ß-blockades and the risk of atrial fibrillation in patients with cardiovascular diseases.

Background: ß-blockers have been widely used in patients with extensive cardiovascular disease (CVD) and have provided benefits. However, they are more likely to cause symptomatic bradycardia, hypotension, or glucose metabolism disorders, which may lead to an increased risk of atrial fibrillation (AF), but evidence is lacking. Aims: This study was to analyze the association between the use of ß-blockers and the risk of developing AF. Methods: This nationwide, prospective cohort study utilized data from the 2013-2020 National Health and Nutrition Examination Survey (NHANES). The patients were stratified into a ß-blocker treatment group (n = 2585) and a non-ß-blocker treatment group (n = 8525). Univariate and multivariate logistic regression analyses were performed to identify the relationship between ß-blockades and the risk of AF. Propensity matching analysis was used to balance patient baseline characteristics and to control for confounders. Results: A total of 11,110 subjects were included in this study (mean [SD] age, 59.89 [15.07] years; 5657 [49.7%] males). A total of 111/2585 subjects developed AF in the ß-blocker treatment group, and 75/8525 developed AF in the non-ß-blocker treatment group (incidence rate, 4.2% vs. 0.8%). Compared with the non-ß-blocker group, the ß-blocker group had an increased risk of incident AF (aOR, 2.339; 95% CI, 1.614-3.410). Some sensitivity analyses also revealed consistent findings of increased AF risk associated with ß-blocker treatment. Conclusion: The findings from this study suggest that ß-blocker treatment is associated with an increased risk of incident AF and may help physicians select a modest medication for patients while also assessing the risk of AF.

Autophagy promotes membrane trafficking of NR2B to alleviate depression by inhibiting AQP4 expression in mice.

Depression is a high-incidence mental illness that seriously affects human health. AQP4 has been reported to be closely associated with depression, while the underlying mechanism is still unclear. This work aimed to investigate the functional role of AQP4 in depression. Depression mouse model was constructed by administration of chronic social defeat stress (CSDS). We found that AQP4 was highly expressed in the hippocampal tissues of CSDS mice. AQP4 knockdown alleviated depression and enhanced the expression of NR2B and PSD95 in CSDS mice. Moreover, primary hippocampal neurons were treated with N-methyl-d-aspartate (NMDA) to induce neuron injury. AQP4 overexpression repressed cell viability and promoted apoptosis of NMDA-treated primary hippocampal neurons. AQP4 up-regulation repressed the expression of NR2B (surface), and enhanced the expression of NR2B (intracellular), P-NR2B, CaMK II and CK2 in the NMDA-treated primary hippocampal neurons. The influence conferred by AQP4 up-regulation was abolished by KN-93 (CaMK II inhibitor) or TBB (CK2 inhibitor) treatment. Rapamycin treatment enhanced the expression of NR2B (surface), and repressed the expression of AQP4, NR2B (intracellular) and P-NR2B in the primary hippocampal neurons by activating autophagy. The activated autophagy alleviated depression in CSDS mice by repressing AQP4 expression. In conclusion, our data demonstrated that autophagy ameliorated depression by repressing AQP4 expression in mice, and AQP4 knockdown promoted membrane trafficking of NR2B and inhibited phosphorylation of NR2B via CaMK II/CK2 pathway. Thus, our work suggests that AQP4 may be a promising molecular target for the development of antidepressant drugs.

Association of Residential Proximity to the Coast With Incident Myocardial Infarction: A Prospective Cohort Study.

BACKGROUND: Little is known about how the residential distance to the coast is associated with incident myocardial infarction (MI) and which mechanisms may explain the association. We aim to explore this association using data from a prospective, population-based cohort with unprecedented sample size, and broad geographical coverage. METHODS: In this study, 377,340 participants from the UK Biobank were included. RESULTS: It was shown that 4,059 MI occurred during a median 8.0 years follow-up. Using group (<1 km) as reference, group (20-50 km) was associated with a lower risk of MI (hazard ratio, HR 0.79, 95% CI 0.64-0.98) and a U-shaped relation between distance to the coast and MI was shown with the low-risk interval between 32 and 64 km (p non-linear = 0.0012). Using participants of the intermediate region (32-64 km) as a reference, participants of the offshore region (<32 km) and inland region (>64 km) were both associated with a higher risk of incident MI (HR 1.12, 95% CI 1.04-1.21 and HR 1.09, 95% CI 1.01-1.18, respectively). HR for offshore region (<32 km) was larger in subgroup with low total physical activity (<24 h/week) (HR 1.24, 95% CI 1.09-1.42, p interaction = 0.043). HR for inland region (>64 km) was larger in subgroup in urban area (HR 1.12, 95% CI 1.03-1.22, p interaction = 0.065) and in subgroup of high nitrogen dioxide (NO2) air pollution (HR 1.29, 95% CI 1.11-1.50, p interaction = 0.021). CONCLUSION: We found a U-shaped association between residential distance to the coast and incident MI, and the association was modified by physical activity, population density, and air pollution.

Ultrasound-triggered microbubble destruction enhances the radiosensitivity of glioblastoma by inhibiting PGRMC1-mediated autophagy in vitro and in vivo.

BACKGROUND: Ultrasound-triggered microbubble destruction (UTMD) is a widely used noninvasive technology in both military and civilian medicine, which could enhance radiosensitivity of various tumors. However, little information is available regarding the effects of UTMD on radiotherapy for glioblastoma or the underlying mechanism. This study aimed to delineate the effect of UTMD on the radiosensitivity of glioblastoma and the potential involvement of autophagy. METHODS: GL261, U251 cells and orthotopic glioblastoma-bearing mice were treated with ionizing radiation (IR) or IR plus UTMD. Autophagy was observed by confocal microscopy and transmission electron microscopy. Western blotting and immunofluorescence analysis were used to detect progesterone receptor membrane component 1 (PGRMC1), light chain 3 beta 2 (LC3B2) and sequestosome 1 (SQSTM1/p62) levels. Lentiviral vectors or siRNAs transfection, and fluorescent probes staining were used to explore the underlying mechanism. RESULTS: UTMD enhanced the radiosensitivity of glioblastoma in vitro and in vivo (P < 0.01). UTMD inhibited autophagic flux by disrupting autophagosome-lysosome fusion without impairing lysosomal function or autophagosome synthesis in IR-treated glioblastoma cells. Suppression of autophagy by 3-methyladenine, bafilomycin A1 or ATG5 siRNA had no significant effect on UTMD-induced radiosensitization in glioblastoma cells (P < 0.05). Similar results were found when autophagy was induced by rapamycin or ATG5 overexpression (P > 0.05). Furthermore, UTMD inhibited PGRMC1 expression and binding with LC3B2 in IR-exposed glioblastoma cells (P < 0.01). PGRMC1 inhibitor AG-205 or PGRMC1 siRNA pretreatment enhanced UTMD-induced LC3B2 and p62 accumulation in IR-exposed glioblastoma cells, thereby promoting UTMD-mediated radiosensitization (P < 0.05). Moreover, PGRMC1 overexpression abolished UTMD-caused blockade of autophagic degradation, subsequently inhibiting UTMD-induced radiosensitization of glioblastoma cells. Finally, compared with IR plus UTMD group, PGRMC1 overexpression significantly increased tumor size [(3.8 ± 1.1) mm2 vs. (8.0 ± 1.9) mm2, P < 0.05] and decreased survival time [(67.2 ± 2.6) d vs. (40.0 ± 1.2) d, P = 0.0026] in glioblastoma-bearing mice. CONCLUSION: UTMD enhanced the radiosensitivity of glioblastoma partially by disrupting PGRMC1-mediated autophagy.

MicroRNA-155-5p Targets SKP2, Activates IKKß, Increases Aß Aggregation, and Aggravates a Mouse Alzheimer Disease Model.

The nuclear factor kappa B (NF-κB) pathway and inhibitor of NF-κB kinase ß (IKKß) are involved in Alzheimer disease (AD) pathogenesis. This study explored the mechanisms underlying IKKß-mediated Aß aggregation and neuron regeneration in APP.PS1 mice. Adenoviral transduction particles were injected into the hippocampal CA1 region of the mice to knock down or inhibit target genes. Morris water maze was performed to evaluate the cognitive function of the mice. Aß deposition was determined by histological examination. sh-IKKß plasmids and microRNA (miR)-155-5p inhibitor were transfected into Aß1-42-induced N2a cells. The expressions of AD-related proteins were detected by Western blot. The interaction between S-phase kinase-associated protein 2 (SKP2) and IKKß was assessed by co-immunoprecipitation. IKKß knockdown (KD) and miR-155-5p inhibition ameliorated cognitive impairment, improved neuron regeneration, and attenuated Aß deposition in APP/PS1 mice. SKP2 KD aggravated cognitive impairment, inhibited neuron regeneration, and promoted Aß deposition in the mice. SKP2 regulated the stability of IKKß protein via ubiquitination. MiR-155-5p regulates Aß deposition and the expression of Aß generation-related proteins in N2a cells via targeting SKP2. These results indicate that the miR-155-5p/SKP2/IKKß axis was critical for pathogenesis in this AD model and suggest the potential of miR-155-5p as a target for AD treatment.

Inhibitor Kappa B Kinase ß, Modulated by DJ-1/p-VHL, Reduces Phosphorylated Tau (p-Tau) Accumulation via Autophagy in Alzheimer's Disease Model.

It has been demonstrated Inhibitor Kappa B Kinase ß (IKKß) facilitates autophagy, which in turn mediates p-Tau protein clearance. However, the specific regulatory mechanism in Alzheimer's disease (AD) remains unclear. Firstly, AD model was generated by the intracerebroventricular (ICV) injection of the Β-amyloid 1-42 (Aß1-42) peptide. Subsequently, mice were injected with shRNA adenoviral transduction particles designed to target DJ-1 or Aß1-42 or Aß1-42 + shNC or Aß1-42 + shRNA against DJ-1. shRNA against DJ-1 were injected into hippocampus of mice (8 × 104 viral particles for each mice) for seven consecutive days. Immunohistochemistry was performed to detect the accumulation of Aß in the hippocampus of mice, and Hematoxylin-Eosin (HE) staining assay was carried to detect pathological changes in the hippocampus of mice. Further, sh-IKKß, shDJ-1, pcDNA-IKKß and pcDNA-DJ-1 plasmids were transfected into HT-22 cells, MTT assay, TUNEL staining and Hoechst staining were performed to detect cell viability and apoptosis, respectively. Western blotting was carried to measure the relative expression of proteins. Findings indicated that Aß1-42 inhibited autophagy and up-regulated p-Tau protein expression; Overexpression of IKKß and DJ-1 all rescued the autophagy inhibited by Aß1-42 and down-regulated p-Tau protein expression induced by Aß1-42; DJ-1 up-regulated IKKß via p-VHL, further promoted autophagy and reduced the expression of p-Tau protein; DJ-1 knockdown inhibited autophagy and up-regulated p-Tau protein expression, resulting in delayed behavior in mice. In conclusion, IKKß, modulated by DJ-1/p-VHL, reduces p-Tau accumulation via autophagy in AD's disease model. This study may provide theoretical basis for the treatment of AD.

Long non-coding RNA uc.80- overexpression promotes M2 polarization of microglias to ameliorate depression in rats.

Microglia polarization is associated with the pathogenesis of depression. A previous study shows that long non-coding RNA uc.80- is down-regulated in the hippocampus of depressed rats. Thus, this article aims to investigate the role of uc.80- in microglia polarization in depression. We first established depression model rats by chronic unpredictable mild stress (CUMS) regiment. We found that hippocampus of depressed rats exhibited an increase of M1 microglias and a decrease of M2 microglias. uc.80- was down-regulated in hippocampus of depressed rats. Furthermore, the detection of behaviouristics of depressed rats showed that uc.80- overexpression alleviated depression of rats. In addition, uc.80- overexpression promoted M2 polarization of microglias in vivo and in vitro. uc.80- overexpression led to a decrease in apoptosis of hippocampal neurons in vivo and in vitro. In conclusion, our study confirms that lncRNA uc.80- overexpression ameliorates depression in rats by promoting M2 polarization of microglias. Thus, our work suggests that uc.80- may be a target gene for depression treatment.

Cystathionine-ß-synthase-derived hydrogen sulfide is required for amygdalar long-term potentiation and cued fear memory in rats.

Hydrogen sulfide (H2S) is an endogenous gaseous molecule that functions as a neuromodulator in the brain. We previously reported that H2S regulated amygdalar synaptic plasticity and cued fear memory in rats. However, whether endogenous H2S is required for amygdalar long-term potentiation (LTP) induction and cued fear memory formation remains unclear. Here, we show that cystathionine-ß-synthase (CBS), the predominant H2S-producing enzyme in the brain, was highly expressed in the amygdala of rats. Suppressing CBS activity by inhibitor prevented activity-triggered generation of H2S in the lateral amygdala (LA) region. Incubating brain slices with CBS inhibitor significantly prevented the induction of NMDA receptors (NMDARs)-dependent LTP in the thalamo-LA pathway, and intra-LA infusion of CBS inhibitor impaired cued fear memory in rats. Notably, treatment with H2S donor, but not CBS activator, significantly reversed the impairments of LTP and fear memory caused by CBS inhibition. Mechanismly, inhibition of CBS activity led to a reduction in NMDAR-mediated synaptic response in the thalamo-LA pathway, and treatment with H2S donor restored the function of NMDARs. Collectively, these results indicate that CBS-derived H2S is required for amygdalar synaptic plasticity and cued fear memory in rats, and the effects of endogenous H2S might involve the regulation of NMDAR function.

The flavonoid baicalein rescues synaptic plasticity and memory deficits in a mouse model of Alzheimer's disease.

Increasing evidence suggests that disruptions of synaptic functions correlate with the severity of cognitive deficit in Alzheimer's disease (AD). Our previous study demonstrated that baicalein enhances long-term potentiation (LTP) in acute rat hippocampal slices and improves hippocampus-dependent contextual fear conditioning in rats. Given that baicalein possess various biological activities, especially its effects on synaptic plasticity and cognitive function, we examined the effect of baicalein on synaptic function both in vitro and in vivo in AD model. The effect of baicalein on Aß42 oligomer impaired LTP was investigated by electrophysiological methods. Baicalein was administered orally via drinking water to the APP/PS1 mice and sex- and age-matched wild-type mice. Treatment started at 5 months of age and mice were assessed for cognition and AD-like pathology at 7-month-old. Cognition was analyzed by Morris water maze test, fear conditioning test, and novel object recognition test. Changes in hippocampal 12/15 Lipoxygenase (12/15LO) and glycogen synthase kinase 3ß (GSK3ß) activity, Aß production, tau phosphorylation, synaptic plasticity, and dendritic spine density were evaluated. Baicalein prevented Aß-induced impairments in hippocampal LTP through activation of serine threonine Kinase (Akt) phosphorylation. Long-term oral administration of baicalein inhibited 12/15LO and GSK3ß activity, reduced ß-secretase enzyme (BACE1), decreased the concentration of total Aß, and prevented phosphorylation of tau in APP/PS1 mice. Meanwhile, baicalein restored spine number, synaptic plasticity, and memory deficits. Our results strengthen the potential of the flavonoid baicalein as a novel and promising oral bioactive therapeutic agent that prevents memory deficits in AD.

D-Serine in the nucleus accumbens region modulates behavioral sensitization and extinction of conditioned place preference.

BACKGROUND: D-serine, the endogenous co-agonist of N-methyl-D-aspartate receptors (NMDARs), is considered to be essential for learning and memory. The aim of the current investigation was to systematically evaluate the role of D-serine on addiction behaviors considered to be mediated by the nucleus accumbens (NAc). METHODS: D-Serine concentration in the NAc was measured by high-performance liquid chromatography (HPLC). Cocaine-induced behavioral sensitization and conditioned place preference (CPP) models were used to evaluate the relation between changes in serine in the nucleus accumbens and cocaine-induced behavioral effects. The expression of serine racemase (SR), D-amino acid oxidase (DAAO), the cAMP response element-binding protein (CREB) and upstream kinases, and N-methyl-D-aspartate (NMDA) receptors subunits were analyzed by western blot. Long-term depression (LTD) in the NAc was investigated by electrophysiological methods. RESULTS: The NAc slices obtained from the behavioral sensitization rats presented significantly reduced D-serine concentrations, increased expression of DAAO, and down-regulated expression of SR in a dose-dependent manner. Furthermore, D-serine injections into the nucleus accumbens blocked the development of behavioral sensitization and caused extinction of CPP. The ERK-CREB-Fos pathway and the NMDA receptor NR2B subunits in the NAc were involved in the cocaine-induced behavioral sensitization. We also found that D-serine was essential for NMDAR-dependent LTD and D-serine-regulated LTD in a bell-shaped concentration-dependent manner. The disrupted NMDAR-dependent LTD in the NAc of cocaine-treated rats was reversed by D-serine. CONCLUSIONS: Our results provide evidence for a critical role of D-serine in synaptic plasticity relevant to cocaine addiction and indicate that D-serine may be an effective therapeutic agent for cocaine addiction.

Protective effect of lipid microspheres 1 on myocardial injury following elective percutaneous coronary intervention in patients with angina pectoris: a pilot study.

BACKGROUND: Prostaglandin E1 incorporated into lipid microspheres (lipo-PGE1) is effective in the treatment of peripheral vascular disorders and diabetic neuropathy. It is unknown whether it has protective effects in patients with angina pectoris undergoing percutaneous coronary intervention (PCI). OBJECTIVES: The goal of this pilot study was to investigate whether lipo-PGE1 has protective effects in patients with angina pectoris undergoing PCI. METHODS: A single-blinded, randomized controlled trial was conducted in 79 patients with stable or unstable angina pectoris. The control group received standard medical therapy, and the Lipo-PGE1 group (n = 40) received 20 µg/day of lipo-PGE1 intravenously, starting at least 48 h before PCI and continuing for 5 days. Cardiac troponin T (cTnT) and creatine kinase myocardial isoenzyme (CK-MB) were measured before lipo-PGE1 infusion and at 6, 12 and 24 h after PCI. RESULTS: The cTnT and CK-MB concentrations were lower in the lipo-PGE1 group than in the control group at 6 h (0.15 ± 0.33 vs. 0.43 ± 0.77; 2.87 ± 3.99 vs. 5.64 ± 6.27, respectively; P < 0.05), 12 h (0.20 ± 0.48 vs. 0.54 ± 0.85; 3.58 ± 5.22 vs. 7.45 ± 9.48; P <  0.05) and 24 h (0.18 ± 0.50 vs. 0.50 ± 0.75; 3.15 ± 4.50 vs. 6.16 ± 6.83; P < 0.05). The incidence of postprocedural myocardial injury, defined as an elevation of cTnT more than 0.1 ng/ml or CK-MB more than 5.0 ng/ml, was less in the PGE1 group than in the control group (30 vs. 54%; 13 vs. 31%, respectively; P < 0.05). Lipo-PGE1 was well tolerated and there were no serious adverse events or side-effects. CONCLUSIONS: Lipo-PGE1 treatment appears to reduce myocardial injury following elective PCI in angina patients.