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In the past studies, it is shown that cardiac troponin I (cTnI, encoded by TNNI3), as a cytoplasmic protein, is an inhibitory subunit in troponin complex, and involves in cardiomyocyte diastolic regulation. Here, we assessed a novel role of cTnI as a nucleoprotein. Firstly, the nuclear translocation of cTnI was found in mouse, human fetuses and rat heart tissues. In addition, there were differences in percentage of intranuclear cTnI in different conditions. Based on weighted gene co-expression network analyses (WGCNA) and verification in cell experiments, a strong expression correlation was found between TNNI3 and Atp2a2, which encodes sarco-endoplasmic reticulum Ca2+ ATPase isoform 2a (SERCA2a), and involves in ATP hydrolysis and Ca 2+ transient. TNNI3 gain and loss caused Atpa2a2 increase/decrease in a dose-dependent manner both in mRNA and protein levels, in vivo and in vitro. By using ChIP-sequence we demonstrated specific binding DNA sequences of cTnI were enriched in ATP2a2 promoter −239∼-889 region and the specific binding sequence motif of cTnI was analyzed by software as "CCAT", which has been reported to be required for YY1 binding to the promoter region of YY1-related genes. Moreover, it was further verified that pcDNA3.1 (−)-TNNI3 could express cTnI proteins and increase the promoter activity of Atp2a2 through luciferase report assay. In the end, we evaluated beat frequencies, total ATP contents, Ca 2+ transients in TNNI3-siRNA myocardial cells. These findings indicated, for the first time, cTnI may regulate Atp2a2 in cardiomyocytes as a co-regulatory factor and participate in the regulation of intracellular Ca ions.

Cardiac Troponin I (cTnI) is a subunit of the thin filament involved in regulation of heart contraction. Mutated cTnI accounts for most genetic mutations associated with restrictive cardiomyopathy (RCM). We previously found phosphodiesterase 4D (PDE4D) decreased in RCM mice with cTnIR193H mutation and the mutant cTnI might be involved in PDE4D reduction. This study aims to elucidate a novel role of cTnIR193H mutant as a gene regulator. Overexpression of cTnIR193H mutant in cardiomyocytes showed decrease in PDED4D protein expression, while the enrichment of histone deacetylase 1 (HDAC1) was increased along with decreases in acetylated lysine 4 (acH3K4) and 9 (acH3K9) levels in the PDE4D promoter. HDAC1 overexpression could also downregulate PDE4D via reducing acH3K4 and acH3K9 levels. Co-IP assays showed that cTnIR193H mutant owed increased binding ability to HDAC1 compared with wild type cTnI. EGCG as a HDAC1 inhibitor could diminish the strength of cTnIR193H-HDAC1 interactions and alleviate the reduction in PDE4D expression. Together, our data indicated that cTnIR193H mutant could repress PDE4D expression in cardiomyocytes through HDAC1 associated histone deacetylation modification. Unlike the typical function of cTnI in cytoplasm, our study suggested a novel role of cTnI mutants in nuclei in regulating gene expression.

Air injection is an accessory technique during scleral buckling (SB). Subclinical subretinal fluid (SRF) may presence and persistent after SB. The impact of air injection on SRF is unclear. In the study, we retrospectively enrolled 51 patients with macular-involving RD who had undergone successful SB. They were categorized into Group A (SB without air injection) and Group B (SB with air injection). First, we found that although group B seem to be severer than group A before surgery, Kaplan–Meier graph showed that SRF absorbed more rapidly in group B after surgery, and the incidence of SRF in group B was much lower during the whole follow-up period. Moreover, the cases with superior breaks had the lowest incidence. Second, during the follow-up period, there was no significant difference about postoperative complication between two groups. Lastly, risk factors for persistent SRF were investigated with binary logistic regression, and no risk factor was found. In conclusion, air injection during the SB might accelerate SRF absorption and reduce the incidence of persistent SRF, especially for the longstanding macular-off RD with superior breaks.

Left ventricular noncompaction (LVNC) is a heterogeneous disorder with unclear genetic causes and an unknown mechanism. eIF3a, an important member of the Eukaryotic translation initiation factor 3 (eIF3) family, is involved in multiple biological processes, including cell proliferation and migration during myocardial development, suggesting it could play a role in LVNC development. To investigate the association between a novel variant (c.1145 A- > G) in eIF3a and LVNC, and explore potential mechanisms that could lead to the development of LVNC. A novel eIF3a variant, c.1145 A- > G, was identified by whole-exome sequencing in a familial pedigree with LVNC. Adenovirus vectors containing wild-type eIF3a and the mutated version were constructed and co-infected into H9C2 cells. Cell proliferation, apoptosis, cell migration, and differentiation, as well as phosphorylation of ERK1/2 were studied and were measured by proliferation assays, flow cytometry, real-time PCR and Western blot, respectively. The eIF3a mutation inhibited the proliferation of H9C2 cells, induced apoptosis, promoted cell migration, and inhibited the differentiation of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). The effect of the eIF3a mutation may be attributed to a decrease in expression of p-ERK1/2. A novel eIF3a gene mutation disrupted the p-ERK1/2 pathway and caused decreased myocardium proliferation, differentiation, accelerated migration.This finding may provide some insight into the mechanism involved in LVNC development.

MG53 is an important membrane repair protein and partially protects bone marrow multipotent adult progenitor cells (MAPCs) against oxidized low-density lipoprotein (ox-LDL). The present study was to test the hypothesis that the limited protective effect of MG53 on MAPCs was due to ox-LDL-induced reduction of MG53. MAPCs were cultured with and without ox-LDL (0-20 μg/mL) for up to 48 hours with or without MG53 and antioxidant N-acetylcysteine (NAC). Serum MG53 level was measured in ox-LDL-treated mice with or without NAC treatment. Ox-LDL induced significant membrane damage and substantially impaired MAPC survival with selective inhibition of Akt phosphorylation. NAC treatment effectively prevented ox-LDL-induced reduction of Akt phosphorylation without protecting MAPCs against ox-LDL. While having no effect on Akt phosphorylation, MG53 significantly decreased ox-LDL-induced membrane damage and partially improved the survival, proliferation and apoptosis of MAPCs in vitro. Ox-LDL significantly decreased MG53 level in vitro and serum MG53 level in vivo without changing MG53 clearance. NAC treatment prevented ox-LDL-induced MG53 reduction both in vitro and in vivo. Combined NAC and MG53 treatment significantly improved MAPC survival against ox-LDL. These data suggested that NAC enhanced the protective effect of MG53 on MAPCs against ox-LDL through preventing ox-LDL-induced reduction of MG53. ispartof: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE vol:24 issue:1 pages:886-898 ispartof: location:England status: published

GATA4 is a particularly important cardiogenic transcription factor and serves as a potent driver of cardiogenesis. Recent progress in the field has made it clear that histone acetylation can influence gene expression through changing the structure of chromatin. Our previous research had revealed that hypo-acetylation could repress gata4 expression in cardiocytes, however the underlying mechanism by which this occurred was still unclear. To reveal the mechanism of histone acetylation involved in the regulation of gata4 transcription, we concentrated on P300, one of the important histone acetyltransferase associated with cardiogenesis. We found that P300 participated in gata4 expression through regulating histone acetylation in embryonic mouse hearts. RNAi-mediated downregulation of P300 modulated the global acetylation of H3 and the acetylation of H3K4, H3K9, and H3K27 in gata4 and Tbx5 promoters. Interestingly, there was an obvious inhibition of gata4 transcription, whereas Tbx5 was not influenced. Furthermore, SGC-CBP30, the selective inhibitor of the bromodomain in CBP/P300, downregulated gata4 transcription by repressing the acetylation of H3K4, H3K9, and H3K27 in the gata4 promoters. Taken together, our results identified that acetylation of H3K4, H3K9, and H3K27 mediated by P300 plays an important role in regulation of gata4 expression in cardiogenesis.

Endothelial progenitor cells (EPCs) are a group of heterogeneous cells in bone marrow (BM) and blood. Ischaemia increases reactive oxygen species (ROS) production that regulates EPC number and function. The present study was conducted to determine if ischaemia‐induced ROS differentially regulated individual EPC subpopulations using a mouse model concomitantly overexpressing superoxide dismutase (SOD)1, SOD3 and glutathione peroxidase. Limb ischaemia was induced by femoral artery ligation in male transgenic mice with their wild‐type littermate as control. BM and blood cells were collected for EPCs analysis and mononuclear cell intracellular ROS production, apoptosis and proliferation at baseline, day 3 and day 21 after ischaemia. Cells positive for c‐Kit+/CD31+ or Sca‐1+/Flk‐1+ or CD34+/CD133+ or CD34+/Flk‐1+ were identified as EPCs. ischaemia significantly increased ROS production and cell apoptosis and decreased proliferation of circulating and BM mononuclear cells and increased BM and circulating EPCs levels. Overexpression of triple antioxidant enzymes effectively prevented ischaemia‐induced ROS production with significantly decreased cell apoptosis and preserved proliferation and significantly increased circulating EPCs level without significant changes in BM EPC populations, associated with enhanced recovery of blood flow and function of the ischemic limb. These data suggested that ischaemia‐induced ROS was differentially involved in the regulation of circulating EPC population.

Epigenetic regulations play an important role in disease development. In this study, we have investigated epigenetic regulations in restrictive cardiomyopathy mice with cTnI 193His mutation. Our results demonstrated that phosphodiesterase (PDEs) 4d was down-regulated in the heart of these mice. Further studies showed that the epigenetic modifications were associated with enhanced acetylation of histone 3 lysine 4 and lysines 9, whereas tri-methylation of histone 3 lysine 4, were decreased in histones near the PDE4d gene promoter regions. The binding levels of histone transmethylase SMYD1 and histone deacetylase HDAC1 were increased in the gene promoter regions in cTnI193His transgenic hearts. Using immune-fluorescent labeling we found an evidence of cTnI existence in the nucleus of cardiomyocytes and Western blotting further confirmed that both wild type and mutated cTnI could be detected in the cell nucleus of the hearts. Furthermore, an interaction between cTnI and SMYD1, or cTnI and HDAC1 was observed. Overexpression of the mutated cTnI in cultured cardiomyocytes reduced the expression of PDE4d. Our data suggest that the decrease of PDE4d expression in RCM mice caused by cTnI mutations may be related to epigenetic regulation, i.e., histone acetylation and methylation, and cTnI might be involved in this procedure via an interaction with HDAC1 and SMAD1 in the hearts.

Background and aims: E-selectin is a cell adhesion molecule of the vascular endothelium that mediates leukocyte rolling in the early inflammatory responses in many diseases including Kawasaki disease (KD). Previous studies have demonstrated that the expression levels of E-selectin was significantly increased in the sera of KD patients and in endothelial cells of KD patient's autopsy. In this study, we aimed to examine E-selectin levels in endothelial cells treated with sera from KD patients and explore the underlying mechanisms.Methods: Human coronary artery endothelial cells (HCAECs) were randomly incubated with sera from either healthy children [healthy control (HC group)] or pediatric KD patients [assigned as KD with coronary artery lesion (KD-CAL+ group) and KD without coronary artery lesion (KD-CAL– group)]. E-selectin levels were determined by RT-qPCR, Western blotting, and immunofluorescence. Cell adhesion assay was performed to quantify the role of E-selectin in intercellular adhesion. High-throughput cell RNA sequencing followed by functional validation was performed to explore the underlying mechanism.Results: E-selectin levels were significantly increased in KD-CAL+ group vs. HC group and KD-CAL– group. Compared with the KD-CAL– group, endothelia–monocyte adhesion was increased in the KD-CAL+ group, while E-selectin-specific siRNA could significantly rescue it. High-throughput cell RNA sequencing analysis also found a significant difference in oxidative phosphorylation (OXPHOS) levels between KD-CAL+ group and KD-CAL– group. Functional validation results further confirmed that the OXPHOS was upregulated in the KD-CAL+ group and KD-CAL– group compared to that in the HC group, while the KD-CAL+ group exhibited a higher OXPHOS than the KD-CAL– group. We also found that the E-selectin levels and endothelia–monocyte adhesion were significantly decreased by OXPHOS inhibitor oligomycin in the KD-CAL+ group and KD-CAL– group, respectively.Conclusion: Sera from KD patients stimulate OXPHOS levels and enhance E-selectin expression in HCAECs, which may contribute to the development of CAL in KD patients.

Malfunction of myocardial mitochondria plays a crucial role in the development of cardiovascular disorders, especially hypertrophic and dilated cardiomyopathies. Cardiac troponin I (cTnI) is an important structural protein and essential to contraction and relaxation of cardiomyocytes. Recent studies suggest that mutated cTnIR193H could function as a regulatory molecule for other cell functions. This study was to determine whether mutated cTnI could contribute to mitochondrial dysfunction of cardiomyocytes. Primary cardiomyocytes were transfected with cTnIR193H adenovirus with empty vector as control. Mitochondrial structure and function were evaluated in the cells 72 h after transfection. Transmission electron microscopy examination showed mitochondria in the cardiomyocytes with R193H mutation displayed broken cristae, vacuolation, and mitophagy. Mitochondrial function studies revealed a significant decrease in complex I activity, ATP and reactive oxygen species levels, and oxygen consumption rate compared with controls. Western blot analysis demonstrated that expressions of mitochondria-related genes, including ND5 (ubiquinone oxidoreductase chain 5), LRPPRC (a leucine-rich protein of pentatricopeptide repeat family), and PGC-1α (PPARG co-activator 1 alpha), were significantly downregulated in R193H mutation cardiomyocytes compared with the control. Swelling and broken cristae were observed in the mitochondria of cardiomyocytes from cTnIR193H mutation transgenic mice with decreased mitochondrial function, not from the littermate control mice. The data from the present study demonstrated that mitochondrial structure and function were significantly impaired in cardiomyocytes with cTnIR193H mutation, suggesting that cTnI might be critically involved in maintaining the structural and functional integrity of myocardial mitochondria.

Background. Tumor microenvironment (TME) is closely related to the progression of glioma and the therapeutic effect of drugs on this cancer. The aim of this study was to develop a signature associated with the tumor immune microenvironment using machine learning. Methods. We downloaded the transcriptomic and clinical data of glioma patients from the Chinese Glioma Genome Atlas (CGGA) databases (mRNAseq_693). The single-sample Gene Set Enrichment Analysis (ssGSEA) database was used to quantify the relative abundance of immune cells. We divided patients into two different infiltration groups via unsupervised clustering analysis of immune cells and then selected differentially expressed genes (DEGs) between the two groups. Survival-related genes were determined using Cox regression analysis. We next randomly divided patients into a training set and a testing set at a ratio of 7 : 3. By integrating the DEGs into least absolute shrinkage and selection operator (LASSO) regression analysis in the training set, we were able to construct a 15-gene signature, which was validated in the testing and total sets. We further validated the signature in the mRNAseq_325 dataset of CGGA. Results. We identified 74 DEGs associated with tumor immune infiltration, 70 of which were significantly associated with overall survival (OS). An immune-related gene signature was established, consisting of 15 key genes: adenosine triphosphate (ATP)-binding cassette subfamily C member 3 (ABCC3), collagen type IV alpha 1 chain (COL4A1), podoplanin (PDPN), annexin A1 (ANXA1), COL4A2, insulin-like growth factor binding protein 2 (IGFBP2), serpin family A member 3 (SERPINA3), CXXC-type zinc finger protein 11 (CXXC11), junctophilin 3 (JPH3), secretogranin III (SCG3), secreted protein acidic and rich in cysteine (SPARC)-related modular calcium-binding protein 1 (SMOC1), Cluster of Differentiation 14 (CD14), COL1A1, S100 calcium-binding protein A4 (S100A4), and transforming growth factor beta 1 (TGF-β1). The OS of patients in the high-risk group was worse than that of patients in the low-risk group. GSEA showed that interleukin-6 (IL-6)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT3) signaling, interferon gamma (IFN-γ) response, angiogenesis, and coagulation were more highly enriched in the high-risk group and that oxidative phosphorylation was more highly enriched in the low-risk group. Conclusion. We constructed a stable gene signature associated with immune infiltration to predict the survival rates of glioma patients.

Congenital myasthenic syndrome (CMS) is a group of genetic disorders of neuromuscular transmission that is characterized by muscle weakness. A mutation in the gene encoding agrin (AGRN) is a rare cause of CMS, and only a few families or isolated cases have been reported. We reported a pediatric proband exhibiting muscle weakness in the trunk and limbs with skeletal malformation and intellectual disability and performed whole-exome sequencing (WES) of the proband parent-offspring trio. Results revealed a new compound heterozygous mutation in AGRN: c.125A>C (p.Glu42Ala) in the N-terminal agrin domain (NtA) and c.4516G>A (p.Ala1506Thr) in the laminin G1 domain (LG1). Bioinformatic analysis predicted the mutation as possibly pathogenic. The new compound heterozygous mutation in AGRN may disrupt agrin's known function of bridging laminin and α-dystroglycan and undermine the formation and maintenance of the neuromuscular junction (NMJ) via both muscular and neural agrin pathways. It may also induce secondary peripheral neuropathy and skeletal malformation.

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Cyanotic congenital heart disease (CCHD), a term describing the most severe congenital heart diseases are characterized by the anatomic malformation of a right to left shunt. Although the incidence of CCHD are far less than the that of congenital heart diseases (CHD), patients with CCHD always present severe clinical features such as hypoxia, dyspnea, and heart failure. Chronic hypoxia induces hypoxemia that significantly contributes to poor prognosis in CCHD. Current studies have demonstrated that the prolyl-4-hydroxylase2 (PHD2, encoded by EGLN1)/hypoxia-inducible factor-1A (HIF-1A) pathway is a key regulator of hypoxic response. Thus, we aim to assess the associations of single polymorphisms (SNPs) of the EGLN1 gene and hypoxic response in CCHD. A missense variant of EGLN1 c.380G>C (rs1209790) was found in 46 patients (46/126), with lower hypoxia incidence and higher rate of collateral vessel formation, compared with the wild type (P C showed improved response to hypoxia compared with the wild-type counterparts. The EGLN1 c.380G>C mutation improves hypoxic response through the PHD2/HIF-1A pathway, which may provide a molecular mechanism for hypoxic response in CCHD. The effects of the EGLN1 c.380G>C mutation on CCHD prognosis deserve further investigation. Keywords: Cyanotic congenital heart disease, EGLN1, Hypoxic response, Mutation, Polymorphism

Cardiac diastolic dysfunction (CDD) is the most common form of cardiovascular disorders, especially in elderly people. Cardiac troponin I (cTnI) plays a critical role in the regulation of cardiac function, especially diastolic function. Our previous studies showed that cTnI‐low expression induced by histone acetylation modification might be one of the causes that result in diastolic dysfunction in ageing hearts. This study was designed to investigate whether epigallocatechin‐3‐gallate (EGCG) would modify histone acetylation events to regulate cTnI expression and then improve cardiac functions in ageing mice. Our study shows that EGCG improved cardiac diastolic function of aged mice after 8‐week treatment. Low expression of cTnI in the ageing hearts was reversed through EGCG treatment. EGCG inhibited the expression of histone deacetylase 1 (HDAC1) and HDAC3, and the binding levels of HDAC1 in the proximal promoter of cTnI. Acetylated lysine 9 on histone H3 (AcH3K9) levels of cTnI's promoter were increased through EGCG treatment. Additionally, EGCG resulted in an ascent of the binding levels of transcription factors GATA4 and Mef2c with cTnI's promoter. Together, our data indicate that EGCG may improve cardiac diastolic function of ageing mice through up‐regulating cTnI by histone acetylation modification. These findings provide new insights into histone acetylation mechanisms of EGCG treatment that may contribute to the prevention of CDD in ageing populations.

Endothelial progenitor cells (EPCs) are important to tissue repair and regeneration especially after ischemic injury, and very heterogeneous in phenotypes and biological features. Reactive oxygen species are involved in regulating EPC number and function. N-acetylcysteine (NAC) inhibits ischemia-induced reactive oxygen species formation and promotes ischemic limb recovery. This study was to evaluate the effect of NAC on EPC subpopulations in bone marrow (BM) and blood in mice with limb ischemia. Limb ischemia was induced by femoral artery ligation in male C57BL/6 mice with or without NAC treatment. EPC subpopulations, intracellular reactive oxygen species production, cell proliferation and apoptosis in BM and blood cells were analyzed at baseline, day 3 (acute ischemia) and 21 (chronic) after ligation. c-Kit+/CD31+, Sca-1+/Flk-1+, CD34+/CD133+, and CD34+/Flk-1+ were used to define EPC subpopulations. Limb blood flow, function, muscle structure, and capillary density were evaluated with laser Doppler perfusion imaging, treadmill test, and immunohistochemistry, respectively, at day 3, 7, 14 and 21 post ischemia. Reactive oxygen species production in circulating and BM mononuclear cells and EPCs populations were significantly increased in BM and blood in mice with acute and chronic ischemia. NAC treatment effectively blocked ischemia-induced reactive oxygen species production in circulating and BM mononuclear cells, and selectively increased EPC population in circulation, not BM, with preserved proliferation in mice with chronic ischemia, and enhanced limb blood flow and function recovery, while preventing acute ischemia-induced increase in BM and circulating EPCs. These data demonstrated that NAC selectively enhanced circulating EPC population in mice with chronic limb ischemia.

Background Our previous studies have demonstrated that Ca2+ desensitizing catechin could correct diastolic dysfunction in experimental animals with restrictive cardiomyopathy. In this study, it is aimed to assess the effects of green tea extract catechin on cardiac function and other clinical features in pediatric patients with cardiomyopathies. Methods Twelve pediatric cardiomyopathy patients with diastolic dysfunction were enrolled for the study. Echocardiography, ECG, and laboratory tests were performed before and after the catechin administration for 12 months. Comparison has been made in these patients before and after the treatment with catechin. Next Generation Sequencing was conducted to find out the potential causative gene variants in all patients. Results A significant decrease of isovolumetric relaxation time (115 ± 46 vs 100 ± 42 ms, P = 0.047 at 6 months; 115 ± 46 vs 94 ± 30 ms, P = 0.033 at 12 months), an increase of left ventricle end diastolic volume (40 ± 28 vs 53 ± 28 ml, P = 0.028 at 6 months; 40 ± 28 vs 48 ± 33 ml, P = 0.011 at 12 months) and stroke volume (25 ± 16 vs 32 ± 17 ml, P = 0.022 at 6 months; 25 ± 16 vs 30 ± 17 ml, P = 0.021 at 12 months) were observed with echocardiography in these patients 6-month after the treatment with catechin. Ejection fraction, left ventricular wall thickness, biatrial dimension remained unchanged. No significant side effects were observed in the patients tested. Conclusions This study indicates that Ca2+ desensitizing green tea extract catechin, is helpful in correcting the impaired relaxation in pediatric cardiomyopathy patients with diastolic dysfunction. Electronic supplementary material The online version of this article (10.1186/s12929-019-0528-7) contains supplementary material, which is available to authorized users.

Down syndrome (DS), as a typical genomic aneuploidy, is a common cause of various birth defects, among which is congenital heart disease (CHD). 40–60% neonates with DS have some kinds of CHD. However, the molecular pathogenic mechanisms of DS associated CHD are still not fully understood. This review summarizes available studies on DS associated CHD from seven aspects so as to provide a crucial and updated overview of what we known so far in this domain. Keywords: Down syndrome, Congenital heart disease, Molecular mechanisms

Synthetic apolipoprotein A-I (apoA-I) mimetic peptide 5F exhibits anti-atherosclerotic ability with largely unknown mechanism(s). Bone marrow (BM)-derived endothelial progenitor cells (EPCs) play a critical role in vascular integrity and function. The objective of the present study was to evaluate the effect of 5F on endothelial differentiation of BM stem cells and related mechanisms. Murine BM multipotent adult progenitor cells (MAPCs) were induced to differentiate into endothelial cells in vitro with or without 5F. The expression of endothelial markers vWF, Flk-1 and CD31 was significantly increased in the cells treated with 5F with enhanced in vitro vascular tube formation and LDL uptake without significant changes on proliferation and stem cell maker Oct-4 expression. Phosphorylated ERK1/2, not Akt, was significantly increased in 5F-treated cells. Treatment of MAPCs with PD98059 or small interfering RNA against ERK2 substantially attenuated ERK1/2 phosphorylation, and effectively prevented 5F-induced enhancement of endothelial differentiation of MAPCs. In vivo studies revealed that 5F increased EPCs number in the BM in mice after acute hindlimb ischemia that was effectively prevented with PD98059 treatment. These data supported the conclusion that 5F promoted endothelial differentiation of MAPCs through activation of ERK1/2 signaling.

In this study, we investigated whether unique pathological characteristics exist in teratomas that can trigger autoimmune anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis. We compared a case of retroperitoneal teratoma associated with anti-NMDAR encephalitis and four control cases. The encephalitis-positive case showed that (i) more dysplastic neuroglia with higher Ki-67 labeling index values than the control cases, which met the diagnostic criteria of astrocytoma, (ii) the NMDAR subunit NR1 was expressed more abundantly in neuroglial tissue where many neuroglial cells co-expressed glial fibrillary acidic protein (GFAP) and NR1 and formed abnormally large cellular masses, (iii) intense NR1 expression occurs in squamous epithelium near neuroglial tissue and lymphocyte infiltration. This study showed that dysplastic neuroglial tissue resembling central nervous system tumors, which might promote autoimmunity, distinguished the case with NMDAR encephalitis from the controls. Additionally, abnormal expression of NR1 occurs in non-neural tissues and could be triggered by inflammation and participate in autoimmunity.

Heart failure is a common, costly, and potentially fatal condition. The cardiac sarcoplasmic reticulum Ca-ATPase (SERCA2a) plays a critical role in the regulation of cardiac function. Previously, low SERCA2a expression was revealed in mice with heart failure. Epigallocatechin-3-gallate (EGCG) can function as an epigenetic regulator and has been reported to enhance cardiac function. However, the underlying epigenetic regulatory mechanism is still unclear. In this study, we investigated whether EGCG can up-regulate SERCA2a via histone acetylation and play role in preventing heart failure. For this, we generated a mouse model of heart failure by performing a minimally invasive transverse aortic constriction (TAC) operation and used this to test the effects of EGCG. The TAC+EGCG group showed nearly normal cardiac function compared to that in the SHAM group. The expression of SERCA2a was decreased at both the mRNA and protein levels in the TAC group but was enhanced in the TAC+EGCG group. Levels of AcH3 and AcH3K9 were determined to decrease near the promoter region of Atp2a2 (the gene encoding SERCA-2a) in the TAC group, but were elevated in the TAC+EGCG group. Meanwhile, HDAC1 activity and binding near the Atp2a2 promoter were increased in the TAC group but decreased with EGCG addition. Further, binding levels of GATA4 and Mef2c near the Atp2a2 promoter region were reduced in TAC hearts, which might have been caused by histone hypoacetylation; this was reversed by EGCG. Together, upregulation of SERCA2a via the modification of histone acetylation plays a role in EGCG-mediated prevention of pressure overload-induced heart failure, and this might represent a novel pharmacological target for the treatment of heart failure.

Early-onset epileptic encephalopathies (EOEEs) are clinically and genetically heterogeneous disorders characterized by intractable seizures and unremitting interictal paroxysmal epileptiform activity. Consequently, these syndromes impair neurodevelopment during the first year of life. Currently, the etiology of these disorders is largely unknown. In this study, Childhood-Onset Epilepsy Gene Panel Testing (containing 511 epilepsy-related genes) was performed in a parent-offspring trio. In this family, the son had refractory seizures, intellectual disability, and motor abnormalities, and he was diagnosed with EOEE. The boy later died from a sudden unexpected death in epilepsy (SUDEP) at the age of 26 months. In this case, we identified a de novo mutation (c.4423G > A; glycine [Gly]1475 arginine [Arg]) classified as heterozygous missense located in the inactivation gate section of the SCN8A (voltage-gated sodium-channel type VIII alpha subunit) gene. This result strengthens the association between the SCN8A gene and EOEE, and more attention should be given to its high rate of SUDEP. Further studies to determine the pathogenic mechanisms of SCN8A mutations should be warranted at the inactivation gate section of this sodium channel in both neurons and cardiac muscles.

Background Bone marrow derived stem cells (BMSCs) have the potential to differentiate into cardiomyocytes, but the rate of differentiation is low and the mechanism of differentiation is unclear completely. Here, we aimed to investigate the role of miR1-2 in differentiation of mouse BMSCs into cardiomyocyte-like cells and reveal the involved signaling pathways in the procedure. Methods Mouse BMSCs were treated with miR1-2 and 5-azacytine (5-aza). The expression of cardiac cell markers: NKx2.5, cTnI and GATA4 in BMSCs were examined by qPCR. The apoptosis rate was detected by flow cytometry and the activity of the Wnt/β-catenin signaling pathway was evaluated by measuring the upstream protein of this signaling pathway. Results After over-expression of miR1-2 in mouse BMSCs, the apoptosis rate was significantly lower than the 5-aza group, while the expressions of cardiac-specific genes: such as Nkx2.5, cTnI and GATA4 were significantly increased compared to the control group and the 5-aza group. Meanwhile, over-expression of miR1-2 in mouse BMSCs enhanced the expression of wnt11, JNK, β-catenin and TCF in the Wnt/β-catenin signaling pathway. Use of LGK-974, an inhibitor of Wnt/β-catenin signaling pathway, significantly reduced the expression of cardiac-specific genes and partially blocked the role of the miR1-2. Conclusion Over-expression of miR1-2 in mouse BMSCs can induce them toward promoted cardiomyocyte differentiation via the activation of the Wnt/β-catenin signaling pathway. Compared to 5-aza, miR1-2 can induce differentiation of BMSCs into cardiomyocytes more effectively with a less cytotoxicity.

One of the most challenging issues in HIV-associated neurocognitive disorders (HAND) caused by HIV-1 virotoxins and drug abuse is the lack of understanding the underlying mechanisms that are commonly associated with disorders of the blood-brain barrier (BBB), which mainly consists of brain microvascular endothelial cells (BMEC). Here, we hypothesized that Glycoprotein 120 (gp120), methamphetamine (METH) and nicotine (NT) can enhance amyloid-beta (Aβ) accumulation in BMEC through Alpha7 nicotinic acetylcholine receptor (α7 nAChR). Both in vitro (human BMEC) (HBMEC) and in vivo (mice) models of BBB were used to dissect the role of α7 nAChR in up-regulation of Aβ induced by gp120, METH and NT. Aβ release from and transport across HBMEC were significantly increased by these factors. Methyllycaconitine (MLA), an antagonist of α7 nAChR, could efficiently block these pathogenic effects. Furthermore, our animal data showed that these factors could significantly increase the levels of Aβ, Tau and Ubiquitin C-Terminal Hydrolase L1 (UCHL1) in mouse cerebrospinal fluid (CSF) and Aβ in the mouse brains. These pathogenicities were significantly reduced by MLA, suggesting that α7 nAChR may play an important role in neuropathology caused by gp120, METH and NT, which are the major pathogenic factors contributing to the pathogenesis of HAND.

Background Abusive alcohol utilization of pregnant woman may cause congenital heart disease (CHD) of fetus, where alcohol ignites histone H3 hyperacetylation leading to abnormal development of heart morphogenesis and associated genes. Knowledge about the regularized upstream genes is little, but bone morphogenetic protein (BMP) signaling may actively and prominently take part in alteration in acetylation of histone H3. The supreme objective of this study was to unearth the involvement of BMP signaling pathway in alcohol-driven hyperacetylation of histone H3 in cardiomyoblast cells. Methods Cardiomyoblast cells (H9c2 cells) were addicted with alcohol (100 mM) for 24 hours. Dorsomorphin (5 μM) was used for the inhibition of BMP signaling pathway. We detected the phosphorylation activity of SMAD1/5/8, mRNA expression, histone acetyltransferases (HAT)/histone deacetylase (HDAC) activity, and acetylation of histone H3. Results Following alcohol exposure, phosphorylation of SMAD1/5/8 and HAT activities was increased to a significant extent, while histone H3 acetylation and expression of heart development-related genes were also increased. The said phenomenon influenced by alcohol was reverted upon dorsomorphin treatment to the cells without effecting HDAC activity. Conclusions The data clearly identified that BMP-mediated histone H3 acetylation of heart development-related genes might be one of the possible cellular mechanisms to control alcohol-induced expression of heart development-related genes. Dorsomorphin, on the other hand, may modulate alcohol-induced hyperacetylation of histone H3 through BMP targeting, which could be a potential way to block CHD.

Background Recurrent convulsions can cause irreversible astrocyte death, impede neuron regeneration, and further aggravate brain damage. MicroRNAs have been revealed as players in the progression of numerous diseases including cancer and Alzheimer’s disease. Particularly, microRNA has been found linked to seizure-induced neuronal death. In this study, a rat model of recurrent convulsions induced by flurothyl treatments was utilised to assess the alterations of microRNA expressions in hippocampus tissues. We also applied an in vitro model in which primary astrocytes were exposed to kainic acid to verify the targets of miR-34b-5p identified in the animal model. Results We discovered that miR-34b-5p, a member of the miR-34 family, increased significantly in flurothyl-treated rat hippocampus tissue. More surprisingly, this upregulation occurred concurrently with accumulating astrocyte apoptosis, indicating the involvement of miR-34b-5p in seizures caused astrocyte apoptosis. Results from the in vitro experiments further demonstrated that miR-34b-5p directly targeted Bcl-2 mRNA, translationally repressed Bcl-2 protein, and thus modulated cell apoptosis by influencing Bcl-2, Bax, and Caspase-3. Conclusion Our findings prove microRNAs play a role in mediating recurrent convulsions-induced astrocyte death and further indicate that miR-34b-5p could acts as a regulator for astrocyte apoptosis induced by recurrent seizures. Electronic supplementary material The online version of this article (doi:10.1186/s12868-016-0291-6) contains supplementary material, which is available to authorized users.