TP53INP2 knockdown inhibits inflammatory response and apoptosis after spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a traumatic neurological disorder with limited therapeutic options. Tumor protein p53-inducible nuclear protein 2 (TP53INP2) is involved in the occurrence and development of various diseases, and it may play a role during SCI via affecting inflammation and neuronal apoptosis. This study investigated the associated roles and mechanisms of TP53INP2 in SCI. METHODS: Mouse and lipopolysaccharide (LPS)-induced SCI BV-2 cell models were constructed to explore the role of TP53INP2 in SCI and the associated mechanisms. Histopathological evaluation of spinal cord tissue was detected by hematoxylin and eosin staining. The Basso, Beattie, and Bresnahan score was used to measure the motor function of the mice, while the spinal cord water content was used to assess spinal cord edema. The expression of TP53INP2 was measured using RT-qPCR. In addition, inflammatory factors in the spinal cord tissue of SCI mice and LPS-treated BV-2 cells were measured using enzyme-linked immunosorbent assay. Apoptosis and related protein expression levels were detected by flow cytometry and western blot analysis, respectively. RESULTS: TP53INP2 levels increased in SCI mice and LPS-treated BV-2 cells. The results of in vivo and in vitro experiments showed that TP53INP2 knockdown inhibited the inflammatory response and neuronal apoptosis in mouse spinal cord tissue or LPS-induced BV-2 cells. CONCLUSIONS: After spinal cord injury, TP53INP2 was upregulated, and TP53INP2 knockdown inhibited the inflammatory response and apoptosis.

An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice.

Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.

Comparison of Delta Spinal Endoscopy and Bilateral Laminotomy for Short-term Patient Outcomes in Degenerative Lumbar Spinal Stenosis.

This prospective randomised controlled trial aimed to compare the clinical efficacy of Delta spinal endoscopy with bilateral laminotomy for degenerative lumbar spinal stenosis (DLSS). Eighty patients with DLSS were randomly assigned to two groups: 40 treatments by Delta spinal endoscopy named (A) and 40 treatments by bilateral laminotomy named (A). Patients were followed up for one year. The incision length, intraoperative bleeding, and hospitalisation time were lower in group A than in B (p <0.01); however, the operation time in group B was lower than in A (p <0.05). The VAS and ODI in both groups improved significantly after surgery, compared with the results before the surgery. The VAS and ODI in group A after surgery were lower than in B, but only for one week after the surgery, (p <0.05). The excellent rate of modified MacNab criteria was not statistically significant between groups A and B (p >0.05). Overall, Delta spinal endoscopy can effectively manage DLSS with faster patient recovery. Key Words: Delta spinal endoscopy, Spinal stenosis, Minimally invasive, Bilateral laminotomy.

Short-Term Patient Outcomes Using the Interlaminar Endoscopic Surgical System Ilessys® Delta System versus Bilateral Laminotomy: A Single-Center Study of 80 Patients with Degenerative Lumbar Spinal Stenosis.

BACKGROUND This study from a single center aimed to compare short-term patient outcomes from the Interlaminar Endoscopic Surgical System iLESSYS® Delta system vs bilateral laminotomy in 80 patients with degenerative lumbar spinal stenosis (DLSS). MATERIAL AND METHODS We selected 80 patients with DLSS for the study. Of these, 40 were treated with the iLESSYS® Delta system and 40 were treated with bilateral laminotomy. We followed these patients for 1 year. We recorded and compared data on incision length, operation time and intraoperative blood loss, hospitalization time, postoperative complications, the visual analog scale (VAS), and Oswestry Disability Index (ODI) before, 1 week, 3 months, 6 months, and 12 months after surgery, and the Modified Macnab evaluation criteria. RESULTS The incision length, intraoperative blood loss, and hospitalization time were significantly better in group A than in group B (P<0.05); however, the operation time in group B was shorter than that in group A, and the differences were statistically significant (P<0.05). The VAS and ODI in both groups improved significantly after surgery compared with before the operation. The VAS and ODI in group A patients after surgery were lower than those in group B, and only at 1 week after surgery,(P<0.05). The excellent rate of modified MacNab criteria was not statistically significant between groups A and B (P>0.05). CONCLUSIONS Use of the Interlaminar Endoscopic Surgical System iLESSYS® Delta system can effectively manage DLSS and speed patient recovery.

LncRNA KCNQ1OT1 promotes the apoptosis and inflammatory response of microglia by regulating the miR-589-5p/NPTN axis after spinal cord injury.

Spinal cord injury (SCI) is a devastating traumatic condition accompanied with excessive inflammatory response and apoptosis of microglia. Long noncoding RNAs (lncRNAs) have been confirmed to be key regulators of cell inflammatory response. Nevertheless, the role of lncRNA KCNQ1OT1 in microglia apoptosis or inflammatory response after SCI remains to be explored. Our study focused on exploring the role and mechanism of KCNQ1OT1 in microglia after SCI. RT-qPCR showed that SCI induced the increase of KCNQ1OT1 level in mice spinal cord. Inhibition of KCNQ1OT1 suppressed the inflammatory response and apoptosis of microglia. In addition, KCNQ1OT1 was proved to bind with miR-589-5p, and NPTN was directly targeted by miR-589-5p. Furthermore, KCNQ1OT1 was negatively correlated with miR-589-5p and positively associated with NPTN. Rescue assays indicated that NPTN overexpression reversed the anti-inflammatory and anti-apoptosis effects of KCNQ1OT1 silencing. In summary, these data revealed that KCNQ1OT1 promoted inflammatory response and apoptosis of microglia by regulating the miR-589-5p/NPTN axis after SCI, which may offer a novel promising therapeutic target for SCI.

Comparison Between PE-TLIF and MIS-TLIF in the Treatment of Middle-Aged and Elderly Patients with Single-Level Lumbar Disc Herniation.

Objective: To evaluate the early clinical effect of percutaneous endoscopic transforaminal lumbar interbody fusion (PE-TLIF) and minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) surgery in the treatment of middle-aged and elderly patients with single-level lumbar disc herniation accompanied by lumbar instability. Methods: From January 2019 to June 2020, a total of 82 consecutive patients were categorised into PE-TLIF group and MIS-TLIF group based on different surgical methods. The visual analog scale (VAS), Oswestry disability index (ODI), Japanese Orthopaedic Association (JOA) score, perioperative objective serological index, operation time, intraoperative blood loss, time to back to work or normal life, and Modified MacNab score were used as the evaluation indexes. The differences between the two groups were analyzed and the clinical effects were compared. Results: The VAS back pain of PE-TLIF group was decreased compared to that of MIS-TLIF group in the postoperative 1 week and 1 month. The operative time in PE-TLIF group was obviously longer than that in MIS-TLIF group. The hospital stay was significantly shorter in PE-TLIF group than that in MIS-TLIF group. More intraoperative blood loss and postoperative drainage were recorded in MIS-TLIF group. Compared with MIS-TLIF, PE-TLIF surgery was associated with a shorter time to ambulation after surgery and a shorter time to back to work or normal life. Significant statistical differences were observed in IL-6, CRP, and CK on postoperative 3 days between the two groups. Conclusion: For middle-aged and elderly patients, PE-TLIF and MIS-TLIF surgery both have obvious clinical efficacy and safety. However, with less intraoperative blood loss, shorter recovery time and less injury to the patients, people undergoing PE-TLIF surgery can return to work or normal life faster. It is speculated that PE-TLIF has a higher incidence of complications and recurrence rate than that MIS-TLIF. PE-TLIF may be a better choice for middle-aged and elderly patients with single-level lumbar disc herniation.

Endo-TLIF versus MIS-TLIF in 1-segment lumbar spondylolisthesis: A prospective randomized pilot study.

OBJECTIVE: To evaluate the curative efficacy by comparing perioperative characteristics and 1.5-year observational outcomes in 1-segment lumbar spondylolisthesis between traditional minimally invasive transforaminal lumbar interbody fusion (MIS-TLIF) and optimized Endoscopic TLIF techniques. METHODS: The study was a single-center, randomized controlled trial comparing two different treatment approaches for 1-segment lumbar spondylolisthesis. 102 patients treated by MIS-TLIF (48 cases) or Endo-TLIF (54 cases) were included from March 2018 to April 2019. Perioperative parameters and clinical outcomes were evaluated. Degree of slip were measured, and fusion rates were determined at 18 months after surgery. RESULTS: The Endo-TLIF group had similar return to work time and rate. Blood loss, left bed time, analgesic ratio were significantly less in Endo-TLIF group. The Endo-TLIF group had a significantly longer operative time. Significant postoperative reduction in %slip was showed in both groups. The VAS and ODI improved significantly in both groups after surgery. Significant decreases in low-back pain in Endo-TLIF group were found at postoperative day 1 and 3 months. The fusion rate in the two groups was similar. CONCLUSION: Endo-TLIF surgery with a C-shaped working tube and a visualization system may be regarded as an efficient alternative surgery for 1-segment lumbar spondylolisthesis. It is a safe and minimally invasive way to perform this surgery and has shown satisfactory clinical outcomes. TRIAL REGISTRATION: ChiCTR1800015197, 13 March 2018. TRIAL REGISTRY: Chinese Clinical Trial Registry. Registered 13 March 2018. http://www.chictr.org.cn/showproj.aspx?proj=25865.

Effect of Smoking on Lung Function Decline in a Retrospective Study of a Health Examination Population in Chinese Males.

Objective: China has established a goal of reducing adult smoking prevalence from 27.7% to 20% by 2030. Understanding the possible ongoing impairment in lung function in smokers, is critically important to encourage the populations to change their smoking behavior. Methods: A total of 14,273 males joined the health examination at Huadong Sanatorium from Jan 2012 to Dec 2019 were included. In cross-sectional analysis, we used multiple linear regression to evaluate the association between baseline lung function and smoking status. Then, 3,558 males who received ≥2 spirometry exams were analyzed in longitudinal study. Annual lung function decline was compared using mixed linear models adjusted for confounders. Results: In cross-sectional analysis, compared with never-smokers, decreases of -133.56 mL (95% CI: -167.27, -99.85) and -51.44 mL (-69.62, -33.26) in FEV1, -1.48% (-1.94, -1.02) and -1.29% (-1.53, -1.04) in FEV1/FVC were observed in former and current smokers. In longitudinal analysis, significant declines were observed in FEV1 [5.04 (2.30, 7.78) mL] and FEV1/FVC [0.09 (0.05, 0.13) %] in current smokers but not observed in former smokers after adjustment. Participants with long duration of smoking cessation had decelerate lung function than short duration. The annual decline rate of current smokers with high smoking intensity (≥30 cigarettes per day) was 13.80 and 14.17 times greater than that of never-smokers in FEV1 and FVC. Thus, early smoking cessation can slow down lung function decline trend for current smokers. Conclusions: The harms of current smoking on lung function emphasize the necessity of smoking cessation, especially for those with comorbidities.

Correction: Feng et al. Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway. Int. J. Mol. Sci. 2020, 21, 4655.

The authors wish to make the following corrections to this paper [...].

Microendoscopic Discectomy Combined with Annular Suture Versus Percutaneous Transforaminal Endoscopic Discectomy for Lumbar Disc Herniation: A Prospective Observational Study.

BACKGROUND: Microendoscopic discectomy (MED) and percutaneous transforaminal endoscopic discectomy (PTED) are 2 of the most popular minimally invasive spinal surgery techniques. We are investigating whether minimally invasive early annular closure can achieve a better clinical effect in the treatment of lumbar disc herniation (LDH). OBJECTIVE: To compare the clinical and imaging outcomes between MED combined with annular suture and PTED in the treatment of LDH. STUDY DESIGN: A prospective observational study with follow-up of 36 months. SETTING: The First People's Hospital of Lianyungang in China. METHODS: A total of 135 prospective consecutive patients underwent MED + annular suture or PTED. Patients were assessed postoperatively at 3 days and 3, 6, 12, 24, and 36 months. The outcome measures were visual analog scales for back pain (VAS-back) and leg pain (VAS-leg) scores, the Oswestry Disability Index (ODI) score, the Medical Outcomes Study 36-Item Short-Form Health Survey bodily pain (SF36-BP), and physical function (SF36-PF) scales, disc height, and recurrence rate. RESULTS: One hundred and six patients have completed the 3-year follow-up. The operation time and length of stay in the MED + annular suture group were longer than that in the PTED group (P < 0.001 and P < 0.001). VAS-back score, VAS-leg score, ODI score, SF36-BP, and SF36-PF significantly improved at follow-up time points after surgery compared to before surgery, but no significant differences were found at postoperative and 36 months between the groups. The disc height in the MED + annular suture group was significantly greater than that in the PTED group after 3 months. Within 36-month follow-up, imaging re-herniation was reported in 4 patients in the MED + annular suture group, and 9 patients in the PTED group (P = 0.170). Symptomatic re-herniation occurred in one patient in the MED + annular suture group and in 4 patients in the PTED group (P = 0.190). LIMITATIONS: First, this was not a randomized controlled trail, which could provide more evidence-based conclusions. Second, we did not accurately measure and compare the amount of nucleus pulposus removed, although less nucleus pulposus was removed in MED + annular suture. CONCLUSION: PTED has the advantages of shorter length of incision, shorter operation time, and shorter length of stay. MED + annular suture is associated with greater preservation of disc height, and showed certain advantages of lower recurrence rate, although there was no statistical difference.

Nicotinamide Phosphoribosyltransferase (Nampt)/Nicotinamide Adenine Dinucleotide (NAD) Axis Suppresses Atrial Fibrillation by Modulating the Calcium Handling Pathway.

Aging and obesity are the most prominent risk factors for onset of atrial fibrillation (AF). Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme that catalyzes nicotinamide adenine dinucleotide (NAD) activity. Nampt and NAD are essential for maintenance of cellular redox homeostasis and modulation of cellular metabolism, and their expression levels decrease with aging and obesity. However, a role for Nampt in AF is unknown. The present study aims to test whether there is a role of Nampt/NAD axis in the pathogenesis of obesity-induced AF. Male C57BL/6J (WT) mice and heterozygous Nampt knockout (NKO) mice were fed with a normal chow diet (ND) or a high-fat diet (HFD). Electrophysiological study showed that AF inducibility was significantly increased in WT+HFD, NKO+ND, and NKO+HFD mice compared with WT+ND mice. AF duration was significantly longer in WT+HFD and NKO+ND mice and further prolonged in NKO+HFD mice compared with WT+ND mice and the calcium handling pathway was altered on molecular level. Also, treatment with nicotinamide riboside, a NAD precursor, partially restored the HFD-induced AF perpetuation. Overall, this work demonstrates that partially deletion of Nampt facilitated HFD-induced AF through increased diastolic calcium leaks. The Nampt/NAD axis may be a potent therapeutic target for AF.

Anterior reduction and fusion for acute unilateral cervical facet dislocation without severe spinal cord injuries.

PURPOSE: This study aimed to evaluate safety and effectiveness of simple anterior reduction and fusion for acute lower cervical unilateral facet dislocation without severe spinal cord injuries. MATERIALS AND METHODS: One hundred and two patients with unilateral cervical facet dislocations without severe spinal cord injuries who were surgically treated by the only anterior approach were analyzed. The treatment effects were evaluated based on the Visual Analogue Scale (VAS) scores, the Cobb angle of kyphosis, the Neck Disability Index (NDI) and Odom's criteria. Neurological recovery of patients was assessed by the Frankel grading. RESULTS: The mean duration of follow-up was 12.4 ± 4.2 years (range, 10 to 17 years). VAS scores, Kyphosis angle and NDI scores were significantly changed from preoperative values of 7.4 ± 0.8, 11.3° ± 6.8° and 29.3 ± 5.1 to last follow-up values of 1.3 ± 0.8, -6.1° ± 7.5° and 8.8 ± 3.6 (P = 0.000). Of patients, 92 (90.2%) had good to excellent outcomes, 9 (8.8%) had satisfactory outcomes, and 1 (1.0%) had poor outcomes. Patients have obtained satisfactory neurological recovery. Three patients needed additional posterior reduction. CONCLUSION: The anterior reduction and fusion is effective and safe for acute unilateral cervical facet dislocation, and can achieve good long-term clinical effects.

Comparison of anterior and posterior approaches for treatment of traumatic cervical dislocation combined with spinal cord injury: Minimum 10-year follow-up.

Anterior reduction and interbody fusion fixation has not been compared directly with posterior reduction and short-segmental pedicle screw fixation for lower cervical dislocation, and so consensus is lacking as to which is the optimal method. The purpose of this paper is to compare long-term outcomes of the anterior versus posterior approach for traumatic cervical dislocation with spinal cord injury. One hundred and fifty-nine patients could be followed for more than 10 years (follow-up rate 84.1%). Ninety-two patients underwent anterior reduction and interbody fusion and fixation, and 67 patients underwent posterior reduction and short-segmental pedicle screw fixation. Japanese Orthopaedic Association (JOA) scores, the Neck Disability Index (NDI), the American Spinal Injury Association grading (ASIA), Odom's criteria, cervical kyphosis, operative parameters, and surgical or post-operative complications were evaluated. Patients were followed for 10 to 17 years. There was no significant difference in main JOA scores, NDI scores or ASIA scores between the two groups at follow-up. The posterior approach was associated with greater loss of alignment by two years (P = 0.012) and at final follow-up (P < 0.001). The posterior approach group had more blood loss (P < 0.001), longer operation times (P < 0.001), longer hospital stays (P < 0.001) and fewer complications than the anterior approach group. The anterior approach is better than the posterior approach for preserving cervical lordosis, which is associated with a better long-term effect.

MicroRNA­138­5p regulates the development of spinal cord injury by targeting SIRT1.

MicroRNAs (miRs) play an important role in the development and progression of spinal cord injury (SCI). The role of miR­138­5p in SCI was investigated in the present study. The anti­inflammatory effects of miR­138­5p and underlying mechanisms were investigated in an SCI rat model and in vitro model. Reverse transcription­quantitative PCR (RT­qPCR) was used to examine the expression of miR­138­5p in the SCI in vivo and in vitro models, as well as patients with SCI; it was found that miR­138­5p was significantly upregulated in SCI. Bioinformatics and dual­luciferase reporter assays were performed to predict and confirm the binding sites between miR­138­5p and the 3'untranslated region of sirtuin 1 (SIRT1). Then, the expression of SIRT1 was detected via RT­qPCR and western blotting, indicating downregulation of SIRT1 in SCI. PC12 cells were transfected with miR­138­5p inhibitor, inhibitor control or miR­138­5p inhibitor + SIRT1 small interfering RNA for 48 h, and then subjected to lipopolysaccharide (100 ng/ml) treatment for 4 h. Then, MTT assay, flow cytometry and ELISA experiments were performed to analyze cell viability, apoptosis, and the levels of tumor necrosis factor­α, interleukin (IL)­1ß and IL­6. Findings suggested that downregulation of miR­138­5p increased PC12 cell viability, inhibited cell apoptosis and attenuated proinflammatory responses, which may result in amelioration of SCI. However, all these effects were reversed by SIRT1 knockdown. Finally, it was observed that miR­138­5p altered the related protein expression of the PTEN/AKT pathway. These results indicated that miR­138­5p could regulate inflammatory responses and cell apoptosis in SCI models by modulating the PTEN/AKT signaling pathway via SIRT1, thus playing an important role in the development of SCI. Collectively, the present study demonstrated that miR­138­5p may be a novel therapeutic target for the treatment of SCI.

Knockdown of long noncoding RNA XIST mitigates the apoptosis and inflammatory injury of microglia cells after spinal cord injury through miR-27a/Smurf1 axis.

Spinal cord injury (SCI) is a devastating neuropathological condition. Long noncoding RNA X-inactive specific transcript (XIST) is an acknowledged cancer-related gene and participates in the development of SCI. However, role of XIST in SCI remains to be well revealed. Expression of XIST, miRNA-27a-3p (miR-27a) and smad ubiquitination regulatory factor 1 (Smurf1) was detected using RT-qPCR and western blotting. Cell apoptosis and inflammatory injury were assessed by sulforhodamine B (SRB) assay, flow cytometry, western blotting and enzyme-linked immunosorbent assay. The relationship among miR-27a, XIST and Smurf1 was confirmed by dual-luciferase reporter assay, RNA immunoprecipitation and RNA pull-down assay. As a result, we observed higher level of XIST and Smurf1, but lower level of miR-27a in SCI rats and lipopolysaccharide (LPS)-induced primary microglial cells. in vitro, LPS induced SCI microglia cells as described by decreased cell viability and B cell lymphoma 2 (Bcl-2) expression, and increased cell apoptosis rate, Bax and cleaved caspase 3 levels, and tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) secretions. in vivo, a T10 laminectomy caused SCI rats as evidenced by decreased Basso-Beattie-Bresnahan Locomotor Rating Scale (BBB) score and induced expression of Bax, cleaved caspase 3, TNF-α and IL-6. However, silencing of XIST could mitigate the apoptosis and inflammatory injury in LPS-induced microglia and SCI rats. Mechanically, miR-27a interacted with XIST and Smurf1 via target binding. Either miR-27a downregulation or Smurf1 overexpression partially reversed the role of XIST deletion in LPS-treated microglial cells. Collectively, knockdown of XIST could alleviate the apoptosis and inflammatory injury of SCI models in vitro and in vivo through directly modulating miR-27a/Smurf1 axis.

Exercise training reduces ventricular arrhythmias through restoring calcium handling and sympathetic tone in myocardial infarction mice.

Exercise can improve morbidity and mortality in heart failure patients; however, the underlying mechanisms remain to be fully investigated. Thus, we investigated the effects of exercise on cardiac function and ventricular arrhythmias in myocardial infarction (MI) induced heart failure mice. Wild-type male mice underwent sham-operation or permanent left coronary artery ligation to induce MI. MI mice were divided into a sedentary (MI-Sed) and two intervention groups: MI-Ex (underwent 6-week treadmill exercise training) and MI-ßb (oral bisoprolol treatment (1 mg/kg/d) without exercise). Cardiac function and structure were assessed by echocardiography and histology. Exercise capacity and cardiopulmonary function was accepted as oxygen consumption at peak exercise (peak VO2 ). Autonomic nervous system function and the incidence of spontaneous ventricular arrhythmia were evaluated via telemetry recording. mRNA and protein expressions in the left ventricle (LV) were investigated by real-time PCR and Western blotting. There were no differences in survival rate, MI size, cardiac function and structure, while exercise training improved peak VO2 . Compared with MI-Sed, MI-Ex, and MI-ßb showed decreased sympathetic tone and lower incidence of spontaneous ventricular arrhythmia. By Western blot, the hyperphosphorylation of CaMKII and RyR2 were restored by exercise and ß-blocker treatment. Furthermore, elevated expression of miR-1 and decreased expression of its target protein PP2A were recovered by exercise and ß-blocker treatment. Continuous intensive exercise training can suppress ventricular arrhythmias in subacute to chronic phase of MI through restoring autonomic imbalance and impaired calcium handling, similarly to that for ß-blockers.

Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function.

Insomnia is one of the most common sleep problems with an estimated prevalence of 10%-15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. In the present study, we found that 3,4-difluoro-2-((2-fluoro-4-iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild-type male mice after intraperitoneal administration, whereas the SWS-inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep.

Clinical significance of respiratory compensation during exercise testing in cardiac patients.

Ventilation (VE) increases linearly with the increase of carbon dioxide output (VCO2) during cardiopulmonary exercise testing. VE-VCO2 slope rises in parallel with exercise intensity, reaches a turning point (called the RC point), then steepens because of respiratory compensation for lactic acidosis. While this RC point can be identified universally, it is undetectable in some patients. In this study we evaluated whether the respiratory compensation during exercise testing has clinical significance in cardiac patients. In total, 152 cardiac patients with a respiratory exchange ratio at peak exercise (peak R) of between 1.10 and 1.20 were enrolled. Cardiopulmonary parameters were compared between patients who manifested the RC point (n = 118) and those who did not (n = 34). The peak R did not significantly differ between these two groups. Compared to the patients without the RC point, those with the RC point had a higher oxygen uptake at peak exercise (peak VO2) (20.2 ± 5.3 vs 13.6 ± 3.4 mL/min/kg, p < 0.001), higher anaerobic threshold (AT) (12.4 ± 3.2 vs 9.2 ± 2.3 mL/min/kg, p < 0.001), and lower VE-VCO2 slope (31.7 ± 5.8 vs 37.8 ± 9.6, p = 0.001). Brain natriuretic peptide (BNP) tended to be lower in the patients with the RC point (175.4 ± 364.7 vs 327.9 ± 381.1 pg/mL, p = 0.067). Peak VO2, the marker of cardiopulmonary function, was found to be the independent predictor of the presence of the RC point. The present findings suggest that the phenomenon of respiratory compensation during heavy exercise indicates better cardiopulmonary function in cardiac patients within a prescribed range of effort.

Vaccaria hypaphorine impairs RANKL-induced osteoclastogenesis by inhibition of ERK, p38, JNK and NF-κB pathway and prevents inflammatory bone loss in mice.

Osteoclasts are sole bone-resorbing cells which exert a profound effect on skeletal metabolism. The search for medicines that affect the differentiation and function of osteoclasts is crucial in developing therapies for osteoclast-based diseases. Vaccaria hypaphorine, the main active compound of the traditionally used Chinese herb Vaccaria segetalis, has anti-inflammatory activity. The present study demonstrated for the first time that vaccaria hypaphorine could significantly inhibit the receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastic differentiation in vitro and alleviate lipopolysaccharide (LPS)-induced bone loss in vivo. Further study showed that vaccaria hypaphorine decreased osteoclastogenesis in a dose-dependent manner. Furthermore, vaccaria hypaphorine was confirmed to inhibit osteoclasts differentiation at early stage but not at later stage. Pit formation assay and F-actin ring staining showed that vaccaria hypaphorine inhibited the bone-resorbing activity of osteoclasts. Mechanistically, vaccaria hypaphorine impaired RANKL-induced osteoclastogenesis through reduction of extracellular signal-regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and NF-κB p65 phosphorylation. Taken together, our results provided evidences that vaccaria hypaphorine might be considered as potential therapeutic agent for treating osteoclast-based bone loss.