCR control of the two sympathetic outputs is attenuated by adenosine naturally released into the NTS. We compared renal and adrenal sympathoinhibitory responses evoked by right atrial injections of 5HT3 receptor agonist phenylbiguanide (2-8 µg/kg) under control conditions, during hemorrhage, and during hemorrhage preceded by blockade of NTS adenosine receptors with bilateral microinjections of 8-(p-sulfophenyl) theophylline (1 nmol/100 nl) in urethane/chloralose anesthetized rats. CCR-mediated inhibition of renal and adrenal sympathetic activity was significantly attenuated during severe hemorrhage despite reciprocal changes in the baseline activity levels, and this attenuation was removed by bilateral blockade of adenosine receptors in the caudal NTS. This confirmed that adenosine endogenously released into the NTS has a similar modulatory effect on integration of cardiovascular reflexes as stimulation of NTS adenosine receptors with exogenous agonists.

Activation of NTS A(1) adenosine receptors inhibits regional sympathetic responses evoked by activation of cardiopulmonary chemoreflex.

Previously we have shown that adenosine operating via the A(1) receptor subtype may inhibit glutamatergic transmission in the baroreflex arc within the nucleus of the solitary tract (NTS) and differentially increase renal (RSNA), preganglionic adrenal (pre-ASNA), and lumbar (LSNA) sympathetic nerve activity (ASNA>RSNA≥LSNA). Since the cardiopulmonary chemoreflex and the arterial baroreflex are mediated via similar medullary pathways, and glutamate is a primary transmitter in both pathways, it is likely that adenosine operating via A(1) receptors in the NTS may differentially inhibit regional sympathetic responses evoked by activation of cardiopulmonary chemoreceptors. Therefore, in urethane-chloralose-anesthetized rats (n = 37) we compared regional sympathoinhibition evoked by the cardiopulmonary chemoreflex (activated with right atrial injections of serotonin 5HT(3) receptor agonist phenylbiguanide, PBG, 1-8 µg/kg) before and after selective stimulation of NTS A(1) adenosine receptors [microinjections of N(6)-cyclopentyl adenosine (CPA), 0.033-330 pmol/50 nl]. Activation of cardiopulmonary chemoreceptors evoked differential, dose-dependent sympathoinhibition (RSNA>ASNA>LSNA), and decreases in arterial pressure and heart rate. These differential sympathetic responses were uniformly attenuated in dose-dependent manner by microinjections of CPA into the NTS. Volume control (n = 11) and blockade of adenosine receptor subtypes in the NTS via 8-(p-sulfophenyl)theophylline (8-SPT, 1 nmol in 100 nl) (n = 9) did not affect the reflex responses. We conclude that activation of NTS A(1) adenosine receptors uniformly inhibits neural and cardiovascular cardiopulmonary chemoreflex responses. A(1) adenosine receptors have no tonic modulatory effect on this reflex under normal conditions. However, when adenosine is released into the NTS (i.e., during stress or severe hypotension/ischemia), it may serve as negative feedback regulator for depressor and sympathoinhibitory reflexes integrated in the NTS.

Fire needle plus cupping for acute herpes zoster: study protocol for a randomized controlled trial.

BACKGROUND: Acute herpes zoster (AHZ) is a common skin disease caused by invasion of the varicella zoster virus into the ganglia and skin, and the severe pain is the most complaint, which can seriously disturb the normal life of patients. Fire needle plus cupping is a special acupuncture treatment, which is widely used to treat AHZ for its better analgesic effect in China although it has not been fully verified by rigorous randomized controlled trial (RCT). METHODS/DESIGN: To test the effect, a three-arm randomized parallel controlled trial protocol has been designed. A total of 105 AHZ patients suffering pain will be randomly divided into three groups in an equal proportion. The interventions are fire needle plus cupping (FC) in group A, famciclovir plus gabapentin (FG) in group B, and fire needle plus cupping plus famciclovir (FCF) in group C. The length for the trial is set for a week time frame. Precisely speaking, the A group (FC) is to carry out 1 treatment per day for the total of 7 treatment sessions within 1 week period. On the other hand, the B group (FG) will take drugs orally three times a day within the trial 1 week. Meanwhile, with its combination element, the C group (FCF) is due to undertake both treatments and drugs as prescribed for A and B groups within the trial week. As an intra-trial arrangement, analgesic medication will be carefully administered for temporary pain release if the sudden intolerable pain appeared. For the primary outcome, this study is due to apply visual analogue scale to identify pain intensity relief. As the secondary outcomes are concerned, this study is aiming to focus on the issues related to changes in substance P and beta-endorphin concentrations in peripheral plasma, as well as those issues of analgesic needs, side effects, symptoms, and physical signs including pain classification, local itching, burning sensation, fever, local lymphadenopathy, skin lesion area, blisters, herpes clusters, vesicular traits, ulcers, and pimples; all these are taken into account for evaluation. For the final stage, the participants are to be followed up for postherpetic neuralgia. DISCUSSION: The results of this trial aim to provide sufficient evidence on FC treatment over both FG and FCF treatments. It will then give a credible alternative treatment to cut down acute pain and to cure AHZ infection. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1800015372 . Registered on 28 March 2018.

Novel, non-nitrocatechol catechol-O-methyltransferase inhibitors modulate dopamine neurotransmission in the frontal cortex and improve cognitive flexibility.

RATIONALE: Cognitive impairment is a primary feature of many neuropsychiatric disorders and there is a need for new therapeutic options. Catechol-O-methyltransferase (COMT) inhibitors modulate cortical dopaminergic function and have been proposed as potential cognitive enhancers. Unfortunately, currently available COMT inhibitors are not good candidates due to either poor blood-brain barrier penetration or severe toxicity. OBJECTIVES: To address the need for safe, brain-penetrant COMT inhibitors, we tested multiple novel compounds in a set of preclinical in vivo efficacy assays in rats to determine their ability to inhibit COMT function and viability as potential clinical candidates. METHODS: We measured the change in concentration of dopamine (DA) metabolites in cerebrospinal fluid (CSF) from the cisterna magna and extracellular fluid (ECF) from the frontal cortex produced by our novel compounds. Additionally, we tested the effects of our brain-penetrant COMT inhibitors in an attentional set-shifting assay (ASST). We benchmarked the performance of the novel COMT inhibitors to the effects produced by the known COMT inhibitor tolcapone. RESULTS: We found that multiple COMT inhibitors, exemplified by LIBD-1 and LIBD-3, significantly modulated dopaminergic function measured as decreases in homovanillic acid (HVA) and increases in 3,4-Dihydroxyphenylacetic acid (DOPAC), two DA metabolites, in CSF and the frontal cortex. Additionally, we found that LIBD-1 significantly improved cognitive flexibility in the ASST, an effect previously reported following tolcapone administration. CONCLUSIONS: These results demonstrate that LIBD-1 is a novel COMT inhibitor with promising in vivo activity and the potential to serve as a new therapy for cognitive impairment.

Design of omnidirectional and multiple channeled filters using one-dimensional photonic crystals containing a defect layer with a negative refractive index.

The band structures of one-dimensional photonic crystals containing a defect layer with a negative refractive index are studied, showing that the defect modes possess three types of dispersion: positive, zero, and negative types. Based on these three types of dispersion, practical designs for large incident angle filters without polarization effect and for narrow frequency and sharp angular filters are suggested. Moreover, the splitting of one degenerate defect mode into multiple defect modes is observed in the band gap when the parameters of the defect layer vary. This mode splitting phenomenon can be used to design multiple channeled filters or filters with a rectangular profile. The dispersion multiplicity of the defect modes can be understood by an approximate formula, and the critical condition for the defect mode splitting is also analyzed. Based on these analyses, practical optimization design of omnidirectional filter is also suggested.

Protective effects of breviscapine on ischemic vascular dementia in rats.

Breviscapine, a traditional Chinese medicine, is extensively used in clinic to treat cardiovascular diseases and cerebrovascular injury. In this study, we demonstrated the effects of breviscapine on vascular dementia (VD) rats, which were mimicked by permanent occlusion of bilateral common carotid arteries. Breviscapine (2 mg/kg for 14 d) improved the performance of learning and memory of VD rats in Morris water maze, decreased the level of lipid peroxidation and free radicals, and attenuated the pathological alterations, such as nuclear shrink, cellular edema and irregular arrangement of pyramidal layer in the hippocampal CA(1) area. In vitro experiment, breviscapine (50 microg/l) protected cortical neuron from injury and decreased intracellular calcium overloading induced by H2O2 (10 mM). The results suggest that breviscapine has therapeutic effect on cerebral ischemia and vascular dementia.