Identification and Functional Prediction of Long Non-Coding RNAs in Dilated Cardiomyopathy by Bioinformatics Analysis.

Dilated cardiomyopathy (DCM) is a relatively common cause of heart failure and the leading cause of heart transplantation. Aberrant changes in long non-coding RNAs (lncRNAs) are involved in DCM disorder; however, the detailed mechanisms underlying DCM initiation and progression require further investigation, and new molecular targets are needed. Here, we obtained lncRNA-expression profiles associated with DCM and non-failing hearts through microarray probe-sequence re-annotation. Weighted gene co-expression network analysis revealed a module highly associated with DCM status. Then eight hub lncRNAs in this module (FGD5-AS1, AC009113.1, WDFY3-AS2, NIFK-AS1, ZNF571-AS1, MIR100HG, AC079089.1, and EIF3J-AS1) were identified. All hub lncRNAs except ZNF571-AS1 were predicted as localizing to the cytoplasm. As a possible mechanism of DCM pathogenesis, we predicted that these hub lncRNAs might exert functions by acting as competing endogenous RNAs (ceRNAs). Furthermore, we found that the above results can be essentially reproduced in an independent external dataset. We observed the localization of hub lncRNAs by RNA-FISH in human aortic smooth muscle cells and confirmed the upregulation of the hub lncRNAs in DCM patients through quantitative RT-PCR. In conclusion, these findings identified eight candidate lncRNAs associated with DCM disease and revealed their potential involvement in DCM partly through ceRNA crosstalk. Our results facilitate the discovery of therapeutic targets and enhance the understanding of DCM pathogenesis.

Key Enzymes for the Mevalonate Pathway in the Cardiovascular System.

ABSTRACT: Isoprenylation is an important post-transcriptional modification of small GTPases required for their activation and function. Isoprenoids, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate, are indispensable for isoprenylation by serving as donors of a prenyl moiety to small G proteins. In the human body, isoprenoids are mainly generated by the mevalonate pathway (also known as the cholesterol-synthesis pathway). The hydroxymethylglutaryl coenzyme A reductase catalyzes the first rate-limiting steps of the mevalonate pathway, and its inhibitor (statins) are widely used as lipid-lowering agents. In addition, the FPP synthase is also of critical importance for the regulation of the isoprenoids production, for which the inhibitor is mainly used in the treatment of osteoporosis. Synthetic FPP can be further used to generate geranylgeranyl pyrophosphate and cholesterol. Recent studies suggest a role for isoprenoids in the genesis and development of cardiovascular disorders, such as pathological cardiac hypertrophy, fibrosis, endothelial dysfunction, and fibrotic responses of smooth-muscle cells. Furthermore, statins and FPP synthase inhibitors have also been applied for the management of heart failure and other cardiovascular diseases rather than their clinical use for hyperlipidemia or bone diseases. In this review, we focus on the function of several critical enzymes, including hydroxymethylglutaryl coenzyme A reductase, FPP synthase, farnesyltransferase, and geranylgeranyltransferase in the mevalonate pathway which are involved in regulating the generation of isoprenoids and isoprenylation of small GTPases, and their pathophysiological role in the cardiovascular system. Moreover, we summarize recent research into applications of statins and the FPP synthase inhibitors to treat cardiovascular diseases, rather than for their traditional indications respectively.

Pacemaker and Atrioventricular Junction Ablation in Patients With Atrial Fibrillation-A Systematic Review of Systematic Review and Meta-Analysis.

BACKGROUND: Cardiac resynchronization therapy (CRT) could be considered for heart failure (HF) patients with atrial fibrillation (AF) unless a potent ventricular capture strategy is conducted. However, the benefit of a pacemaker (PM; as part of CRT) in patients with AF and whether atrioventricular junction (or nodal) ablation (AVAB) can improve the prognosis of these patients compared with those treated medically to support ventricular capture are unclear. METHODS AND RESULTS: Systematic reviews and meta-analyses investigating the roles of PMs and AVAB in patients with AF were obtained in a search of the PubMed, Embase, and Medline databases and then analyzed with respect to the following outcomes: mortality, left ventricular ejection fraction, and clinical findings including the New York Heart Association class, 6-min walk distance (6MWD), quality of life as assessed in a specific questionnaire, and response to CRT. The quality of the included reviews was assessed using the Assessing the Methodological Quality of Systematic Reviews 2 tool, which includes 16 items. This study was finally based on 13 systematic reviews or meta-analyses. The results showed that patients with AF have higher all-cause mortality rates compared with patients with sinus rhythm and that AVAB can reduce all-cause mortality in patients with AF. Although the functional improvement was better in sinus rhythm than in patients with AF, in the latter, AVAB increased the 6MWD and reduced the CRT nonresponse rate in patients with AF. CONCLUSION: Atrial fibrillation is associated with a higher all-cause mortality rate in patients with CRT implantation. AVAB, by increasing the 6MWD and survival, can improve the prognosis of these patients.

The Biomarkers for Acute Myocardial Infarction and Heart Failure.

The use of a large number of cardiovascular biomarkers, meant to complement the use of the electrocardiogram, echocardiography cardiac imaging, and clinical symptom assessment, has become a routine in clinical diagnosis, differential diagnosis, risk stratification, and prognosis and guides the management of patients with suspected cardiovascular diseases. There is a broad consensus that cardiac troponin and natriuretic peptides are the preferred biomarkers in clinical practice for the diagnosis of the acute coronary syndrome and heart failure, respectively, while the roles and possible clinical applications of several other potential biomarkers are still under study. This review mainly focuses on the recent studies of the roles and clinical applications of troponin and natriuretic peptides, which seem to be the best-validated markers in distinguishing and predicting the future cardiac events of patients with suspected cardiovascular diseases. Additionally, the review briefly discusses some of the large number of potential markers that may play a more prominent role in the future.

Comparison of transesophageal echocardiography findings after different anticoagulation strategies in patients with atrial fibrillation: a systematic review and meta-analysis.

BACKGROUND: High risk of embolic events exists in both patients with chronic atrial fibrillation (AF) and patients in the perioperative period of ablation (effective treatment for AF). Therefore, anticoagulant therapy is important. Oral anticoagulants can be divided into two major categories: vitamin K antagonists (VKAs) and non-vitamin K antagonist oral anticoagulants (NOACs). VKAs, represented by warfarin, have been widely used as traditional anticoagulants, whereas NOACs have been used in clinical practice, but their anticoagulant effects and side effects are still the focus of research. We used a meta-analysis to compare the incidence of left atrial thrombi (LAT) between different anticoagulants. METHODS: We searched PubMed, EMBASE, Web of Science, and the Cochrane Library databases for observational studies that compared the transesophageal echocardiography (TEE) findings for patients treated with NOACs and VKAs. The incidence of LAT and dense spontaneous echocardiographic contrast (dense SEC) were extracted as the basis of the meta-analysis. RESULTS: Fifteen studies were included in the meta-analysis. We found that patients anticoagulated with NOACs and VKAs had similar incidence of LAT (OR = 0.74, 95%CI: 0.55-1.00). After excluding the heterogeneous article by sensitivity analysis, we found the incidence of LAT in patients anticoagulated with NOACs is lower than VKAs (OR = 0.59, 95%CI: 0.42-0.84). The results of subgroup analysis showed that the incidence of LAT among three types of NOACs have no significant difference (dabigatran vs. rivaroxaban, OR = 1.16 [0.75, 1.81]; rivaroxaban vs. apixaban, OR = 0.97 [0.54, 1.74]; dabigatran vs. apixaban, OR = 1.09 [0.55, 2.16]). CONCLUSION: Patients anticoagulated with NOACs may have lower incidence of LAT than VKAs. The incidence of LAT among different type of NOACs are similar.

Symptoms of posttraumatic stress disorder and depression among bereaved and non-bereaved survivors following the 2008 Sichuan earthquake.

Many studies have suggested that unexpected death of a loved one is an important risk factor of posttraumatic stress disorder (PTSD) and depression among disaster survivors, but few have examined the magnitude of psychiatric morbidities among bereaved survivors. This study examined the prevalence rates of clinically significant PTSD and depressive symptoms and their associated risk factors among Chinese adult survivors following the 2008 Sichuan earthquake. Two hundred and fifty-one bereaved adults were compared with 1474 non-bereaved adult survivors. The estimated rates of PTSD and depressive symptoms were 65.6% and 64.8% for those who lost first-degree family members, 34.1% and 45.5% for those who lost second-degree relatives, and 27.1% and 37.5% for non-bereaved survivors respectively. Loss of a child was a significant predictor of psychopathological symptoms. The results suggested that effective and sustainable mental health services were required, especially for bereaved single-child parents.

Tamoxifen lowers the MMP-9/TIMP-1 ratio and inhibits the invasion capacity of ER-positive non-small cell lung cancer cells.

Tamoxifen (TAM) serves for decades as a therapy drug for the prevention and treatment of breast cancers, especially effective for the estrogen receptor (ER)-positive ones. An increasing number of studies are trying to explore its potential application in treating other types of tumor including lung cancer. However, the effects of TAM on lung cancer cells, especially ER-positive ones, remain unclear. Thus, the present study was undertaken to assess the impact of TAM on the invasion capacity of an ER-positive human lung cancer cell model. In this study, the immunohistochemical staining was applied to verify the expression of estrogen receptors in SPC-A-1, a human lung adenocarcinoma cell line. The real-time PCR analysis was performed to test the expressions of MMP-9 and TIMP-1 in SPC-A-1 cells treated with different doses of TAM, while the invasion capacity was determined using transwell assays. In TAM-treated SPC-A-1 cells, which are ER-positive, an impaired ratio of MMP-9/TIMP-1 was observed as a net result of an increased transcriptional level of TIMP-1 as well as a reduced one of MMP-9. Furthermore, TAM suppressed the invasion of SPC-A-1 cells in vitro. Thus, we propose that TAM could work as an anti-metastasis drug inhibiting the invasion of human lung cancer cells.

Blocking neuropilin-2 enhances corneal allograft survival by selectively inhibiting lymphangiogenesis on vascularized beds.

PURPOSE: To investigate the potential inhibitory effects of RNA interference-mediated knockdown of neuropilin-2 (NP2) on inflammation-induced corneal hemangiogenesis and lymphangiogenesis, and whether selective inhibition of lymphangiogenesis on vascularized recipient beds before transplantation improves the graft survival. METHODS: Mouse lymphatic endothelial cells were transfected with the plasmid expressing artificial microRNA (amiRNA) against mouse NP2, and the down-regulation of VEGF-C-induced NP2 expression by NP2 amiRNA was evaluated by real-time PCR and western blot assays. Next, NP2 amiRNA or negative control amiRNA was injected intrastromally into BALB/c mouse model of suture-induced corneal neovascularization three days after surgery. Corneas were harvested 1 week after suture placement and the formation of lymphatic and blood vessels as well as the recruitment of macrophage was evaluated by immunohistochemical staining. The neovascularized graft beds treated by NP2 amiRNA or control then served as recipients of orthotopic corneal transplants, and age-matched C57BL/6 donors were used. Corneal allografts were examined twice a week for 8 weeks, and graft clarity was quantified by means of an opacity score. RESULTS: VEGF-C-induced NP2 expression at both mRNA and protein levels was significantly suppressed by NP2 amiRNA in mouse lymphatic endothelial cells. Intrastromal administration of NP2 amiRNA reduced corneal lymphangiogenesis by 45% versus control (p=0.015), but corneal hemangiogenesis (p=0.815) and the recruitment of CD11 antigen-like family member B (CD11b)-positive macrophage (p=0.589) were unchanged. Kaplan-Meier survival analysis revealed a better graft survival rate in the vascularized recipient beds pre-treated by NP2 amiRNA in comparison to controls (p=0.014). CONCLUSIONS: Knockdown of NP2 improves corneal graft survival by selectively inhibiting lymphangiogenesis in vascularized beds before transplantation. Thus our results open new treatment options for transplant rejection and other lymphatic disorders.

[Study on the relationship between microsatellite alterations of RASSF1A gene and the development of cervical carcinoma].

OBJECTIVE: To explore the relationship between microsatellite alterations of RASSF1A gene and the development of cervical carcinoma, and HPV16 infection. METHODS: Two sites of microsatellite polymorphism of RASSF1A gene were selected, we used polymerase chain reaction (PCR) technique to detect the LOH and MSI of cervical tissues, and to detect the infection state of HPV16. RESULTS: There were significant differences of LOH rates at the two sites between clinical stage and pathological grade (P < 0.05). Significant differences were noted between the cervical carcinomas with lymph node metastasis and those without lymph node metastasis in regard to their LOH and MSI at the two sites ( P < 0.05). The incidence of LOH of RASSF1A gene was higher in HPV16(+) than that in HPV16(-) ( P < 0.05). CONCLUSION: The change of RASSF1A gene is a relatively late event in cervical carcinomas. The detection of the LOH and MSI of RASSF1A gene might be helpful to the early diagnosis and the screening of cervical carcinoma. It might also be useful for predicting the prognosis of cervical carcinoma. Infection of HPV16 and LOH of RASSF1A gene had reacted together in the development of cervical carcinoma.