The low fetal fraction at the first trimester is associated with adverse pregnancy outcomes in IVF singleton pregnancies with single embryo transfer from frozen cycles.

PURPOSE: To study the associations between fetal fraction at the first trimester and subsequent adverse pregnancy outcomes (APOs) in IVF singleton pregnancies with single embryo transfer from frozen cycles. METHODS: This is a single-center retrospective cohort study on IVF singleton pregnancies with single embryo transfer from frozen cycles. A total of 8457 women were collected between March 2015 and September 2018 from the Center for Reproductive Medicine, Shandong University, China. Participants underwent cell-free DNA (cfDNA) sequencing at 11-13 weeks' gestation. Multivariable logistic regressions were performed with the risk of APOs based on various predictor variables. RESULTS: A total of 8457 women were included in the analysis of which 1563 (18.48%) women developed one or more APOs. The hypertensive disorders of pregnancy (HDP) (N = 515), gestational diabetes mellitus (GDM) (N = 684), preterm birth (PTB) (N = 567), and low birth weight (LBW) (N = 306) groups had lower fetal fraction compared with the no pregnancy complication (NPC) group (all p values < 0.05). Based on the multivariable logistic regression results, the optimal cutoff values of fetal fraction were 9.30%, 12.54%, 9.10%, 12.65%, and 13.83% for at least one APO, HDP, GDM, PTB, and LBW, respectively. After adjustment for potential maternal confounders, women in the low fetal fraction (LFF) group had a higher risk for the APOs compared with high fetal fraction (HFF) group. CONCLUSIONS: The fetal fraction in HDP, GDM, PTB, and LBW groups were lower than NPC group in IVF singleton pregnancies with single embryo transfer from frozen cycles in China.

LincRNA-p21 Upregulates Nuclear Orphan Receptor Nr4a2 and Aggravates Myocardial Ischemia/Reperfusion Injury via Targeting MiR-466i-5p.

Myocardial ischemia/reperfusion (I/R) injury can bring about more cardiomyocyte death and aggravate cardiac dysfunction, but its pathogenesis remains unclear. This study aimed to investigate the role of long intergenic noncoding RNA-p21 (LincRNA-p21) in myocardial I/R injury and its underlying mechanism. Mice were subjected to myocardial I/R injury by ligation and release of the left anterior descending artery, and HL-1 cardiomyocytes were treated with hydrogen peroxide. Infarct area, cardiac function, and cardiomyocyte apoptosis were determined. Consequently, LincRNA-p21 was found to significantly be elevated both in the reperfused hearts and H2O2-treated cardiomyocytes. Moreover, genetic inhibition of LincRNA-p21 brought about reduced infarct area and improved cardiac function in mice subjected to myocardial I/R injury. LincRNA-p21 knockdown was also demonstrated to inhibit cardiomyocyte apoptosis both in vivo and in vitro. Notably, LincRNA-p21 silencing increased the expression of microRNA-466i-5p (miR-466i-5p) and suppressed the expression of nuclear receptor subfamily 4 group A member 2 (Nr4a2). Mechanically, LincRNA-p21 downregulated and directly interacted with miR-466i-5p, while application of miR-466i-5p inhibitor promoted cardiomyocyte apoptosis that was improved by LincRNA-p21 inhibition. Furthermore, Nr4a2 upregulation caused by LincRNA-p21 overexpression was partially reversed by miR-466i-5p mimics. Thus, LincRNA-p21 positively regulated the expression of Nr4a2, through sponging miR-466i-5p, promoting cardiomyocyte apoptosis in myocardial I/R injury. The current study revealed a novel LincRNA-p21/miR-466i-5p/Nr4a2 pathway for myocardial I/R injury, indicating that LincRNA-p21 may serve as a potential target for future therapy.

Inhibition of adenosine kinase attenuates myocardial ischaemia/reperfusion injury.

Increased adenosine helps limit infarct size in ischaemia/reperfusion-injured hearts. In cardiomyocytes, 90% of adenosine is catalysed by adenosine kinase (ADK) and ADK inhibition leads to higher concentrations of both intracellular adenosine and extracellular adenosine. However, the role of ADK inhibition in myocardial ischaemia/reperfusion (I/R) injury remains less obvious. We explored the role of ADK inhibition in myocardial I/R injury using mouse left anterior ligation model. To inhibit ADK, the inhibitor ABT-702 was intraperitoneally injected or AAV9 (adeno-associated virus)-ADK-shRNA was introduced via tail vein injection. H9c2 cells were exposed to hypoxia/reoxygenation (H/R) to elucidate the underlying mechanisms. ADK was transiently increased after myocardial I/R injury. Pharmacological or genetic ADK inhibition reduced infarct size, improved cardiac function and prevented cell apoptosis and necroptosis in I/R-injured mouse hearts. In vitro, ADK inhibition also prevented cell apoptosis and cell necroptosis in H/R-treated H9c2 cells. Cleaved caspase-9, cleaved caspase-8, cleaved caspase-3, MLKL and the phosphorylation of MLKL and CaMKII were decreased by ADK inhibition in reperfusion-injured cardiomyocytes. X-linked inhibitor of apoptosis protein (XIAP), which is phosphorylated and stabilized via the adenosine receptors A2B and A1/Akt pathways, should play a central role in the effects of ADK inhibition on cell apoptosis and necroptosis. These data suggest that ADK plays an important role in myocardial I/R injury by regulating cell apoptosis and necroptosis.

Applications of noninvasive prenatal testing in vanishing twin syndrome pregnancies after treatment of assisted reproductive technology in a single center.

OBJECTIVE: The objective of the study is to assess the clinical application of noninvasive prenatal testing (NIPT) for VTS pregnancies after the treatment of assisted reproductive technology (ART). METHOD: This was a retrospective study on VTS pregnancies through ART treatment. Participants underwent NIPT at 11 to 13 weeks gestation by sequencing. Resampling was recommended for both positive and testing failure cases. For NIPT positive results, participants were advised to have invasive testing. Clinical outcomes were obtained by telephone interview. RESULTS: In total of 579 cases, testing failure rates after first sampling and resampling were 7.6% and 1.4%, respectively. Twelve positive results were reported by NIPT. But only one true positive was confirmed, giving a PPV of 8%. A total of 576 cases completed the follow-up (including 533 NIPT negative, 12 positive, and 31 testing failure) and three cases lost follow-up. Among the 536 cases with NIPT negative results, 504 (94.0%) resulted in live-birth and 29 (5.4%) resulted in miscarriage or stillbirths. No false-negative result was reported. CONCLUSION: NIPT has the potential to be used in prenatal screening for VTS pregnancies. For the pregnant women who obtained positive and testing failure results, resampling after 15 weeks of gestation is recommended.

Aldehyde dehydrogenase 2 protects against sympathetic excitation-induced cardiac fibrosis.

Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G0/G1 phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.

ALDH2 Activation Inhibited Cardiac Fibroblast-to-Myofibroblast Transformation Via the TGF-ß1/Smad Signaling Pathway.

Pathological stimulus-triggered differentiation of cardiac fibroblasts plays a major role in the development of myocardial fibrosis. Aldehyde dehydrogenase 2 (ALDH2) was reported to exert a protective role in cardiovascular disease, and whether ALDH2 is involved in cardiac fibroblast differentiation remains unclear. In this study, we used transforming growth factor-ß1 (TGF-ß1) to induce the differentiation of human cardiac fibroblasts (HCFs) and adopted ALDH2 activator Alda-1 to verify the influence of ALDH2 on HCF differentiation. Results showed that ALDH2 activity was obviously impaired when treating HCFs with TGF-ß1. Activation of ALDH2 with Alda-1 inhibited the transformation of HCFs into myofibroblasts, demonstrated by the decreased smooth muscle actin (α-actin) and periostin expression, reduced HCF-derived myofibroblast proliferation, collagen production, and contractility. Moreover, application of Smad2/3 inhibitor alleviated TGF-ß1-induced HCF differentiation and improved ALDH2 activity, which was reversed by the application of ALDH2 inhibitor daidzin. Finally, Alda-1-induced HCF alterations alleviated neonatal rat cardiomyocyte hypertrophy, supported by the immunostaining of α-actin. To summarize, activation of ALDH2 enzymatic activity inhibited the differentiation of cardiac fibroblasts via the TGF-ß1/Smad signaling pathway, which might be a promising strategy to relieve myocardial fibrosis of various causes.

Donor substrate promiscuity of bacterial ß1-3-N-acetylglucosaminyltransferases and acceptor substrate flexibility of ß1-4-galactosyltransferases.

ß1-3-N-Acetylglucosaminyltransferases (ß3GlcNAcTs) and ß1-4-galactosyltransferases (ß4GalTs) have been broadly used in enzymatic synthesis of N-acetyllactosamine (LacNAc)-containing oligosaccharides and glycoconjugates including poly-LacNAc, and lacto-N-neotetraose (LNnT) found in the milk of human and other mammals. In order to explore oligosaccharides and derivatives that can be synthesized by the combination of ß3GlcNAcTs and ß4GalTs, donor substrate specificity studies of two bacterial ß3GlcNAcTs from Helicobacter pylori (Hpß3GlcNAcT) and Neisseria meningitidis (NmLgtA), respectively, using a library of 39 sugar nucleotides were carried out. The two ß3GlcNAcTs have complementary donor substrate promiscuity and 13 different trisaccharides were produced. They were used to investigate the acceptor substrate specificities of three ß4GalTs from Neisseria meningitidis (NmLgtB), Helicobacter pylori (Hpß4GalT), and bovine (Bß4GalT), respectively. Ten of the 13 trisaccharides were shown to be tolerable acceptors for at least one of these ß4GalTs. The application of NmLgtA in one-pot multienzyme (OPME) synthesis of two trisaccharides including GalNAcß1-3Galß1-4GlcßProN3 and Galß1-3Galß1-4Glc was demonstrated. The study provides important information for using these glycosyltransferases as powerful catalysts in enzymatic and chemoenzymatic syntheses of oligosaccharides and derivatives which can be useful probes and reagents.

Acute Hepatic Insulin Resistance Contributes to Hyperglycemia in Rats Following Myocardial Infarction.

Although hyperglycemia is common in patients with acute myocardial infarction (MI), the underlying mechanisms are largely unknown. Insulin signaling plays a key role in the regulation of glucose homeostasis. In this study, we test the hypothesis that rapid alteration of insulin signaling pathways could be a potential contributor to acute hyperglycemia after MI. Male rats were used to produce MI by ligation of the left anterior descending coronary artery. Plasma glucose and insulin levels were significantly higher in MI rats than those in controls. Insulin-stimulated tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) was reduced significantly in the liver tissue of MI rats compared with controls, followed by decreased attachment of phosphatidylinositol 3-kinase (PI3K) p85 subunit with IRS1 and Akt phosphorylation. However, insulin-stimulated signaling was not altered significantly in skeletal muscle after MI. The relative mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and G6Pase were slightly higher in the liver tissue of MI rats than those in controls. Rosiglitazone (ROSI) markedly restored hepatic insulin signaling, inhibited gluconeogenesis and reduced plasma glucose levels in MI rats. Insulin resistance develops rapidly in liver but not skeletal muscle after MI, which contributes to acute hyperglycemia. Therapy aimed at potentiating hepatic insulin signaling may be beneficial for MI-induced hyperglycemia.

Synthetic disialyl hexasaccharides protect neonatal rats from necrotizing enterocolitis.

Two novel synthetic α2-6-linked disialyl hexasaccharides, disialyllacto-N-neotetraose (DSLNnT) and α2-6-linked disialyllacto-N-tetraose (DS'LNT), were readily obtained by highly efficient one-pot multienzyme (OPME) reactions. The sequential OPME systems described herein allowed the use of an inexpensive disaccharide and simple monosaccharides to synthesize the desired complex oligosaccharides with high efficiency and selectivity. DSLNnT and DS'LNT were shown to protect neonatal rats from necrotizing enterocolitis (NEC) and are good therapeutic candidates for preclinical experiments and clinical application in treating NEC in preterm infants.

A chemoenzymatic route to synthesize unnatural sugar nucleotides using a novel N-acetylglucosamine-1-phosphate pyrophosphorylase from Camphylobacter jejuni NCTC 11168.

A novel N-acetylglucosamine-1-phosphate pyrophosphorylase was identified from Campylobacter jejuni NCTC 11168. An unprecedented degree of substrate promiscuity has been revealed by systematic studies on its substrate specificities towards sugar-1-P and NTP. The yields of the synthetic reaction of seven kinds of sugar nucleotides catalyzed by the enzyme were up to 60%. In addition, the yields of the other nine were around 20%. With this enzyme, three novel sugar nucleotide analogs were synthesized on a preparative scale and well characterized.

Biosynthesis of nucleotide sugars by a promiscuous UDP-sugar pyrophosphorylase from Arabidopsis thaliana (AtUSP).

Nucleotide sugars are activated forms of monosaccharides and key intermediates of carbohydrate metabolism in all organisms. The availability of structurally diverse nucleotide sugars is particularly important for the characterization of glycosyltransferases. Given that limited methods are available for preparation of nucleotide sugars, especially their useful non-natural derivatives, we introduced herein an efficient one-step three-enzyme catalytic system for the synthesis of nucleotide sugars from monosaccharides. In this study, a promiscuous UDP-sugar pyrophosphorylase (USP) from Arabidopsis thaliana (AtUSP) was used with a galactokinase from Streptococcus pneumoniae TIGR4 (SpGalK) and an inorganic pyrophosphatase (PPase) to effectively synthesize four UDP-sugars. AtUSP has better tolerance for C4-derivatives of Gal-1-P compared to UDP-glucose pyrophosphorylase from S. pneumoniae TIGR4 (SpGalU). Besides, the nucleotide substrate specificity and kinetic parameters of AtUSP were systematically studied. AtUSP exhibited considerable activity toward UTP, dUTP and dTTP, the yield of which was 87%, 85% and 84%, respectively. These results provide abundant information for better understanding of the relationship between substrate specificity and structural features of AtUSP.

Control of SOX2 protein stability and tumorigenic activity by E3 ligase CHIP in esophageal cancer cells.

SOX2 is highly expressed and controls tumor initiation and cancer stem cell function in various squamous cell carcinomas including esophageal squamous cancer. However, the molecular mechanism leading to SOX2 overexpression in cancer is incompletely understood. Here, we identified CHIP, a chaperone-associated ubiquitin E3 ligase, as a novel negative regulator of SOX2 protein stability and tumorigenic activity in esophageal squamous carcinoma cells. We showed that CHIP interacted with SOX2 primarily via chaperone HSP70, together they catalyzed SOX2 ubiquitination and degradation via proteasome. In contrast, HSP90 promoted SOX2 stability and inhibition of HSP90 activity induced SOX2 ubiquitination and degradation. Notably, unlike the case in normal esophageal tissues where CHIP was detected in both the cytoplasm and nucleus, CHIP in clinical esophageal tumor specimens was predominantly localized in the cytoplasm. Consistent with this observation, we observed increased expression of exportin-1/CRM-1 in clinical esophageal tumor specimens. We further demonstrated that CHIP catalyzed SOX2 ubiquitination and degradation primarily in the nuclear compartment. Taken together, our study has identified CHIP as a key suppressor of SOX2 protein stability and tumorigenic activity and revealed CHIP nuclear exclusion as a potential mechanism for aberrant SOX2 overexpression in esophageal cancer. Our study also suggests HSP90 inhibitors as potential therapeutic agents for SOX2-positive cancers.

GSK3ß-driven SOX2 overexpression is a targetable vulnerability in esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest forms of human malignancy that currently lacks approved targeted therapeutics. Accumulating evidence suggests that SOX2 overexpression is a key driving factor for ESCC and various squamous cell carcinoma. Here, through screening a small-molecule kinase inhibitor library, we identified GSK3ß as a kinase that is critically required for robust SOX2 expression in ESCC cells. GSK3ß did not promote SOX2 transcriptionally but was required for SOX2 protein stability. We demonstrated that GSK3ß interacts with and phosphorylates SOX2 at residue S251, which blocks SOX2 from ubiquitination and proteasome-dependent degradation instigated by ubiquitin E3 ligase CUL4ADET1-COP1. Pharmacological inhibition or knockdown of GSK3ß by RNA interference selectively impaired SOX2-positive ESCC cell proliferation, cancer stemness, and tumor growth in mouse xenograft model, suggesting that GSK3ß promotes ESCC tumorigenesis primarily by driving SOX2 overexpression. GSK3ß was found to be frequently overexpressed in clinical esophageal tumors, and there was a positive correlation between GSK3ß and SOX2 protein levels. Notably, we found that SOX2 enhanced GSK3ß expression transcriptionally, suggesting the existence of a vicious cycle that drives a coordinated GSK3ß and SOX2 overexpression in ESCC cells. Finally, we demonstrated in tumor xenograft model that GSK3ß inhibitor AR-A014418 was effective in suppressing SOX2-positive ESCC tumor progression and inhibited tumor progression cooperatively with chemotherapeutic agent carboplatin. In conclusion, we uncovered a novel role for GSK3ß in driving SOX2 overexpression and tumorigenesis and provided evidence that targeting GSK3ß may hold promise for the treatment of recalcitrant ESCCs.

Investigation of the nucleotide triphosphate substrate specificity of Homo sapiens UDP-N-acetylgalactosamine pyrophosphorylase (AGX1).

Nucleotide sugars are essential glycosyl donors for Leloir-type glycosyltransferases. The UDP-N-acetylgalactosamine pyrophosphorylase (UDP-GalNAc PP; AGX1) from Homo sapiens catalyzes the synthesis of UDP-N-acetylgalactosamine from N-acetylgalactosamine 1-phosphate and UTP. In this Letter, we systematically studied nucleotide substrate specificity of AGX1 during its uridyltransfer reaction, and described the capability of AGX1 to catalyze dUTP and dTTP to their corresponding nucleotide sugars for the first time. Furthermore, using such a eukaryotic enzyme, we synthesized dUDP-GalNAc and dTDP-GalNAc in multiple mg scale in vitro efficiently and rapidly.

Substrate specificity of galactokinase from Streptococcus pneumoniae TIGR4 towards galactose, glucose, and their derivatives.

Galactokinases (GalKs) have attracted significant research attention for their potential applications in the enzymatic synthesis of unique sugar phosphates. The galactokinase (GalKSpe4) cloned from Streptococcus pneumoniae TIGR4 presents a remarkably broad substrate range including 14 diverse natural and unnatural sugars. TLC and MS studies revealed that GalKSpe4 had relaxed activity towards galactose derivatives with modifications on the C-6, 4- or 2-positions. Additionally, GalKSpe4 can also tolerate glucose while glucose derivatives with modifications on the C-6, 4- or 2-positions were unacceptable. More interestingly, GalKSpe4 can phosphorylate L-mannose in moderate yield (43%), while other L-sugars such as L-Gal cannot be recognized by this enzyme. These results are very significant because there is rarely enzyme reported that can phosphorylate such uncommon substrates as l-mannose.

Insights into role of the hydrogen bond networks in substrate recognition by UDP-GalNAc 4-epimerases.

UDP-hexose 4-epimerases are critical in galactose metabolism and often important in lipopolysaccharide biosynthesis as well. Three groups of these enzymes have been reported based on their substrate specificity towards non-acetylated substrates (group 1), dual specificity towards N-acetylated and non-acetylated substrates (group 2) and specificity towards N-acetylated substrates (group 3). We recently reported the structure of a novel UDP-GalNAc 4-epimerase called WbgU and based on the structure proposed a model of specific substrate recognition by UDP-GalNAc 4-epimerases. In this work, we present an analysis of the proposed model of substrate recognition using site-directed mutagenesis of WbgU and crystal structure of the His305Ala mutant. This investigation reveals that the wild-type activity of WbgU is retained in most single-point mutants targeting the active site. However, a graded loss in activity is observed in double-and triple-point mutants with the quadruple-point mutant being completely inactive corroborating the proposed rationale of substrate recognition. Furthermore, crystal structure of the His305Ala mutant shows that the structure is significantly similar to the wild-type WbgU, albeit a loss in the critical hydrogen bond network seated at His305 and ensuing minor conformational changes. It is inferred that the specific and non-specific interactions throughout the active site confer it sufficient elasticity to sustain wild-type activity for several of the single-point mutations.

Aldehyde dehydrogenase 2 protects against acute kidney injury by regulating autophagy via the Beclin-1 pathway.

The mitochondrial enzyme aldehyde dehydrogenase 2 (ALDH2) catalyzes the detoxification of acetaldehyde and endogenous lipid aldehydes. Approximately 40% of East Asians, accounting for 8% of the human population, carry the E504K mutation in ALDH2 that leads to accumulation of toxic reactive aldehydes and increases the risk for cardiovascular disease, cancer, and Alzheimer disease, among others. However, the role of ALDH2 in acute kidney injury (AKI) remains poorly defined and is therefore the subject of the present study using various cellular and organismal sources. In murine models, in which AKI was induced by either the contrast agent iohexol or renal ischemia/reperfusion, KO, activation/overexpression of ALDH2 were associated with increased and decreased renal injury, respectively. In murine renal tubular epithelial cells (RTECs), ALDH2 upregulated Beclin-1 expression, promoted autophagy activation, and eliminated ROS. In vivo and in vitro, both 3-MA and Beclin-1 siRNAs inhibited autophagy and abolished ALDH2-mediated renoprotection. In mice with iohexol-induced AKI, ALDH2 knockdown in RTECs using AAV-shRNA impaired autophagy activation and aggravated renal injury. In human renal proximal tubular epithelial HK-2 cells exposed to iohexol, ALDH2 activation potentiated autophagy and attenuated apoptosis. In mice with AKI induced by renal ischemia/reperfusion, ALDH2 overexpression or pretreatment regulated autophagy mitigating apoptosis of RTECs and renal injury. In summary, our data collectively substantiate a critical role of ALDH2 in AKI via autophagy activation involving the Beclin-1 pathway.

Analysis of potential factors contributing to refusal of invasive strategy after ST-segment elevation myocardial infarction in China.

BACKGROUND: Reduced application of percutaneous coronary intervention (PCI) is associated with higher mortality rates after ST-segment elevation myocardial infarction (STEMI). We aimed to evaluate potential factors contributing to the refusal of PCI in STEMI patients in China. METHODS: We studied 957 patients diagnosed with STEMI in the emergency departments (EDs) of six public hospitals in China. The differences in baseline characteristics and 30-day outcome were investigated between patients who refused PCI and those who underwent PCI. Multivariable logistic regression was used to evaluate the potential factors associated with refusing PCI. RESULTS: The potential factors contributing to refusing PCI were older than 65 years (odds ratio [OR] 2.66, 95% confidence interval [CI] 1.56-4.52, P < 0.001), low body mass index (BMI) (OR 0.91, 95% CI 0.84-0.98, P = 0.013), not being married (OR 0.29, 95% CI 0.17-0.49, P < 0.001), history of myocardial infarction (MI) (OR 2.59, 95% CI 1.33-5.04, P = 0.005), higher heart rate (HR) (OR 1.02, 95% CI 1.01-1.03, P = 0.002), cardiac shock in the ED (OR 5.03, 95% CI 1.48-17.08, P = 0.010), pre-hospital delay (>12 h) (OR 3.31, 95% CI 1.83-6.02, P < 0.001) and not being hospitalized in a tertiary hospital (OR 0.45, 95% CI 0.27-0.75, P = 0.002). Compared to men, women were older, were less often married, had a lower BMI and were less often hospitalized in tertiary hospitals. CONCLUSIONS: Patients who were older, had lower economic or social status, and had poorer health status were more likely to refuse PCI after STEMI. There was a sex difference in the potential predictors of refusing PCI. Targeted efforts should be made to improve the acceptance of PCI among patients with STEMI in China.

Aldehyde dehydrogenase 2 preserves mitochondrial morphology and attenuates hypoxia/reoxygenation-induced cardiomyocyte injury.

BACKGROUND: Disturbance of mitochondrial fission and fusion (termed mitochondrial dynamics) is one of the leading causes of ischemia/reperfusion (I/R)-induced myocardial injury. Previous studies showed that mitochondrial aldehyde dehydrogenase 2 (ALDH2) conferred cardioprotective effect against myocardial I/R injury and suppressed I/R-induced excessive mitophagy in cardiomyocytes. However, whether ALDH2 participates in the regulation of mitochondrial dynamics during myocardial I/R injury remains unknown. METHODS: In the present study, we investigated the effect of ALDH2 on mitochondrial dynamics and the underlying mechanisms using the H9c2 cells exposed to hypoxia/reoxygenation (H/R) as an in vitro model of myocardial I/R injury. RESULTS: Cardiomyocyte apoptosis was significantly increased after oxygen-glucose deprivation and reoxygenation (OGD/R), and ALDH2 activation largely decreased the cardiomyocyte apoptosis. Additionally, we found that both ALDH2 activation and overexpression significantly inhibited the increased mitochondrial fission after OGD/R. Furthermore, we found that ALDH2 dominantly suppressed dynamin-related protein 1 (Drp1) phosphorylation (Ser616) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation (Thr172) but not interfered with the expression levels of mitochondrial shaping proteins. CONCLUSIONS: We demonstrate the protective effect of ALDH2 against cardiomyocyte H/R injury with a novel mechanism on mitochondrial fission/fusion.

Differentially expressed lncRNAs, miRNAs and mRNAs with associated ceRNA networks in a mouse model of myocardial ischemia/reperfusion injury.

Non­coding RNAs, including long non­coding RNAs (lncRNAs) and microRNAs (miRNAs/miRs), have significant regulatory effects on a number of biological processes in myocardial ischemia/reperfusion (I/R) injury, including cell differentiation, proliferation and apoptosis. In the present study, the expression levels of lncRNAs, miRNAs and mRNAs were evaluated in a mouse model of myocardial I/R injury. The potential functions of these differentially expressed genes were then analyzed via Gene Ontology and pathway analyses. Additionally, the interactions between lncRNA­miRNA­mRNA were predicted by constructing a competing endogenous RNA regulatory network. It was found that 14,366 lncRNAs, 151 miRNAs and 9,377 mRNAs were differentially expressed in mice hearts after I/R compared with the Sham group (fold change >2; P<0.05). The results indicated that these differentially expressed genes were involved in multiple molecular functions, including 'guanosine diphosphate binding', 'RNA polymerase II carboxy­terminal domain kinase activity', 'TATA­binding protein­class protein binding', 'nicotinamide adenine dinucleotide binding' and 'protein phosphatase type 2A regulator activity'. The interactions between lncRNA­miRNA­mRNA, including five lncRNAs, 38 miRNAs and 196 mRNAs, were predicted, specifically Gm12040­mmu­miR­125a­5p­decapping mRNA 1B, Rpl7l1­ps1­mmu­miR­124­3p­G protein­coupled receptor 146, Gm11407­mmu­miR­190a­5p­homeobox and leucine zipper encoding (HOMEZ), 1600029O15Rik­mmu­miR­132­3p­HOMEZ and AK155692­mmu­miR­1224­3p­activating transcription factor 6ß. Collectively, these findings provided novel insights for future research on lncRNAs, miRNAs and mRNAs in myocardial I/R injury.