Benefits of napping habits in healthy adults: Maintaining alerting performance and cortisol levels change within 90 min of habitual napping time.

BACKGROUND: Napping is garnering increased attention as a strategy for adults to sustain alertness and alleviate stress in contemporary society. The nuances of napping habits are emerging as an independent factor influencing the extent of individual benefits. This study aimed to demonstrate the long-term benefits of napping and explore the impact of napping habits on individual alertness, as well as whether this effect was correlated with cortisol levels. METHODS: The study involved 80 healthy adults categorized into two groups based on self-reported napping habits: habitual nappers (n = 49) and non-habitual nappers (n = 31). Karolinska Sleepiness Scale (KSS), psychomotor vigilance task (PVT), and saliva collection were performed every 30 min within 90 min in the absence of napping during the afternoon dip. The measurements were analyzed using repeated measures ANOVA and Pearson correlation analyses. RESULTS: There was an interaction between groups and time in reaction speed and lapse number of PVT and cortisol (all p < 0.05). Post hoc analysis found that habitual nappers maintained higher objective alertness and experienced more significant increases in cortisol over time (all p < 0.05). The cortisol levels at sleepiness time were negatively associated with the slowest 10 % reaction speed of PVT in non-habitual nappers (r = -0.409, p = 0.022). CONCLUSION: Under the premise of mitigating the impacts of acute nap deprivation on sleep homeostasis and rhythm, napping habits emerge as a potential factor influencing the ability of individuals to sustain heightened alertness.

Unraveling the 2,3-diketo-L-gulonic acid-dependent and -independent impacts of L-ascorbic acid on somatic cell reprogramming.

BACKGROUND: L-ascorbic acid (Asc) plays a pivotal role in regulating various biological processes, including somatic cell reprogramming, through multiple pathways. However, it remains unclear whether Asc regulates reprogramming directly or functions through its metabolites. RESULTS: Asc exhibited dual capabilities in promoting reprogramming through both 2,3-diketo-L-gulonic acid (DKG), a key metabolite during Asc degradation, dependent and independent routes. On the one hand, Asc facilitated reprogramming by promoting cell proliferation and inducing the conversion from pre-induced pluripotent stem cells (pre-iPSCs) to iPSCs through DKG-independent pathways. Additionally, Asc triggered mesenchymal-epithelial transition (MET) and activated glycolysis via DKG-dependent mechanisms. Notably, DKG alone activated a non-canonical tricarboxylic acid cycle characterized by increased succinate, fumarate, and malate. Consequently, this shift redirected oxidative phosphorylation toward glycolysis and induced MET. Moreover, owing to its antioxidant capabilities, Asc directly inhibited glycolysis, thereby preventing positive feedback between glycolysis and epithelial-mesenchymal transition, ultimately resulting in a higher level of MET. CONCLUSION: These findings unveil the intricate functions of Asc in the context of reprogramming. This study sheds light on the DKG-dependent and -independent activities of Asc during reprogramming, offering novel insights that may extend the application of Asc to other biological processes.

Nuclear localization of TET2 requires ß-catenin activation and correlates with favourable prognosis in colorectal cancer.

Mutation-induced malfunction of ten-eleven translocation methylcytosine dioxygenase 2 (TET2) is widely reported in haematological malignancies. However, the role of TET2 in solid cancers, including colorectal cancer (CRC), is unclear. Here, we found that TET2 malfunction in CRC is mostly due to decreased nuclear localization and that nuclear localization of TET2 is correlated with better survival of patients. To explore the underlying mechanisms, 14 immortalized solid tumour cell lines and 12 primary CRC cell lines were used. TET2 was mostly detected in the nucleus, and it induced significant DNA demethylation and suppressed cell growth by demethylating RORA and SPARC in cell lines like SW480. While in cell lines like SW620, TET2 was observed in the cytosol and did not affect DNA methylation or cell growth. Further examination with immunoprecipitation-mass spectrometry illustrated that ß-catenin activation was indispensable for the nuclear localization and tumour suppression effects of TET2. In addition, the ß-catenin pathway activator IM12 and the TET2 activator vitamin C were used simultaneously to enhance the effects of TET2 under low-expression conditions, and synergistic inhibitory effects on the growth of cancer were observed both in vitro and in vivo. Collectively, these data suggest that ß-catenin-mediated nuclear localization of TET2 is an important therapeutic target for solid tumours.

Low glutaminase and glycolysis correlate with a high transdifferentiation efficiency in mouse cortex.

Both exogenous transcriptional factors and chemical-defined medium can transdifferentiate astrocytes into functional neurons. However, the regional preference for such transdifferentiation has not been fully studied. A previously reported 5C medium was infused into the mouse cortex and striatum to determine the regional preference for transdifferentiation from astrocytes to neurons. The numbers of NeuN+ GFAP+ EdU+ cells (intermediates) and NeuN+ EdU+ cells (end products) were determined by immunofluorescence to explore the regional preference of transdifferentiation. In addition, to optimize the delivery of the transdifferentiation medium, three key growth factors, insulin, bFGF and transferrin, were loaded onto chitosan nanoparticles, mixed with gelatin methacryloyl and tested in animals with motor cortex injury. A higher transdifferentiation efficiency was identified in the mouse cortex. Differences in cellular respiration and the balance between glutaminase (Gls) and glutamine synthetase were confirmed to be key regulators. In addition, the sustained drug release system induced transdifferentiation of cortex astrocytes both in vivo and in vitro, and partially facilitated the behaviour recovery of mice with motor cortex injury. We also applied this method in pigs and obtained consistent results. In summary, low Gls and glycolysis can be used to predict high transdifferentiation efficiency, which may be useful to identify better indications for the current transdifferentiation system. In addition, the current drug delivery system has the potential to treat diseases related to cortex injuries.

Naloxone Facilitates Contextual Learning and Memory in a Receptor-Independent and Tet1-Dependent Manner.

Opioids, like morphine and naloxone, regulate the proliferation and neuronal differentiation of neural stem cells (NSCs) in a receptor-independent and ten-eleven translocation methylcytosine dioxygenase (TET1)-dependent manner in vitro. Whether naloxone regulates hippocampal NSCs and contextual learning in vivo in a similar manner was determined. Naloxone infusion increased the Ki67 and Doublecortin positive cells in subgranular zone of wild type mice, which suggested the increased proliferation and differentiation of hippocampal NSCs in vivo and was consistent with the in vitro functions of naloxone. In addition, naloxone infusion also facilitated the contextual learning and memory of wild type mice. To determine the contribution of µ-opioid receptor (OPRM1) and TET1 to these functions of naloxone, several types of knockout mice were used. Since Tet1-/- mice have high deficiency in contextual learning and memory, Tet1+/- mice were used instead. The abilities of naloxone to regulate NSCs and to facilitate contextual learning were significantly impaired in Tet1+/- mice. In addition, these abilities of naloxone were not affected in Oprm1-/- mice. Therefore, naloxone facilitates contextual learning and memory in a receptor-independent and Tet1-dependent manner, which provides new understanding on the receptor-independent functions of opioids.

Positive feedback between retinoic acid and 2-phospho-L-ascorbic acid trisodium salt during somatic cell reprogramming.

Retinoic acid (RA) and 2-phospho-L-ascorbic acid trisodium salt (AscPNa) promote the reprogramming of mouse embryonic fibroblasts to induced pluripotent stem cells. In the current studies, the lower abilities of RA and AscPNa to promote reprogramming in the presence of each other suggested that they may share downstream pathways at least partially. The hypothesis was further supported by the RNA-seq analysis which demonstrated a high-level overlap between RA-activated and AscPNa activated genes during reprogramming. In addition, RA upregulated Glut1/3, facilitated the membrane transportation of dehydroascorbic acid, the oxidized form of L-ascorbic acid, and subsequently maintained intracellular L-ascorbic acid at higher level and for longer time. On the other hand, AscPNa facilitated the mesenchymal-epithelial transition during reprogramming, downregulated key mesenchymal transcriptional factors like Zeb1 and Twist1, subsequently suppressed the expression of Cyp26a1/b1 which mediates the metabolism of RA, and sustained the intracellular level of RA. Furthermore, the different abilities of RA and AscPNa to induce mesenchymal-epithelial transition, pluripotency, and neuronal differentiation explain their complex contribution to reprogramming when used individually or in combination. Therefore, the current studies identified a positive feedback between RA and AscPNa, or possibility between vitamin A and C, and further explored their contributions to reprogramming.

Naloxone regulates the differentiation of neural stem cells via a receptor-independent pathway.

The abilities of opioids to activate downstream signaling pathways normally depend on the binding between opioids and their receptors. However, opioids may also function in a receptor-independent manner, especially in neural stem cells (NSCs) in which the expression of opioid receptors and endogenous opioid agonists is low. When two opioids, morphine and naloxone, were used during the early stage of NSC differentiation, increased neurogenesis was observed. However, naloxone methiodide, a membrane impenetrable analog of naloxone, did not affect the NSC differentiation. The abilities of morphine and naloxone to facilitate neurogenesis were also observed in opioid receptor-knockout NSCs. Therefore, morphine and naloxone promote neurogenesis in a receptor-independent manner at least during the early stage. In addition, the receptor-independent functions of opioids were not observed in methylcytosine dioxygenase ten-eleven translocation 1 (Tet1) knockout NSCs. When the expression of opioid receptors increased and the expression of Tet1 decreased during the late stage of NSC differentiation, morphine, but not naloxone, inhibited neurogenesis via traditional receptor-dependent and miR181a-Prox1-Notch-related pathway. In summary, the current results demonstrated the time-dependent effects of opioids during the differentiation of NSCs and provided additional insight on the complex functions of opioids.

Morphine and Naloxone Facilitate Neural Stem Cells Proliferation via a TET1-Dependent and Receptor-Independent Pathway.

Normally, opioids function in a receptor-dependent manner. They bind to opioid receptors, activate or inhibit receptor activation, and subsequently modulate downstream signal transduction. However, the complex functions of opioids and the low expression of opioid receptors and their endogenous peptide agonists in neural stem cells (NSCs) suggest that some opioids may also modulate NSCs via a receptor-independent pathway. In the current study, two opioids, morphine and naloxone, are demonstrated to facilitate NSC proliferation via a receptor-independent and ten-eleven translocation methylcytosine dioxygenase 1 (TET1)-dependent pathway. Morphine and naloxone penetrate cell membrane, bind to TET1 protein via three key residues (1,880-1,882), and subsequently result in facilitated proliferation of NSCs. In addition, the two opioids also inhibit the DNA demethylation ability of TET1. In summary, the current results connect opioids and DNA demethylation directly at least in NSCs and extend our understanding on both opioids and NSCs.

Metabolic switch and epithelial-mesenchymal transition cooperate to regulate pluripotency.

Both metabolic switch from oxidative phosphorylation to glycolysis (OGS) and epithelial-mesenchymal transition (EMT) promote cellular reprogramming at early stages. However, their connections have not been elucidated. Here, when a chemically defined medium was used to induce early EMT during mouse reprogramming, a facilitated OGS was also observed at the same time. Additional investigations suggested that the two events formed a positive feedback loop via transcriptional activation, cooperated to upregulate epigenetic factors such as Bmi1, Ctcf, Ezh2, Kdm2b, and Wdr5, and accelerated pluripotency induction at the early stage. However, at late stages, by over-inducing glycolysis and preventing the necessary mesenchymal-epithelial transition, the two events trapped the cells at a new pluripotency state between naïve and primed states and inhibited further reprogramming toward the naïve state. In addition, the pluripotent stem cells at the new state have high similarity to epiblasts from E4.5 and E5.5 embryos, and have distinct characteristics from the previously reported epiblast-like or formative states. Therefore, the time-dependent cooperation between OGS and EMT in regulating pluripotency should extend our understanding of related fields.

Hemi-methylated CpG sites connect Dnmt1-knockdown-induced and Tet1-induced DNA demethylation during somatic cell reprogramming.

The relationship between active DNA demethylation induced by overexpressing Tet1 and passive DNA demethylation induced by suppressing Dnmt1 remains unclear. Here, we found that DNMT1 preferentially methylated, but TET1 preferentially demethylated, hemi-methylated CpG sites. These phenomena resulted in a significant overlap in the targets of these two types of DNA demethylation and the counteractions of Dnmt1 and Tet1 during somatic cell reprogramming. Since the hemi-methylated CpG sites generated during cell proliferation were enriched at core pluripotency loci, DNA demethylation induced by Tet1 or sh-RNA against Dnmt1 (sh-Dnmt1) was enriched in these loci, which, in combination with Yamanaka factors, led to the up-regulation of these genes and promoted somatic cell reprogramming. In addition, since sh-Dnmt1 induces DNA demethylation by impairing the further methylation of hemi-methylated CpG sites generated during cell proliferation, while Tet1 induced DNA demethylation by demethylating these hemi-methylated CpG sites, Tet1-induced DNA demethylation, compared with sh-Dnmt1-induced DNA demethylation, exhibited a higher ability to open the chromatin structure and up-regulate gene expression. Thus, Tet1-induced but not sh-Dnmt1-induced DNA demethylation led to the up-regulation of an additional set of genes that can promote the epithelial-mesenchymal transition and impair reprogramming. When vitamin C was used to further increase the demethylation ability of TET1 during reprogramming, Tet1 induced a larger up-regulation of these genes and significantly impaired reprogramming. Therefore, the current studies provide additional information regarding DNA demethylation during somatic cell reprogramming.

The homeobox transcription factor MSX2 partially mediates the effects of bone morphogenetic protein 4 (BMP4) on somatic cell reprogramming.

Bone morphogenetic proteins (BMPs) induce mesenchymal-epithelial transition (MET) and enhance the generation of induced pluripotent stem cells (iPSCs). However, BMPs are also signaling molecules critical for arresting reprogramming in the pre-iPSC state. In this study, using mouse embryonic fibroblasts, we found that the time- and concentration-dependent effects of BMPs on reprogramming are mediated by Msh homeobox 2 (MSX2), a homeobox-containing transcription factor. BMPs up-regulated Msx2 by activating SMAD1/5, and MSX2 then directly bound to the promoters and up-regulated the expression of the cadherin 1 (Cdh1, also known as E-cadherin), GATA-binding protein 3 (Gata3), and Nanog genes. Cdh1 contributed to BMP4- and MSX2-induced MET and subsequently promoted reprogramming. On the other hand, GATA3 promoted reprogramming, possibly by up-regulating Spalt-like transcription factor 4 (SALL4) expression. As key transcriptional factors in maintaining pluripotency, up-regulation of SALL4 and NANOG enhanced reprogramming. Moreover, the ability of MSX2 to up-regulate Cdh1, Gata3, Nanog, and Sall4 was further potentiated in the presence of Krüppel-like factor 4 (KLF4). However, MSX2 did not mediate the effects of BMP4 signaling on activation of the microRNAs miR-205 and miR-200 or the inhibitory effects that arrested reprogramming in the pre-iPSC state. In conclusion, MSX2 partially mediates the effects of BMP4 signaling during reprogramming, improving our understanding of the role of BMP signaling in MET and of the connection between cell lineage specifiers such as MSX2 and GATA3 and pluripotency.

Protective effects of nicorandil against cerebral injury in a swine cardiac arrest model.

The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100ß, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100ß were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P<0.05). Additionally, NSE and S100ß levels were significantly lower in the nicorandil group compared with the control (P<0.05). Pathological examinations and electron microscopy indicated that nicorandil reduced brain tissue damage. TNF-α and IL-6 levels were significantly decreased in the nicorandil group compared with the control group (P<0.05). Furthermore, AQP-4 expression in brain tissue 6 h following ROSC was significantly lower in the nicorandil group compared with the control group (P<0.05). MDA and GSH levels in swine brain tissue decreased and increased, respectively, in the nicorandil group compared with the control group (P<0.05). The results of the present study demonstrate that nicorandil exerts a protective effect against brain injury following cardiac arrest by reducing oxidative damage, inflammatory responses and brain edema post-ROSC.

[Effects of mild hypothermia on ß-adrenergic signaling pathway in a cardiac arrest swine model].

OBJECTIVE: To observe the effect of mild hypothermia on myocardial ß-adrenergic receptor (ß-AR) signal pathway after cardiopulmonary resuscitation (CPR) in pigs with cardiac arrest (CA) and explore the mechanism of myocardial protection. METHODS: Healthy male Landraces were collected for reproducing the CA-CPR model (after 8-minute untreated ventricular fibrillation, CPR was implemented). The animals were divided into two groups according to random number table (n = 8). In the mild hypothermia group, the blood temperature of the animals was induced to 33 centigrade and maintained for 6 hours within 20 minutes after return of spontaneous circulation (ROSC) by using a hypothermia therapeutic apparatus. In the control group, the body temperature of the animals was maintained at (38.0±0.5)centigrade with cold and warm blankets. The heart rate (HR), mean arterial pressure (MAP), the maximum rate of increase or decrease in left rentricular pressure (+dp/dt max) were measured during the course of the experiment. The cardiac output (CO) was measured by heat dilution methods before CA (baseline), and 0.5, 1, 3, 6 hours after ROSC respectively, the venous blood was collected to detect the concentration of cTnI. Left ventricular ejection fraction (LVEF) was measured with cardiac ultrasound before CA and 6 hours after ROSC. Animals were sacrificed at 6 hours after ROSC and the myocardial tissue was harvested quickly, the mRNA expression of ß1-AR in myocardium was detected by reverse transcription-polymerase chain reaction (RT-PCR), the contents of adenylate cyclase (AC) and cyclic adenosine monophosphate (cAMP) were detected by enzyme linked immunosorbent assay (ELISA), the protein content of G protein-coupled receptor kinase 2 (GRK2) was detected by Western Blot. RESULTS: After successful resuscitation, the HR of both groups were significantly higher than the baseline values, CO, ±dp/dt max were significantly decreased, MAP were not significantly changed, serum cTnI levels were significantly increased. Compared with the control group, HR at 0.5, 1, 3 hours after ROSC were significantly decreased in mild hypothermia group (bpm: 142.80±12.83 vs. 176.88±15.14, 115.80±11.48 vs. 147.88±18.53, 112.60±7.40 vs. 138.50±12.02, all P < 0.01), CO was significantly increased at 1 hours and 3 hours after ROSC (L/min: 3.97±0.40 vs. 3.02±0.32, 4.00±0.11 vs. 3.11±0.59, both P < 0.01), +dp/dt max at 3 hours and 6 hours was also significantly increased after ROSC [+dp/dt max (mmHg/s): 3 402.5±612.7 vs. 2 130.0±450.6, 3 857.5±510.4 vs. 2 562.5±633.9; -dp/dt max (mmHg/s): 2 935.0±753.2 vs. 1 732.5±513.6, 3 520.0±563.6 vs. 2 510.0±554.3, all P < 0.05], the cTnI was significantly decreased at 3 hours and 6 hours afher ROSC (µg/L: 1.39±0.40 vs. 3.24±0.78, 1.46±0.35 vs. 3.78±0.93, both P < 0.01). The left at 6 hours after ROSC in both groups was decreased as compared with that before CA. The LVEF in the mild hypothermia group was higher than that in the control group (0.52±0.04 vs. 0.40±0.05, P < 0.05). The mRNA expression of ß1-AR, and concentrations of AC and cAMP in hypothermia group were significantly higher than those in control group [ß1-AR mRNA (2-ΔΔCT): 1.18±0.39 vs. 0.55±0.17, AC (ng/L): 197.0±10.5 vs. 162.0±6.3, cAMP (nmol/L): 1 310.58±48.82 vs. 891.25±64.95, all P < 0.05], GRK2 was lower than that in the control group (GRK2/GAPDH: 0.45±0.05 vs. 0.80±0.08, P < 0.05). CONCLUSIONS: Mild hypothermia can reduce the degree of cardiac function injury after CPR, and its mechanism may be related to the reduction of impaired myocardial ß-AR signaling after CPR.

Passive DNA demethylation preferentially up-regulates pluripotency-related genes and facilitates the generation of induced pluripotent stem cells.

A high proliferation rate has been observed to facilitate somatic cell reprogramming, but the pathways that connect proliferation and reprogramming have not been reported. DNA methyltransferase 1 (DNMT1) methylates hemimethylated CpG sites produced during S phase and maintains stable inheritance of DNA methylation. Impairing this process results in passive DNA demethylation. In this study, we show that the cell proliferation rate positively correlated with the expression of Dnmt1 in G1 phase. In addition, as determined by whole-genome bisulfate sequencing and high-performance liquid chromatography, global DNA methylation of mouse embryonic fibroblasts was significantly higher in G1 phase than in G2/M phase. Thus, we suspected that high cellular proliferation requires more Dnmt1 expression in G1 phase to prevent passive DNA demethylation. The methylation differences of individual CpG sites between G1 and G2/M phase were related to the methylation status and the positions of their surrounding CpG sites. In addition, larger methylation differences were observed on the promoters of pluripotency-related genes; for example, Oct4, Nanog, Sox2, Esrrb, Cdh1, and Epcam When such methylation differences or passive DNA demethylation accumulated with Dnmt1 suppression and proliferation acceleration, DNA methylation on pluripotency-related genes was decreased, and their expression was up-regulated, which subsequently promoted pluripotency and mesenchymal-epithelial transition, a necessary step for reprogramming. We infer that high cellular proliferation rates promote generation of induced pluripotent stem cells at least partially by inducing passive DNA demethylation and up-regulating pluripotency-related genes. Therefore, these results uncover a connection between cell reprogramming and DNA methylation.

Sequential EMT-MET induces neuronal conversion through Sox2.

Direct neuronal conversion can be achieved with combinations of small-molecule compounds and growth factors. Here, by studying the first or induction phase of the neuronal conversion induced by defined 5C medium, we show that the Sox2-mediated switch from early epithelial-mesenchymal transition (EMT) to late mesenchymal-epithelial transition (MET) within a high proliferation context is essential and sufficient for the conversion from mouse embryonic fibroblasts (MEFs) to TuJ+ cells. At the early stage, insulin and basic fibroblast growth factor (bFGF)-induced cell proliferation, early EMT, the up-regulation of Stat3 and Sox2, and the subsequent activation of neuron projection. Up-regulated Sox2 then induced MET and directed cells towards a neuronal fate at the late stage. Inhibiting either stage of this sequential EMT-MET impaired the conversion. In addition, Sox2 could replace sequential EMT-MET to induce a similar conversion within a high proliferation context, and its functions were confirmed with other neuronal conversion protocols and MEFs reprogramming. Therefore, the critical roles of the sequential EMT-MET were implicated in direct cell fate conversion in addition to reprogramming, embryonic development and cancer progression.

Cardioprotective effect of nicorandil against myocardial injury following cardiac arrest in swine.

INTRODUCTION: Nicorandil, a vasodilatory drug used to treat angina, was reported to protect against myocardial ischemia-reperfusion injury in various animal models. However, its cardioprotective action following cardiac arrest is unknown. We examined the cardioprotective effects of nicorandil in a porcine model of cardiac arrest and resuscitation. METHODS: Ventricular fibrillation was induced electrically for 4min in anesthetized domestic swine, followed by cardiopulmonary resuscitation. Sixteen successfully resuscitated animals were randomized to saline control (n=8) or nicorandil (n=8) groups. Nicorandil (150µg/kg) was administered by central intravenous injection at onset of restoration of spontaneous circulation (ROSC), followed by 3µg/kg/min infusion until reperfusion end. Sham-operated animals received surgery only (n=4). Hemodynamic parameters were monitored continuously. Blood samples were taken at baseline, 5, 30, 180, and 360min after ROSC. Left ventricular ejection fraction was assessed by echocardiography at baseline and 6h after ROSC. The animals were euthanized 6h after ROSC, and the cardiac tissue was removed for analysis. RESULTS: 6 h after ROSC, nicorandil had significantly improved all hemodynamic variables (all P<0.05) except the maximum rate of left ventricular pressure decline and heart rate (P>0.05) compared with the control group. Control animals showed elevated cardiac troponin I and lactate levels compared with sham animals, which were significantly decreased following nicorandil treatment (P<0.05). In the saline control group, the adenosine triphosphate (ATP) content was largely reduced but subsequently rescued by nicorandil (P<0.05). Histopathologic injury was reduced with nicorandil treatment. Nicorandil reduced cardiomyocyte apoptosis as evidenced by reduced terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, decreased Bax and caspase-3 expression, and increased Bcl-2 expression in the myocardium (all P<0.05). CONCLUSION: Nicorandil exhibited cardioprotective effects on myocardial injury following cardiac arrest via improvement in post-resuscitation myocardial dysfunction and energy metabolism, reduction in myocardial histopathologic injury, and antiapoptotic effects.

Effect of atorvastatin on serum omentin-1 in patients with coronary artery disease.

OBJECTIVE: An association between coronary artery disease (CAD) and serum omentin-1 was recently identified. The aim of the present study was to investigate the effect of atorvastatin on serum levels of omentin-1 in patients with CAD. METHODS: One-hundred and ninety-eight patients with CAD were divided into two groups: those with acute coronary syndrome (ACS) and those with stable angina pectoris (SAP). All patients were randomized to receive atorvastatin therapy at a dose of either 20 or 40 mg/day for 12 weeks. Serum omentin-1 levels and other parameters were determined at baseline and at the end of the study. RESULTS: Atorvastatin at 20 and 40 mg/day increased serum omentin-1 levels in patients with ACS (20 mg, P=0.007; 40 mg, P<0.001) and in those with SAP (20 mg, P=0.017; 40 mg, P<0.001). Atorvastatin at 40 mg induced greater changes in serum omentin-1 levels compared with 20 mg atorvastatin in both the ACS group (P=0.003) and the SAP group (P=0.012). The increments of serum omentin-1 levels with atorvastatin administration inversely correlated with changes in LDL cholesterol (r=-0.145, P=0.041), interleukin-6 (r=-0.162, P=0.023), and high-sensitivity C-reactive protein (r=-0.185, P=0.009) in patients with CAD. Furthermore, changes in LDL cholesterol (ß=-0.158, P=0.027) and interleukin-6 (ß=-0.154, P=0.044) remained independent determinants of omentin-1 alterations in standard multiple regression analysis (R=0.122, P=0.006) after adjusting for age, sex, smoking, family history of CAD, and BMI in patients with CAD. CONCLUSION: Atorvastatin increased serum omentin-1 concentrations in patients with CAD in a dose-dependent manner.

Lysine-specific histone demethylase 1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch.

Lysine-specific histone demethylase 1 (LSD1) regulates histone methylation and influences the epigenetic state of cells during the generation of induced pluripotent stem cells (iPSCs). Here we reported that LSD1 inhibition via shRNA or specific inhibitor, tranylcypromine, promoted reprogramming at early stage via two mechanisms. At early stage of reprogramming, LSD1 inhibition increased the retrovirus-mediated exogenous expression of Oct4, Klf4, and Sox2 by blocking related H3K4 demethylation. Since LSD1 inhibition still promoted reprogramming even when iPSCs were induced with small-molecule compounds in a virus-free system, additional mechanisms should be involved. When RNA-seq was used for analysis, it was found that LSD1 inhibition reversed some gene expression changes induced by OKS, which subsequently promoted reprogramming. For example, by partially rescuing the decreased expression of Hif1α, LSD1 inhibition reversed the up-regulation of genes in oxidative phosphorylation pathway and the down-regulation of genes in glycolysis pathway. Such effects facilitated the metabolic switch from oxidative phosphorylation to glycolysis and subsequently promoted iPSCs induction. In addition, LSD1 inhibition also promoted the conversion from pre-iPSCs to iPSCs by facilitating the similar metabolic switch. Therefore, LSD1 inhibition promotes reprogramming by facilitating the expression of exogenous transcriptional factors and metabolic switch.

Meta-Analysis of EMT Datasets Reveals Different Types of EMT.

As a critical process during embryonic development, cancer progression and cell fate conversions, epithelial-mesenchymal transition (EMT) has been extensively studied over the last several decades. To further understand the nature of EMT, we performed meta-analysis of multiple microarray datasets to identify the related generic signature. In this study, 24 human and 17 mouse microarray datasets were integrated to identify conserved gene expression changes in different types of EMT. Our integrative analysis revealed that there is low agreement among the list of the identified signature genes and three other lists in previous studies. Since removing the datasets with weakly-induced EMT from the analysis did not significantly improve the overlapping in the signature-gene lists, we hypothesized the existence of different types of EMT. This hypothesis was further supported by the grouping of 74 human EMT-induction samples into five distinct clusters, and the identification of distinct pathways in these different clusters of EMT samples. The five clusters of EMT-induction samples also improves the understanding of the characteristics of different EMT types. Therefore, we concluded the existence of different types of EMT was the possible reason for its complex role in multiple biological processes.