Cell cycle deregulation in neurodegenerative diseases.

Background: Cell cycle is critical for a wide range of cellular processes such as proliferation, differentiation and apoptosis in dividing cells. Neurons are postmitotic cells which have withdrawn from the cell division cycle. Recent data show us that inappropriate activation of cell cycle regulators including cyclins, cyclin dependent kinases (CDKs) and endogenous cyclin dependent kinase inhibitors (CDKIs) may take part in the aetiology of neurodegenerative diseases. However, the mechanisms for cell cycle reentry in neurodegenerative disease remain unclear.Methods: Electronic databases such as Pubmed, Science Direct, Directory of Open Access Journals, PLOS were searched for relevant articles.Conclusion: The present work reviews basic aspects of cell cycle mechanism, as well as the evidence showing the expression of cell cycle proteins in neurodegenerative disease. We provide a brief summary of these findings and hope to highlight the interaction between the cell cycle reentry and neurodegenerative diseases. Moreover, we outline the possible signaling pathways. However more understanding of the mechanism of cell cycle is of great importance. Because these represents an alternative target for therapeutic interventions, leading to novel treatments of neurodegenerative diseases.

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

BACKGROUND/AIMS: Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. METHODS: Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. RESULTS: Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. CONCLUSION: Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R.

Metoprolol Inhibits Cardiac Apoptosis and Fibrosis in a Canine Model of Chronic Obstructive Sleep Apnea.

AIMS: Emerging evidence suggested that obstructive sleep apnea (OSA) was independently associated with the development of heart failure. In this study, we explored the influence of chronic OSA on left ventricular structural remodeling in canines, and the potential therapeutical role of metoprolol. METHODS: Chronic OSA model was established by stopping the ventilator and closing the airway for 4 h/day apnea-ventilation cycles every other day for 12 weeks while metoprolol (5 mg· kg(-1)· day(-1)) were administered continuously. Norepinephrine concentration was measured by Enzyme Linked Immunosorbent Assay. Transmission electron microscopy, Hematoxylin and eosin, TUNEL and Masson trichrome staining were employed to detect the morphology, apoptosis and fibrosis of cardiomyocytes. Protein expression of apoptosis and fibrosis-related factors including apoptosis-inducing factor (AIF), caspase 3, Bcl-2, Bax, α-smooth muscle actin (α-SMA), transforming growth factor-ß1 (TGF-ß1), and p38 mitogen-activated protein kinase (MAPK) were examined by Western blotting. RESULTS: Norepinephrine concentration was markedly increased in chronic OSA dogs and reduced by metoprolol. Both the apoptotic ratio and collagen volume fraction were significantly increased in left ventricular myocytes of chronic OSA dogs, and was reversed by metoprolol. Moreover, chronic OSA-induced upregulation of AIF, cleaved caspase 3, Bax, α-SMA, and TGF-ß1 as well as downregulation of Bcl-2 was markedly recovered by metoprolol, which was mediated by p38 MAPK. CONCLUSION: Metoprolol protects against chronic OSA-induced cardiac apoptosis and fibrosis in left ventricular myocytes of canines, which may provide new potential strategy for drug therapy of OSA.

Catechin Protects against Lipopolysaccharide-induced Depressive-like Behaviour in Mice by Regulating Neuronal and Inflammatory Genes.

BACKGROUND: Many studies have suggested that tea has antidepressant effects; however, the underlying mechanism is not fully studied. As the main anti-inflammatory polyphenol in tea, catechin may contribute to the protective role of tea against depression. OBJECTIVE: The objective of this study is to prove that catechin can protect against lipopolysaccharide (LPS)-induced depressive-like behaviours in mice, and then explore the underlying molecular mechanisms. METHODS: Thirty-one C57BL/6J mice were categorized into the normal saline (NS) group, LPS group, catechin group, and amitriptyline group according to their treatments. Elevated Plus Maze (EPM), Tail Suspension Test (TST), and Open Field Test (OFT) were employed to assess depressive- like behaviours in mice. RNA sequencing (RNA-seq) and subsequent Bioinformatics analyses, such as differential gene analysis and functional enrichment, were performed on the four mouse groups. RESULTS: In TST, the mice in the LPS group exhibited significantly longer immobility time than those in the other three groups, while the immobility times for the other three groups were not significantly different. Similarly in EPM, LPS-treated mice exhibited a significantly lower percentage in the time/path of entering open arms than the mice in the other three groups, while the percentages of the mice in the other three groups were not significantly different. In OFT, LPS-treated mice exhibited significantly lower percentages in the time/path of entering the centre area than those in the other three groups. The results suggested that the LPS-induced depression models were established successfully and catechin can reverse (LPS)-induced depressive-like behaviours in mice. Finally, RNA-seq analyses revealed 57 differential expressed genes (DEGs) between LPS and NS with 19 up-regulated and 38 down-regulated. Among them, 13 genes were overlapped with the DEGs between LPS and cetechin (in opposite directions), with an overlapping p-value < 0.001. The 13 genes included Rnu7, Lcn2, C4b, Saa3, Pglyrp1, Gpx3, Lyz2, S100a8, S100a9, Tmem254b, Gm14288, Hbb-bt, and Tmem254c, which might play key roles in the protection of catechin against LPS-induced depressive-like behaviours in mice. The 13 genes were significantly enriched in defense response and inflammatory response, indicating that catechin might work through counteracting changes in the immune system induced by LPS. CONCLUSION: Catechin can protect mice from LPS-induced depressive-like behaviours through affecting inflammatory pathways and neuron-associated gene ontologies.

A Novel PLLA/MgF2 Coating on Mg Alloy by Ultrasonic Atomization Spraying for Controlling Degradation and Improving Biocompatibility.

Problems of rapid degradation and poor biocompatibility (endothelialization and hemocompatibility) limit magnesium (Mg) alloy's further applications in vascular stents. To solve these problems, a novel composite coating was designed on Mg alloy via a two-step method. First, a Mg alloy sample was immersed in hydrofluoric acid. Then, a poly-l-lactic acid (PLLA) coating was made by ultrasonic atomization spraying with 5 and 10 layers (referred to as PLLA(5)-HF-Mg and PLLA(10)-HF-Mg). Characterizations were analyzed from the microstructure, element distribution, and wettability. The degradation behavior was tested with an electrochemical test and immersion test. Endothelialization was investigated using human umbilical vein endothelial cells (HUVECs). Hemocompatibility was examined with a platelet adhesion test. The results showed that the PLLA coating could not only cover the surface, but also could permeate through and cover the holes on the MgF2 layer, mechanically locked with the substrate. Thus, the composite coating had higher corrosion resistance. The PLLA/MgF2 coating, especially on PLLA(10)-HF-Mg, enhanced HUVECs' viability and growth. While incubated with platelets, the PLLA/MgF2 coating, especially on PLLA(10)-HF-Mg, had the lowest platelet adhesion number and activity. Taken together, the novel PLLA/MgF2 coating controls Mg alloy's degradation by spraying different layers of PLLA, resulting in better endothelialization and hemocompatibility, providing a promising candidate for cardiovascular stents.

Effect of eIF2α in Neuronal Injury Induced by High Glucose and the Protective Mechanism of Resveratrol.

Diabetes mellitus (DM) is a type of metabolic disease characterized by chronic hyperglycemia, which can lead to different degrees of cognitive decline. Therefore, it is crucial to explore the molecular biological mechanisms of neuronal injury. In this study, we investigated the effect of high glucose on eIF2α expression and the mechanism of neuronal injury, and on this basis, the protective mechanism of resveratrol is explored. Treatment with 50 mM high glucose in cortical neurons increased the levels of eIF2α phosphorylation; the expressions of ATF4 and CHOP increased. ISRIB alleviated high glucose-induced neuronal injury by reducing eIF2α phosphorylation when neurons were pretreated with ISRIB before high glucose treatment. Compared with the high glucose-treated group, resveratrol pretreatment reduced eIF2α phosphorylation, the levels of its downstream molecules ATF4 and CHOP, and LDH release. Resveratrol reduced the level of cortical eIF2α phosphorylation and the expression of its downstream molecules in DM mice and improved the ability of spatial memory and learning in DM mice without affecting anxiety and motor performance. Meanwhile, resveratrol modulated the expression of Bcl-2 protein and also effectively decreased the DM-induced up-regulation of Bax, caspase-3, p53, p21, and p16. Taken together, these results suggested that high glucose caused neuronal injury through the eIF2α/ATF4/CHOP pathway which was inhibited by ISRIB and resveratrol. The present study indicates that eIF2α is the new target for the treatment of high glucose-induced neuronal injury, and resveratrol is a potential new medicine to treat diabetes encephalopathy.

Overexpression of miR-99a in hippocampus leads to impairment of reversal learning in mice.

As one of the most common human genetic disorders, Down syndrome (DS) is characterized by a mild-to-moderate cognitive disability, which mainly results from genes overexpression on chromosome 21. The expression of miR-99a, a gene harboring on chromosome 21, is increased by 50 folds in DS brain samples. This study aims to investigate the effect of miR-99a overexpression in the hippocampus on mouse behaviors and explore the underlying mechanisms. Lentivirus vectors were delivered into the hippocampus for focal miR-99a overexpression in mice. Then behaviors were observed by an open field, elevated plus maze, rotarod motor test, and Morris water maze. The genes affected by miR-99a were identified by RNA sequencing (RNA-seq) and confirmed by quantitative RT-PCR (qRT-PCR) in samples isolated from the hippocampus injected with lentivirus-GFP-miR-99a or lentivirus-GFP vectors. It was found that the expression of miR-99a with intrahippocampal delivery of lentivirus-GFP-miR-99a resulted in reversal learning impairment in mice although it had no influence on motor function and anxiety. Meanwhile, RNA-seq results showed that 92 genes including mRNAs and microRNAs were significantly regulated by miR-99a, consistent with qRT-PCR consequence. Moreover, dual-luciferase reporter assay showed that miR-99a could directly bind to the 3'-untranslated regions (3'UTR) of target genes (Clic6 and Kcnj13) with an inhibitory effect on their activity. Furthermore, we also found that miR-99a overexpression affected different biological processes by bioinformatic analyses. Our study showed that miR-99a overexpression in the hippocampus leads to cognitive impairment through regulating the expressions of various genes, which reveals a novel function of miR-99a and provides new insights into understanding the pathophysiologic process of DS.

Influence and analysis of ambulance on the containment of COVID-19 in China.

New coronavirus (COVID-19) is a newly emerging and highly infectious form of typical pneumonia with a high rate of transmission. The COVID-19 pneumonia has spread to 147 countries and areas as of Mar.16th 2020, which has tremendous impact on the global public health. It is well known that, in China, the pandemic has been contained effectively with a series of emergency measures. It is necessary to share the existing experience of China in the fight against the pandemic to the world. Especially, during the process of prevention and containment of the pandemic, ambulances play an important role in transporting infectious patients. In this paper, focusing on the safety and quantity of negative pressure ambulances, the influence of ambulance on newly confirmed cases is given. Analysis of negative pressure ambulance on the containment of COVID-19 is shown. The potential development of ambulance is discussed. While the pandemic still continues spreading across the world, we hope to share our experience in the implementation of these strategies by China to save more life.

Effects and mechanisms of probucol on aging-related hippocampus-dependent cognitive impairment.

BACKGROUND: In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms. METHODS: D-galactose (100 mg/kg, once daily for 6 weeks) was subcutaneously injected to induce aging in mice. Then the mice were administered with probucol or vehicle once a day for 2 weeks. The hippocampus-related cognition was evaluated with Morris water maze test, novel object recognition test, and contextual fear conditioning test. Moreover, synaptic plasticity was assessed, and RNA-sequencing was applied to further explore the molecular mechanisms. RESULTS: Aging mice induced by D-galactose showed conspicuous learning and memory impairment, which was significantly ameliorated by probucol. Meanwhile, probucol enhanced the spine density and dendritic branches, improved long-term potentiation, and increased the expression of PSD95 of aging mice. Probucol regulated 70 differentially expressed genes compared to D-galactose group, of which 38 genes were upregulated and 32 genes were downregulated. At last, RNA-sequencing results were verified by quantitative reverse transcription-polymerase chain reaction. CONCLUSIONS: Probucol improved learning and memory in aging mice through enhancing synaptic plasticity and regulating gene expression, indicating the potential application of probucol to prevent and treat aging-related disorders.

Inhibition of lysine-specific demethylase 1A suppresses neointimal hyperplasia by targeting bone morphogenetic protein 2 and mediating vascular smooth muscle cell phenotype.

OBJECTIVES: Vascular disorders are associated with phenotypical switching of vascular smooth muscle cells (VSMCs). We investigated the effect of bone morphogenetic protein (BMP)-2 in controlling VSMC phenotype and vascular disorder progression. Lysine (K)-specific demethylase 1A (KDM1A) has been identified to target BMP-2 and is employed as a therapeutic means of regulating BMP-2 expression in VSMCs. MATERIALS AND METHODS: VSMCs were stimulated with angiotensin II, and the expression of KDM1A and BMP-2 was detected. VSMC proliferation, apoptosis, and phenotype were evaluated. An in vivo aortic injury model was established, and VSMC behaviour was evaluated by the expression of key markers. The activation of BMP-2-associated signalling pathways was examined. RESULTS: We confirmed the inhibitory effect of KDM1A on BMP-2 activity and demonstrated that KDM1A inhibition prevented VSMC transformation from a contractile to synthetic phenotype. In angiotensin II-treated VSMCs, KDM1A inhibition triggered a decrease in cell proliferation and inflammatory response. In vivo, KDM1A inhibition alleviated post-surgery neointimal formation and collagen deposition, preventing VSMCs from switching into a synthetic phenotype and suppressing disease onset. These processes were mediated by BMP-2 through canonical small mothers against decapentaplegic signalling, which was associated with the activation of BMP receptors 1A and 1B. CONCLUSIONS: The regulatory correlation between KDM1A and BMP-2 offers insights into vascular remodelling and VSMC phenotypic modulation. The reported findings contribute to the development of innovative strategies against vascular disorders.