Sleep fragmentation exacerbates myocardial ischemia‒reperfusion injury by promoting copper overload in cardiomyocytes.

Sleep disorders increase the risk and mortality of heart disease, but the brain-heart interaction has not yet been fully elucidated. Cuproptosis is a copper-dependent type of cell death activated by the excessive accumulation of intracellular copper. Here, we showed that 16 weeks of sleep fragmentation (SF) resulted in elevated copper levels in the male mouse heart and exacerbated myocardial ischemia-reperfusion injury with increased myocardial cuproptosis and apoptosis. Mechanistically, we found that SF promotes sympathetic overactivity, increases the germination of myocardial sympathetic nerve terminals, and increases the level of norepinephrine in cardiac tissue, thereby inhibits VPS35 expression and leads to impaired ATP7A related copper transport and copper overload in cardiomyocytes. Copper overload further leads to exacerbated cuproptosis and apoptosis, and these effects can be rescued by excision of the sympathetic nerve or administration of copper chelating agent. Our study elucidates one of the molecular mechanisms by which sleep disorders aggravate myocardial injury and suggests possible targets for intervention.

M-type pyruvate kinase 2 (PKM2) tetramerization alleviates the progression of right ventricle failure by regulating oxidative stress and mitochondrial dynamics.

BACKGROUND: Right ventricle failure (RVF) is a progressive heart disease that has yet to be fully understood at the molecular level. Elevated M-type pyruvate kinase 2 (PKM2) tetramerization alleviates heart failure, but detailed molecular mechanisms remain unclear. OBJECTIVE: We observed changes in PKM2 tetramerization levels during the progression of right heart failure and in vitro cardiomyocyte hypertrophy and explored the causal relationship between altered PKM2 tetramerization and the imbalance of redox homeostasis in cardiomyocytes, as well as its underlying mechanisms. Ultimately, our goal was to propose rational intervention strategies for the treatment of RVF. METHOD: We established RVF in Sprague Dawley (SD) rats by intraperitoneal injection of monocrotaline (MCT). The pulmonary artery pressure and right heart function of rats were assessed using transthoracic echocardiography combined with right heart catheterization. TEPP-46 was used both in vivo and in vitro to promote PKM2 tetramerization. RESULTS: We observed that oxidative stress and mitochondrial disorganization were associated with increased apoptosis in the right ventricular tissue of RVF rats. Quantitative proteomics revealed that PKM2 was upregulated during RVF and negatively correlated with the cardiac function. Facilitating PKM2 tetramerization promoted mitochondrial network formation and alleviated oxidative stress and apoptosis during cardiomyocyte hypertrophy. Moreover, enhancing PKM2 tetramer formation improved cardiac mitochondrial morphology, mitigated oxidative stress and alleviated heart failure. CONCLUSION: Disruption of PKM2 tetramerization contributed to RVF by inducing mitochondrial fragmentation, accumulating ROS, and finally promoted the progression of cardiomyocyte apoptosis. Facilitating PKM2 tetramerization holds potential as a promising therapeutic approach for RVF.

Identification of the key immune-related genes and immune cell infiltration changes in renal interstitial fibrosis.

Background: Chronic kidney disease (CKD) is the third-leading cause of premature mortality worldwide. It is characterized by rapid deterioration due to renal interstitial fibrosis (RIF) via excessive inflammatory infiltration. The aim of this study was to discover key immune-related genes (IRGs) to provide valuable insights and therapeutic targets for RIF in CKD. Materials and methods: We screened differentially expressed genes (DEGs) between RIF samples from CKD patients and healthy controls from a public database. Least absolute shrinkage and selection operator regression analysis and receiver operating characteristic curve analysis were applied to identify significant key biomarkers. The single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm was used to analyze the infiltration of immune cells between the RIF and control samples. The correlation between biomarkers and immune cell composition was assessed. Results: A total of 928 DEGs between CKD and control samples from six microarray datasets were found, 17 overlapping immune-correlated DEGs were identified by integration with the ImmPort database, and six IRGs were finally identified in the model: apolipoprotein H (APOH), epidermal growth factor (EGF), lactotransferrin (LTF), lysozyme (LYZ), phospholipid transfer protein (PLTP), and secretory leukocyte peptidase inhibitor (SLPI). Two additional datasets and in vivo experiments indicated that the expression levels of APOH and EGF in the fibrosis group were significantly lower than those in the control group, while the expression levels of LTF, LYZ, PLTP, and SLPI were higher (all P < 0.05). These IRGs also showed a significant correlation with renal function impairment. Moreover, four upregulated IRGs were positively associated with various T cell populations, which were enriched in RIF tissues, whereas two downregulated IRGs had opposite results. Several signaling pathways, such as the "T cell receptor signaling pathway" and "positive regulation of NF-κB signaling pathway", were discovered to be associated not only with immune cell infiltration, but also with the expression levels of six IRGs. Conclusion: In summary, six IRGs were identified as key biomarkers for RIF, and exhibited a strong correlation with various T cells and with the NF-κB signaling pathway. All these IRGs and their signaling pathways may evolve as valuable therapeutic targets for RIF in CKD.

Dexmedetomidine exerts an anti-inflammatory effect via α2 adrenoceptors to alleviate cognitive dysfunction in 5xFAD mice.

Background: Inflammation promotes the progression of Alzheimer's disease (AD). In this study, we explored the effect of dexmedetomidine on inflammation and cognitive function in a mouse model of AD. Methods: 5xFAD mice were intragastrically administered saline, dexmedetomidine, or dexmedetomidine and yohimbine for 14 days. The effects of dexmedetomidine on the acquisition and retention of memory in the Morris water-maze test and Y maze were evaluated. The deposition of amyloid beta protein (Abeta) and cytokine levels in the hippocampus were assessed. The expression of Bace1 protein and NFκB-p65 protein was assessed by Western blotting. Results: Compared with WT mice, 5xFAD mice exhibited cognitive impairment in the Morris water maze test and Y maze test. Cognitive decline was alleviated by dexmedetomidine and this was reversed by the α2 adrenoceptor antagonist yohimbine. Compared with saline treatment, dexmedetomidine led to a reduction in the Abeta deposition area (p < 0.05) and in the mean gray value (p < 0.01) in the hippocampus of 5xFAD mice. Compared with saline treatment, dexmedetomidine inhibited the activation of astrocytes and microglia in the hippocampal DG of 5xFAD mice and reduced the area of GFAP (p < 0.01) and IBA1 (p < 0.01). The level of IL-1ß in the hippocampus decreased significantly after dexmedetomidine treatment compared with saline treatment in 5xFAD mice (p < 0.01). Yohimbine neutralized the effects of dexmedetomidine. Dexmedetomidine inhibited the expression of BACE1 and NF-κB p65 (p < 0.01), and these changes were reversed by yohimbine treatment. Conclusion: Dexmedetomidine alleviates cognitive decline, inhibits neuroinflammation, and prevents the deposition of Abeta in 5xFAD mice. The effect is mediated by the α2 adrenoceptor-mediated anti-inflammatory pathway. Dexmedetomidine may be effective for the treatment of AD and a better choice for the sedation of AD.

Novel benzodiazepine remimazolam tosylate delays neurodegeneration of aged mice via decreasing tau phosphorylation.

Benzodiazepines like midazolam were generally considered one of the possible causes affecting postoperative cognitive recovery. As a new kind of rapid-effect benzodiazepine, remimazolam tosylate was widely used in clinical anesthesia for its pharmacological advantage, but few studies reported its effects on cognitive function in the elderly. Here, we aimed to research the effects of remimazolam tosylate on cognitive function in aged mice and its underlying biological mechanisms. We measured the memory function of aged mice immediately and one month after intraperitoneal injection of remimazolam tosylate compared to the saline control. The brain metabolism level was detected by Positron Emission Tomography/Computed tomography (PET/CT). Compared with the control, we observed a decrease in memory ability， as well as an increase in tau phosphorylation level and a decrease in phosphatase level in the short term; however, one month later, contrary to the previous results, we observed better memory and brain metabolism and lower tau phosphorylation levels in the experimental group compared to the control. Therefore, we concluded that remimazolam tosylate did not cause long-term damage to the cognitive function of aged mice and even delayed the decline of memory function in the aging process to some extent.

Acute sleep deprivation increases inflammation and aggravates heart failure after myocardial infarction.

Sleep disorders have been observed among patients with heart failure. The aim of this study was to investigate whether acute sleep deprivation (SD) aggravates left heart function. Male C57B/L6 mice were assigned to four experimental groups. Ligation of the left anterior descending branch (LAD) caused myocardial infarction (MI) in mice in the LAD group and the LAD+SD group, while mice in the sham and sham+SD groups underwent the same surgery without ligation. Echocardiography was performed before and 8 weeks after ligation of the LAD to evaluate the left ventricular internal diameter at diastole (LVIDd), left ventricular internal diameter at systole (LVIDs), ejection fraction (EF), and fractional shortening (FS). Seven days of sleep deprivation induced using the modified single platform method resulted in a lower EF and FS and a higher LVIDd and LVIDs, as well as increased expression of the IL-1ß, IL-18, and IL-10 mRNAs in the left ventricular tissue of MI mice. ELISA also indicated higher levels of IL-1ß and IL-10 in the LAD+SD group. It was concluded that acute sleep deprivation induced cardiovascular alterations in cardiac structure and function in HF mice, accompanied by increased levels of inflammatory cytokines.

Regulation of the Immune Microenvironment by an NLRP3 Inhibitor Contributes to Attenuation of Acute Right Ventricular Failure in Rats with Pulmonary Arterial Hypertension.

BACKGROUND: Right heart failure is the terminal stage of PAH. When PAH patients suffer from pulmonary infection or puerperal infection heart failure often rapidly develops. Low dose of lipopolysaccharide induces rapid right ventricular failure in rats with pulmonary arterial hypertension. PURPOSE: The objective of this study was to investigate whether the NLRP3 inflammasome mediates disturbance of the ventricular immune microenvironment of PAH rats and promotes right ventricular failure. METHODS: Intraperitoneal injection of monocrotaline was used to induce PAH in rats. Right ventricular function was measured via echocardiography before and after the rats were treated with lipopolysaccharide and MCC950. The degree of immune microenvironment disturbance in right ventricular tissue was measured with a rat chemokine and cytokine antibody array, Western blot, flow cytometry and quantitative real-time PCR analysis. RESULTS: After the rats were injected with LPS, they exhibited right ventricular dysfunction and a significant increase in right ventricular tissue inflammation with elevated M1 macrophage proportion. Administration of MCC950 suppressed inflammation and improved right ventricular function. The number of M1 macrophages was decreased after MCC950 treatment. NLRP3 inflammasome inhibition ameliorated LPS-induced changes in the immune microenvironment in the right heart and right ventricular dysfunction in rats with PAH. CONCLUSION: Selective inhibition of NLRP3 pathway interfered the interaction between hypertrophic cardiomyocytes and macrophages in the initial stage of inflammation and maintained the immune microenvironment balance, eventually contributing to attenuation of LPS-induced acute heart failure in PAH rats.

Silent Hypoxemia in Patients with COVID-19 Pneumonia: A Review.

During the coronavirus disease 2019 (COVID-19) pandemic due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, patients presented with COVID-19 pneumonia of varying severity. The phenomenon of severe hypoxemia without signs of respiratory distress is also known as silent or hidden hypoxemia. Although silent hypoxemia is not unique to pneumonia due to SARS-CoV-2 infection, this phenomenon is now recognized to be associated with severe COVID-19 pneumonia. Proper management of critically ill patients is the key to reducing mortality. Herein, we summarize the possible and rare factors contributing to silent hypoxemia in patients with COVID-19. Microvascular thrombosis causes dead space ventilation in the lungs, and the flow of pulmonary capillaries is reduced, which leads to an imbalance in the V/Q ratio. The dissociation curve of oxyhemoglobin shifts to the left and limits the release of oxygen to the tissue. SARS-CoV-2 interferes with the synthesis of hemoglobin and reduces the ability to carry oxygen. The accumulation of endogenous carbon monoxide and carboxyhemoglobin will reduce the total oxygen carrying capacity and interfere with pulse oxygen saturation readings. There are also some non-specific factors that cause the difference between pulse oximetry and oxygen partial pressure. We propose some potentially more effective clinical alternatives and recommendations for optimizing the clinical management processes of patients with COVID-19. This review aims to describe the prevalence of silent hypoxemia in COVID-19 pneumonia, to provide an update on what is known of the pathophysiology, and to highlight the importance of diagnosing silent hypoxemia in patients with COVID-19 pneumonia.

A network meta-analysis of the long- and short-term efficacy of sleep medicines in adults and older adults.

BACKGROUND: This study focuses on seven commonly used hypnotics to comprehensively analyze the effects of long- and short-term use on sleep outcomes among adults and older adults. METHODS: A network meta-analysis was performed. The insomnia medications were classified into seven categories: benzodiazepines, z-drugs, melatonin, H1-antagonists, orexin receptor antagonists (ORAs), antidepressants, and anticonvulsants. We compared their efficacy of total sleep time, sleep latency, sleep efficiency and wake after sleep onset in subgroups short-term, long-term, elderly, and adults. RESULTS: A total of 111 RCTs involving 25,923 participants were included in this study. CONCLUSIONS: ORAs can be widely used in adults and the elderly, and both short-term and long-term use are effective for primary insomnia. H1-antagonists are more effective in adults than in the elderly. Although benzodiazepines have a more obvious effect on sleep maintenance, it is best to reduce their use due to their side effects, especially for the elderly. As a food supplement, melatonin has little effect on adults, but it still has a certain effect on the elderly.

Risk factors for postoperative deep venous thrombosis in patients underwent craniotomy. / å¼€é¢ æ‰‹æœ¯åŽæ·±é™è„‰è¡€æ “å½¢æˆçš„å±é™©å› ç´ .

OBJECTIVES: To analyze the risk factors for postoperative deep vein thrombosis (DVT) in neurosurgical patients to provide the basis for the prevention of postoperative DVT. METHODS: A total of 141 patients underwent neurosurgery were enrolled. Thrombelastography (TEG) test was performed before and at the end of surgery. According to whether there was DVT formation after operation, the patients were divided into a thrombosis group and a non-thrombosis group. T-test and rank sum test were used to compare the general clinical characteristics of the 2 groups, such as age, gender, intraoperative blood loss, D-dimer, intraoperative crystal input, colloid input, blood product transfusion, operation duration, length of postoperative hospitalization. The application of chi-square test and rank-sum test were used to compared TEG main test indicators such as R and K values between the 2 groups. Logistic regression was used to analyze the possible risk factors for postoperative DVT in neurosurgical patients. RESULTS: There were significant differences in postoperative TEG index R, clotting factor function, intraoperative blood loss, hypertension or not, length of postoperative hospital stay, and postoperative absolute bed time (all P<0.05). Logistic regression analysis showed hypercoagulability, more intraoperative blood loss and longer postoperative absolute bed time were risk factors for DVT formation after craniotomy. CONCLUSIONS: Hypercoagulability in postoperative TEG test of patients is an important risk factor for the formation of postoperative DVT after neurosurgery, which can predict the occurrence of postoperative DVT to some extent.

Long non-coding RNA expression profiling in the lungs of pulmonary arterial hypertension rats with acute inflammation.

BACKGROUND: We performed RNA-sequencing to investigate the changes and expression profiles in long non-coding RNAs (lncRNAs) and their potential functional roles in the lungs of pulmonary arterial hypertension rats responding to acute inflammation. METHODS: To establish a pulmonary arterial hypertension rat model, monocrotaline was injected intraperitoneally and lipopolysaccharide was given to induce acute inflammation. Selected lncRNAs were validated by quantitative real-time polymerase chain reaction (qRT-PCR). Bioinformatics analyses were carried out to predict the potential biological roles of key lncRNAs. RESULTS: Twenty-eight lncRNAs and seven mRNAs with elevated expression and 202 lncRNAs and 36 mRNAs with decreased expression were found in the lung tissues of lipopolysaccharide-treated pulmonary arterial hypertension rats compared with control group. The qRT-PCR validation results were consistent with the bioinformatics analysis. Gene ontology analyses showed that the mRNAs and lncRNAs were differentially expressed in different pathways regarding biological process, cellular components, and molecular function. The functions of differentially expressed messenger RNAs (DEmRNAs) and DElncRNAs were indicated by Kyoto Encyclopedia of Genes and Genomes enrichment. CONCLUSION: The DEmRNAs co-expressed with DElncRNAs were obviously enriched in inflammation. DElncRNAs and DEmRNAs in the lungs of pulmonary arterial hypertension rats changed with acute inflammation may provide new insights into the pathogenesis of pulmonary arterial hypertension.