Comprehensive analysis of differentially expressed profiles of lncRNAs and mRNAs reveals ceRNA networks in the transformation of diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is one of the malignancies with a high mortality rate. The molecular mechanisms involved in transformation of DLBCL remain unclear. Therefore, it is critically important to investigate the biological mechanisms of DLBCL. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) serve key functions in tumorigenesis, cancer progression and metastasis. Compared with follicular lymphoma (FL), a total of 123 upregulated lncRNAs and 192 downregulated lncRNAs in DLBCL were identified. Subsequently, a specific DLBCL-associated competing endogenous RNA (ceRNA) network and a specific FL-associated ceRNA network was constructed. Gene Oncology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that differentially expressed lncRNAs served key functions in regulating signal transduction, transcription, cell adhesion, development and protein amino acid phosphorylation. Furthermore, the molecular functions of PRKCQ antisense RNA 1, HLA complex P5, OIP5 antisense RNA 1, growth arrest specific 5 and taurine upregulated 1 were investigated, and it was revealed that these lncRNAs served important functions in regulating a series of biological processes, including anti-apoptosis, cell cycle, DNA repair, response to oxidative stress and transcription. The present study may provide a potential novel therapeutic and prognostic target for the treatment of DLBCL.

Humanin prevents high glucose-induced monocyte adhesion to endothelial cells by targeting KLF2.

Endothelial dysfunction and vascular complications induced by hyperglycemia play an important role in the pathological development of atherosclerosis in diabetes. Humanin, a 24-amino acid mitochondria-derived polypeptide, has displayed its cytoprotective effects in diverse cell types and tissues. In the current study, we aimed to characterize the effects of humanin on high glucose-induced endothelial dysfunction. Firstly, we found that humanin treatment induced the expression of Krüppel-like factor 2 (KLF2), an essential transcriptional regulator of endothelial function, at the transcriptional level in human umbilical vein endothelial cells (HUVECs). Additionally, our results indicate that humanin treatment regulated the expression of KLF2 target genes such as endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1). Evidence demonstrated that the effects of humanin on KLF2 expression was mediated by the phosphorylation of extracellular signal regulated kinase 5 (ERK5). Furthermore, humanin restored high glucose-induced reduction of KLF2 expression. We also showed that humanin significantly reduced the expression of vascular cell adhesion molecule 1 (VCAM-1) and E-selectin. Notably, humanin treatment markedly prevented high glucose-induced attachment of the monocyte THP-1 cells to HUVECs. However, knockdown of KLF2 abolished these effects. Lastly, we report that humanin treatment inhibited high glucose-induced secretion of tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). These findings suggest that humanin may have therapeutic potential for the treatment of hyperglycemia-associated endothelial dysfunction.

Long Noncoding RNA AK12348 is Involved in the Regulation of Myocardial Ischaemia-Reperfusion Injury by Targeting PARP and Caspase-3.

BACKGROUD: Recently long non-coding RNAs (lncRNAs) have attracted attention in several biomedical fields. The purpose of this study is to investigate the profile of myocardial lncRNAs and their potential roles in myocardial ischaemia-reperfusion injury (IRI). METHODS: EdgeR bioconductor package was used to screen differentially expressed lncRNAs in myocardial IRI, and lncRNA AK12348 was selected. The mRNA levels of lncRNA AK12348 in normal and anoxia/reoxygenation (A/R) cardiomyocytes were determined by qRT-PCR. After transfection with siRNA-lncRNA, AK12348, LDH release and cell apoptotic rates in normal and A/R cardiomyocytes were determined. The protein expression values of PARP and Caspase-3 were also determined by western blotting. RESULTS: The relative level of lncRNA AK12348, LDH release and cell apoptotic rate in A/R cardiomyocytes was significantly higher than that in normal cardiomyocytes. After transfection with siRNA-lncRNA AK12348, LDH release and cell apoptotic rates in A/R cardiomyocytes were reduced, while the values in normal cardiomyocytes had almost no change. The protein expression values of PARP and Caspase-3 in A/R cardiomyocytes were much higher than the Control. After knockdown of lncRNA AK12348, the values decreased. CONCLUSION: Long non-coding RNAs AK12348 could be potential therapeutic targets for the treatment of myocardial IRI.

α-Tocopherol, especially α-tocopherol phosphate, exerts antiapoptotic and angiogenic effects on rat bone marrow-derived endothelial progenitor cells under high-glucose and hypoxia conditions.

OBJECTIVE: Considering the poor efficacy of local intramuscular injections with endothelial progenitor cells (EPCs) for critical limb ischemia in patients with diabetes, the study aimed to investigate the effect of α-tocopherol (α-T) and α-tocopherol phosphate (α-TP) on apoptosis and angiogenesis in a rat model under oxidative stress conditions. METHODS: Primary EPCs from Sprague-Dawley rats were harvested and treated with α-T and α-TP for 24 hours. Gene transcription and protein expression were evaluated by real-time polymerase chain reaction and Western blot, respectively. Cell apoptosis, migration, and tube formation ability were detected by flow cytometry, Transwell assay (Chemicon International, Temecula, Calif), and Matrigel-based angiogenesis assay (Corning Inc, Corning, NY). The in vivo experiments were carried out using 30 single hind limb ischemic models of diabetic rats that were treated with allogeneic EPCs. Capillary density was evaluated by immunohistochemistry. RESULTS: α-T and α-TP attenuated high glucose/hypoxia-induced cell apoptosis by promoting Bcl-2 and Akt and inhibiting nuclear factor κB p65, JNK, Notch-1, and p38MAPK genes. Furthermore, α-T and α-TP promoted the transcription and expression of vascular endothelial growth factor receptor 2 and decreased the transcription and expression of Tie-2 and Notch-1 in EPCs under high-glucose/hypoxic conditions. Moreover, α-T and especially α-TP enhanced the migratory activity of EPCs under high-glucose/hypoxic conditions. Capillary density of ischemic hind limbs was increased on day 14 after administration of EPCs pretreated with α-T and α-TP. CONCLUSIONS: α-T, especially α-TP, possesses therapeutic potential in the inhibition of apoptosis and increases the migratory capacity of EPCs under high-glucose/hypoxic conditions. It promotes angiogenesis by upregulating Bcl-2, Akt, and vascular endothelial growth factor receptor 2 and decreasing nuclear factor κB p65, p38MAPK, Notch-1, JNK, and Tie-2.

Drug-delivering endovascular treatment versus angioplasty in artery occlusion diseases: a systematic review and meta-analysis.

OBJECTIVE: The best management of patients with femoropopliteal and infrapopliteal artery occlusion disease is not clear. This study aimed to compare the efficacy of drug-coated balloons (DCBs) and drug-eluting stents (DESs) with percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal or infrapopliteal arterial occlusive disease. METHODS: Medline, Cochrane, Embase, and Google Scholar databases were searched for randomized controlled trials from 1 January 2000 until 30 June 2016. RESULTS: Compared with PTA, significant benefits in favor of DCB and DES were found for target lesion revascularization (TLR) (OR = 0.38, 95% CI = 0.22 to 0.66, p = .001 for DCB; OR = 0.51, 95% CI = 0.32 to 0.81, p < .001 for DES). Primary patency rate was greater with DCB (p = .001) and DES (p < .001) than PTA. Compared with PTA, a significant reduction in mortality was observed in the DCB group (p = .039) but not in the DES group. Subgroup analysis found a lower rate of TLR and a higher rate of primary patency in the active group (DCB and DES) compared with the control group (PTA) in patients with femoropopliteal arterial occlusion (p ≤ .016) but not in patients with infrapopliteal arterial occlusion (p ≥ .063). Mortality was similar between active replacement and control groups both in the femoropopliteal arterial occlusion and the infrapopliteal arterial occlusion subgroups (all p > .05). CONCLUSIONS: Significantly better TLR and primary patency rate were found in the drug-delivering endovascular treatments compared with the PTA group for patients with femoropopliteal arterial occlusion but not for patients with infrapopliteal arterial occlusion.

Advanced Glycation End-Products Downregulate HoxA9EC through Activation of Nuclear Factor Kappa B by Reciprocal Interaction.

Advanced glycation end-products (AGEs) have been recognized as an important pathophysiological mechanism in endothelial dysfunction during diabetic atherogenesis. Homeobox (Hox) genes have been identified as playing a regulatory role in the adult cardiovascular system. Regulation of HoxA9EC is involved in diabetic endothelial dysfunction, but the mechanism of HoxA9EC regulation has remained undefined. Here, we sought to investigate how HoxA9EC is regulated in AGE-induced endothelial dysfunction and to explore the mechanism involved. We used human umbilical venous endothelial cells (HUVECs) cocultured with AGEs, and examined endothelial nitric oxide synthase (eNOS) activation, nitric oxide (NO) release, cell migration, and the expression of HoxA9EC and nuclear factor kappa B (NF-κB). AGEs suppressed eNOS activation, NO release, and the migration of HUVECs. Knockout of HoxA9EC also reduced eNOS activation, NO release, and the migration of HUVECs, and the enhancement of HoxA9EC improved the function of HUVECs. Furthermore, AGEs downregulated HoxA9EC expression and activated NF-κB, and the depression of HoxA9EC was significantly attenuated by the NF-κB inhibitor. On the other hand, knockout of HoxA9EC activated NF-κB and the enhancement of HoxA9EC suppressed NF-κB activation. In conclusion, AGEs could induce endothelial dysfunction through NF-κB-dependent HoxA9EC downregulation by reciprocal interaction, and the enhancement of HoxA9EC expression could attenuate the impairment.

ox-LDL increases microRNA-29a transcription through upregulating YY1 and STAT1 in macrophages.

Macrophages and oxidized low-density lipoprotein (ox-LDL) have been verified playing vital roles in the pathogenesis of atherosclerosis (AS). Previous studies demonstrated that microRNA-29a (miR-29a) was upregulated in many atherogenic process and cells, thus acting as an important participant in AS. But the detailed regulation mechanism of miR-29a in AS has not been fully understood. In our study, we demonstrated a positive feedback loop of ox-LDL-SRA-miR-29a. Furthermore, we found that YY1 and STAT1 were upregulated in ox-LDL-stimulating macrophages followed by translocation in the nucleus and binding to the transcriptional promoter region of miR-29a, thus leading to the increase of miR-29a expression. In addition, we demonstrated that JAK1/2 signaling was involved in miR-29a upregulation. Finally, we found that miR-29a played important roles in the secretion of proinflammation factors and lipid uptake in macrophages. We uncovered the molecular mechanism and provide novel insights into the function and regulatory network of miR-29a expression regulated by ox-LDL in macrophages.

Case report of pulmonary epithelial trophoblastic tumor in a young female patient.

INTRODUCTION: An epithelial trophoblastic tumor (ETT) is a kind of rare trophoblastic tumor that may have the correlation with a prior gestational event. Especially, the one that appears in the lung is extremely rare. CASE SUMMARY: Here, we present a 24-year-old female patient with the chief complain of vaginal bleeding for more than 1 month, who was found to have a large mass (7.5 × 4.5 cm) in the right lower lobe, and it was finally confirmed as lung ETT by postoperative pathology after a successful radical resection of the pulmonary lobe. CONCLUSIONS: As the reason of an extreme rare occurrence of the ETT, doctors can easily misdiagnose the disease. When the patient was found to have a mass with irregular vaginal bleeding and a high level of beta-human chorionic gonadotropin, we need to consider ETT. Currently, surgery is still the most effective method.

Inhibition of AMPK-related kinase 5 (ARK5) enhances cisplatin cytotoxicity in non-small cell lung cancer cells through regulation of epithelial-mesenchymal transition.

Lung cancer incidence and mortality rates are amongst the highest of all malignant tumors worldwide. ARK5 is a member of the human AMP-activated protein kinase (AMPK) family which is implicated in tumor survival and progression. The current study was designed to explore the role of ARK5 in resistance of non-small cell lung cancer (NSCLC) to cisplatin. We studied the sensitivity of two NSCLC cell lines, NCI-H1229 and A549, to cisplatin by using proliferation and cell viability assays. We then examined expression of ARK5, Twist, and the epithelial to mesenchymal transition (EMT) biomarkers, E-cadherin and Vimentin, by Western blot and immunofluorescence. We found that ARK5 downregulation significantly increased the cisplatin chemosensitivity of NSCLC cells, and that NCI-H1299 cells, which express high levels of ARK5 and possess a mesenchymal phenotype, were more resistant to cisplatin than A549 cells, which show low expression ARK5. Furthermore, siRNA-mediated silencing of ARK5 resulted in altered EMT patterns in NSCLC cells. These data support a role for ARK5 in regulating EMT in NSCLC cells. Together, our findings suggest that ARK5 is a potential drug target for combating drug resistance and regulating EMT in NSCLC cells.

Endovascular Management of Native Postcoarctation Thoracic Aortic Aneurysms.

PURPOSE: Postcoarctation thoracic aortic aneurysm formation is one of the most serious complications for coarctation of aorta. Open surgery to repair these aneurysms is associated with high morbidity and mortality. Endovascular therapy is an attractive alternative to open surgery. We have studied the efficacy and safety of endovascular therapy for postcoarctation thoracic aortic aneurysms, and will share our findings and experience through this document. METHODS: The data was retrospectively collected on consecutive patients who were presented with postcoarctation thoracic aortic aneurysms at our medical center. RESULTS: Between January 2006 and May 2016, 5 patients underwent elective endoluminal therapy for postcoarctation thoracic aortic aneurysms. They were treated with stent graft deployment to exclude aneurysms. All procedures were technically successful and there were no perioperative morbidity nor mortality. The median follow-up was 51.6 months (range 3-116 months). All aneurysms remained excluded and stent grafts were patent. CONCLUSION: Endovascular repair is a promising alternative to open surgery for native postcoarctation thoracic aortic aneurysms.

Identification of key genes associated with the human abdominal aortic aneurysm based on the gene expression profile.

The present study was aimed at screening the key genes associated with abdominal aortic aneurysm (AAA) in the neck, and to investigate the molecular mechanism underlying the development of AAA. The gene expression profile, GSE47472, including 14 AAA neck samples and eight donor controls, was downloaded from the Gene Expression Omnibus database. The total AAA samples were grouped into two types to avoid bias. Differentially expressed genes (DEGs) were screened in patients with AAA and subsequently compared with donor controls using linear models for microarray data, or the Limma package in R, followed by gene ontology enrichment analysis. Furthermore, a protein­protein interaction (PPI) network based on the DEGs was constructed to detect highly connected regions using a Cytoscape plugin. In total, 388 DEGs in the AAA samples were identified. These DEGs were predominantly associated with limb development, including embryonic limb development and appendage development. Nuclear receptor co­repressor 1 (NCOR1), histone 4 (H4), E2F transcription factor 4 (E2F4) and hepatocyte nuclear factor 4α (HNF4A) were the four transcription factors associated with AAA. Furthermore, HNF4A indirectly interacted with the other three transcription factors. Additionally, six clusters were selected from the PPI network. The DEG screening process and the construction of an interaction network enabled an understanding of the mechanism of AAA to be gleaned. HNF4A may exert an important role in AAA development through its interactions with the three other transcription factors (E2F4, NCOR1 and H4), and the mechanism of this coordinated regulation of the transcription factors in AAA may provide a suitable target for the development of therapeutic intervention strategies.

Cyclic RNA hsa­circ­000595 regulates apoptosis of aortic smooth muscle cells.

Aortic aneurysm is a cardiovascular condition with a serious risk of mortality and the dismal prognosis of any type of major cardiovascular disease. The present study found that tissues from aortic aneurysm patients and hypoxic aortic smooth muscle cells showed aberrant high expression of the cyclic RNA hsa­circ­000595, as demonstrated by polymerase chain reaction array screening. Knockdown of hsa­circ­000595 resulted in a decreased apoptotic rate of human aortic smooth muscle cells. Furthermore, it was determined that miR­19a is a target of hsa­circ­000595. The results of the present study laid an epigenetic foundation for exploring the underlying mechanisms of the development of aortic aneurysm.

Genetic control of juvenile growth and botanical architecture in an ornamental woody plant, Prunus mume Sieb. et Zucc. as revealed by a high-density linkage map.

Mei, Prunus mume Sieb. et Zucc., is an ornamental plant popular in East Asia and, as an important member of genus Prunus, has played a pivotal role in systematic studies of the Rosaceae. However, the genetic architecture of botanical traits in this species remains elusive. This paper represents the first genome-wide mapping study of quantitative trait loci (QTLs) that affect stem growth and form, leaf morphology and leaf anatomy in an intraspecific cross derived from two different mei cultivars. Genetic mapping based on a high-density linkage map constricted from 120 SSRs and 1,484 SNPs led to the detection of multiple QTLs for each trait, some of which exert pleiotropic effects on correlative traits. Each QTL explains 3-12% of the phenotypic variance. Several leaf size traits were found to share common QTLs, whereas growth-related traits and plant form traits might be controlled by a different set of QTLs. Our findings provide unique insights into the genetic control of tree growth and architecture in mei and help to develop an efficient breeding program for selecting superior mei cultivars.

Relationship between endothelial cell protein C receptor gene 6936A/G polymorphisms and deep venous thrombosis.

BACKGROUND: Deep venous thrombosis (DVT) can result in pulmonary embolism, a fatal complication that is due to the dislodgement and movement of a blood clot (thrombus) from a limb into the lungs. Genetic risk factors related to DVT development include mutations in coagulation proteins, especially the endothelial protein C receptor (EPCR), a component of the anticoagulation protein C (PC) pathway. The objective of the present study was to analyze the relationship between the 6936A/G polymorphism in the EPCR gene and the occurrence of DVT. METHODS: This study involved 65 patients with DVT and 71 age- and gender-matched healthy controls. Peripheral blood samples were collected from all subjects. Plasma levels of soluble EPCR (sEPCR) were measured by enzyme-linked immunosorbent assay. Genomic DNA was extracted and EPCR gene product was amplified by a standard PCR reaction. Gene product bands were sequenced to identify EPCR gene polymorphisms. RESULTS: In the control group, the level of sEPCR in subjects with 6936AG genotype was significantly higher than that in subjects with 6936AA genotype ((0.97 ± 0.32) pg/ml vs. (0.61 ± 0.24) pg/ml, P < 0.01). Similarly in the DVT group, the level of sEPCR in subjects with the 6936AG were greater than that in subjects with the 6936AA genotype ((0.87 ± 0.21) pg/ml vs. (0.50 ± 0.18) pg/ml, P < 0.01). The sEPCR level in DVT patients was significantly higher than that in healthy controls ((0.68 ± 0.32) pg/ml vs. (0.54 ± 0.22) pg/ml, P < 0.05). The 6936AG genotype frequency in DVT patients was significantly higher than that in healthy controls (P < 0.05). In contrast, the 6936AA genotype frequency in DVT patients was lower than that in healthy controls (P < 0.05). Subjects carrying 6936AG had an increased risk of thrombosis (OR = 2.75, 95%CI: 1.04 - 7.30, P < 0.05). CONCLUSIONS: EPCR gene 6936A/G polymorphism is associated with increased plasma levels of sEPCR. Subjects carrying 6936AG likely have an increased risk of thrombosis.

[Relationship between endothelial protein C receptor gene 6936A/G polymorphisms and deep venous thrombosis].

OBJECTIVE: To investigate the relationship between endothelial protein C receptor(EPCR) gene 6936A/G polymorphism and deep vein thrombosis (DVT). METHODS: The study group included 65 DVT patients and 71 normal controls. Plasma sEPCR was measured by ELISA. Genomic DNA was extracted by using Genomic Purification Kit. A 315bp EPCR product was amplified by a standard PCR reaction, and the bands were confirmed by direct sequencing after purification. RESULTS: (1) sEPCR levels in healthy controls with 6936AG genotype were significantly higher than that in those with 6936AA genotype \[(0.97 ± 0.32) ng/L vs (0.61 ± 0.24) ng/L, P < 0.01)\], and so did in DVT patients \[(0.87 ± 0.21) ng/L vs (0.50 ± 0.18) ng/L, P < 0.01\]. (2) The sEPCR levels of DVT patients \[(0.68 ± 0.32) ng/L\] were significantly higher than that of healthy controls \[(0.54 ± 0.22) ng/L\](P < 0.05). (3) The distribution of 6936A/G genotype was higher in DVT patients than in healthy controls (P < 0.05). (4) Subjects with 6936A/G had an increased risk of thrombosis (OR = 2.75, 95%CI = 1.04 - 7.30) (P < 0.05). CONCLUSIONS: EPCR gene 6936A/G polymorphism is associated with increased plasma sEPCR levels. The sEPCR levels in DVT patients were significantly higher than that in healthy controls. The subject with 6936AG likely had an increased risk of thrombosis.