Evaluation of lncRNA Expression Pattern and Potential Role in Heart Failure Pathology.

During the last few decades, the morbidity and mortality of heart failure (HF) have remained on an upward trend. Despite the advances in therapeutic and diagnostic measures, there are still many aspects requiring further research. This study is aimed at finding potential long noncoding RNAs (lncRNAs) that could aid with the diagnosis and treatment of HF. We performed RNA sequencing on the peripheral blood of healthy controls as well as HF patients. The expression of lncRNAs was validated by RT-qPCR. Bioinformatic analysis was performed to investigate the possible mechanism of differentially expressed lncRNAs and mRNAs. The diagnostic value of lncRNAs was analysed by ROC analysis. Finally, a total of 207 mRNAs and 422 lncRNAs were identified. GO and KEGG pathway analyses revealed that biological pathways such as immune response, regulation of cell membrane, and transcriptional regulatory process were associated with the pathological progress of HF. The lncRNA-mRNA coexpression network was conducted, and several mRNAs were identified as key potential pathological targets, while lncRNA CHST11, MIR29B2CHG, CR381653.1, and FP236383.2 presented a potential diagnostic value for HF. These findings provide novel insights for the underlying mechanisms and possible therapeutic targets for HF.

Oxidative RNA Damage in the Pathogenesis and Treatment of Type 2 Diabetes.

Excessive production of free radicals can induce cellular damage, which is associated with many diseases. RNA is more susceptible to oxidative damage than DNA due to its single-stranded structure, and lack of protective proteins. Yet, oxidative damage to RNAs received little attention. Accumulating evidence reveals that oxidized RNAs may be dysfunctional and play fundamental role in the occurrence and development of type 2 diabetes (T2D) and its complications. Oxidized guanine nucleoside, 8-oxo-7, 8-dihydroguanine (8-oxoGuo) is a biomarker of RNA oxidation that could be associated with prognosis in patients with T2D. Nowadays, some clinical trials used antioxidants for the treatment of T2D, though the pharmacological effects remained unclear. In this review, we overview the cellular handling mechanisms and the consequences of the oxidative RNA damage for the better understanding of pathogenesis of T2D and may provide new insights to better therapeutic strategy.

Therapeutic potential and recent advances on targeting mitochondrial dynamics in cardiac hypertrophy: A concise review.

Pathological cardiac hypertrophy begins as an adaptive response to increased workload; however, sustained hemodynamic stress will lead it to maladaptation and eventually cardiac failure. Mitochondria, being the powerhouse of the cells, can regulate cardiac hypertrophy in both adaptive and maladaptive phases; they are dynamic organelles that can adjust their number, size, and shape through a process called mitochondrial dynamics. Recently, several studies indicate that promoting mitochondrial fusion along with preventing mitochondrial fission could improve cardiac function during cardiac hypertrophy and avert its progression toward heart failure. However, some studies also indicate that either hyperfusion or hypo-fission could induce apoptosis and cardiac dysfunction. In this review, we summarize the recent knowledge regarding the effects of mitochondrial dynamics on the development and progression of cardiac hypertrophy with particular emphasis on the regulatory role of mitochondrial dynamics proteins through the genetic, epigenetic, and post-translational mechanisms, followed by discussing the novel therapeutic strategies targeting mitochondrial dynamic pathways.

Cardiomyocyte mitochondrial dynamic-related lncRNA 1 (CMDL-1) may serve as a potential therapeutic target in doxorubicin cardiotoxicity.

Doxorubicin (DOX)-induced cardiotoxicity has been one of the major limitations for its clinical use. Although extensive studies have been conducted to decipher the molecular mechanisms underlying DOX cardiotoxicity, no effective preventive or therapeutic measures have yet been identified. Microarray analysis showed that multiple long non-coding RNAs (lncRNAs) are differentially expressed between control- and DOX-treated cardiomyocytes. Functional enrichment analysis indicated that the differentially expressed genes are annotated to cardiac hypertrophic pathways. Among differentially expressed lncRNAs, cardiomyocyte mitochondrial dynamic-related lncRNA 1 (CMDL-1) is the most significantly downregulated lncRNA in cardiomyocytes after DOX exposure. The protein-RNA interaction analysis showed that CMDL-1 may target dynamin-related protein 1 (Drp1). Mechanistic analysis shows that lentiviral overexpression of CMDL-1 prevents DOX-induced mitochondrial fission and apoptosis in cardiomyocytes. However, overexpression of CMDL-1 cannot effectively reduce mitochondrial fission when Drp1 is minimally expressed by small interfering RNA Drp1 (siDrp1). Overexpression of CMDL-1 promotes the association between CMDL-1 and Drp1, as well as with phosphorylated (p-)Drp1, as evidenced by RNA immunoprecipitation analysis. These data indicate the role of CMDL-1 in posttranslational modification of a target protein via regulating its phosphorylation. Collectively, our data indicate that CMDL-1 may play an anti-apoptotic role in DOX cardiotoxicity by regulating Drp1 S637 phosphorylation. Thus, CMDL-1 may serve as a potential therapeutic target in DOX cardiotoxicity.

Targeting the epigenome in in-stent restenosis: from mechanisms to therapy.

Coronary artery disease (CAD) is one of the most common causes of death worldwide. The introduction of percutaneous revascularization has revolutionized the therapy of patients with CAD. Despite the advent of drug-eluting stents, restenosis remains the main challenge in treating patients with CAD. In-stent restenosis (ISR) indicates the reduction in lumen diameter after percutaneous coronary intervention, in which the vessel's lumen re-narrowing is attributed to the aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) and dysregulation of endothelial cells (ECs). Increasing evidence has demonstrated that epigenetics is involved in the occurrence and progression of ISR. In this review, we provide the latest and comprehensive analysis of three separate but related epigenetic mechanisms regulating ISR, namely, DNA methylation, histone modification, and non-coding RNAs. Initially, we discuss the mechanism of restenosis. Furthermore, we discuss the biological mechanism underlying the diverse epigenetic modifications modulating gene expression and functions of VSMCs, as well as ECs in ISR. Finally, we discuss potential therapeutic targets of the small molecule inhibitors of cardiovascular epigenetic factors. A more detailed understanding of epigenetic regulation is essential for elucidating this complex biological process, which will assist in developing and improving ISR therapy.

Functional roles and mechanisms of ginsenosides from Panax ginseng in atherosclerosis.

Atherosclerosis (AS) is a leading cause of cardiovascular diseases (CVDs) and it results in a high rate of death worldwide, with an increased prevalence with age despite advances in lifestyle management and drug therapy. Atherosclerosis is a chronic progressive inflammatory process, and it mainly presents with lipid accumulation, foam cell proliferation, inflammatory response, atherosclerotic plaque formation and rupture, thrombosis, and vascular calcification. Therefore, there is a great need for reliable therapeutic drugs or remedies to cure or alleviate atherosclerosis and reduce the societal burden. Ginsenosides are natural steroid glycosides and triterpene saponins obtained mainly from the plant ginseng. Several recent studies have reported that ginsenosides have a variety of pharmacological activities against several diseases including inflammation, cancer and cardiovascular diseases. This review focuses on describing the different pharmacological functions and underlying mechanisms of various active ginsenosides (Rb1,-Rd, -F, -Rg1, -Rg2, and -Rg3, and compound K) for atherosclerosis, which could provide useful insights for developing novel and effective anti-cardiovascular drugs.

tsRNAs: Novel small molecules from cell function and regulatory mechanism to therapeutic targets.

tsRNAs are small fragments of RNAs with specific lengths that are generated by particular ribonucleases, such as dicer and angiogenin (ANG), clipping on the rings of transfer RNAs (tRNAs) in specific cells and tissues under specific conditions. Depending on where the splicing site is, tsRNAs can be segmented into two main types, tRNA-derived stress-induced RNAs (tiRNAs) and tRNA-derived fragments (tRFs). Many studies have shown that tsRNAs are functional molecules, not the random degradative products of tRNAs. Notably, due to their regulatory mechanism in regulating mRNA stability, transcription, ribosomal RNA (rRNA) synthesis and RNA reverse transcription, tsRNAs are significantly involved in the cell function, such as cell proliferation, migration, cycle and apoptosis, as well as the occurrence and development of a variety of diseases. In addition, tsRNAs may represent a new generation of clinical biomarkers or therapeutic targets because of their stable structures, high conservation and widely distribution, particularly in the peripheral tissues, bodily fluids and exosomes. In this review, we describe the generation, function and mechanism of tsRNAs and illustrate the current research progress of tsRNAs in various diseases, highlight their potentials as biomarkers and therapeutic targets in clinical application. Although our understanding of tsRNAs is still in infancy, the application prospects shown in this field deserve further exploration.

Piwi-interacting RNAs (piRNAs) as potential biomarkers and therapeutic targets for cardiovascular diseases.

Cardiovascular diseases (CVDs) are the leading causes of death worldwide. Increasing reports demonstrated that non-coding RNAs (ncRNAs) have been crucially involved in the development of CVDs. Piwi-interacting RNAs (piRNAs) are a novel cluster of small non-coding RNAs with strong uracil bias at the 5' end and 2'-O-methylation at the 3' end that are mainly present in the mammalian reproductive system and stem cells and serve as potential modulators of developmental and pathophysiological processes. Recently, piRNAs have been reported to be widely expressed in human tissues and can potentially regulate various diseases. Specifically, concomitant with the development of next-generation sequencing techniques, piRNAs have been found to be differentially expressed in CVDs, indicating their potential involvement in the occurrence and progression of heart diseases. However, the molecular mechanisms and signaling pathways involved with piRNA function have not been fully elucidated. In this review, we present the current understanding of the piRNAs from the perspectives of biogenesis, characteristics, biological function, and regulatory mechanisms, and highlight their potential roles and underlying mechanisms in CVDs, which will provide new insights into the potential applications of piRNAs in the clinical diagnosis, prognosis, and therapeutic strategies for heart diseases.

Burnout in nurses working in China: A national questionnaire survey.

AIM: This study aimed to assess the overall status of burnout in nurses in China on a national scale and investigate the demographic characteristics related to burnout and the relationships between demographics, job satisfaction and burnout. METHODS: This was a national cross-sectional study conducted by the Chinese Nursing Association between July 2016 and July 2017. Data were collected using a structured, self-administered questionnaire. RESULTS: A total of 51 406 registered nurses in 311 Chinese cities completed the questionnaire. Fifty per cent of the participants suffered burnout, and 33.8% of nurses had high scores on emotional exhaustion, 66.6% had high scores on depersonalization and 93.5% had low scores on personal accomplishment; 16.2% reported a high level of job satisfaction, only 0.4% was satisfied with their jobs and 70.7% intended to leave their jobs. Marital status, educational level, income and years of working experience affected job burnout. Nurses with a high level of burnout were more likely to have a high degree of job dissatisfaction and intend to leave their jobs. CONCLUSION: We found a high prevalence of burnout among nurses in China. Nursing managers need to pay more attention to job burnout and its influencing factors. Interventions to reduce nurse burnout should be implemented.

NLRP3 inflammasome in endothelial dysfunction.

Inflammasomes are a class of cytosolic protein complexes. They act as cytosolic innate immune signal receptors to sense pathogens and initiate inflammatory responses under physiological and pathological conditions. The NLR-family pyrin domain-containing protein 3 (NLRP3) inflammasome is the most characteristic multimeric protein complex. Its activation triggers the cleavage of pro-interleukin (IL)-1ß and pro-IL-18, which are mediated by caspase-1, and secretes mature forms of these mediators from cells to promote the further inflammatory process and oxidative stress. Simultaneously, cells undergo pro-inflammatory programmed cell death, termed pyroptosis. The danger signals for activating NLRP3 inflammasome are very extensive, especially reactive oxygen species (ROS), which act as an intermediate trigger to activate NLRP3 inflammasome, exacerbating subsequent inflammatory cascades and cell damage. Vascular endothelium at the site of inflammation is actively involved in the regulation of inflammation progression with important implications for cardiovascular homeostasis as a dynamically adaptable interface. Endothelial dysfunction is a hallmark and predictor for cardiovascular ailments or adverse cardiovascular events, such as coronary artery disease, diabetes mellitus, hypertension, and hypercholesterolemia. The loss of proper endothelial function may lead to tissue swelling, chronic inflammation, and the formation of thrombi. As such, elimination of endothelial cell inflammation or activation is of clinical relevance. In this review, we provided a comprehensive perspective on the pivotal role of NLRP3 inflammasome activation in aggravating oxidative stress and endothelial dysfunction and the possible underlying mechanisms. Furthermore, we highlighted the contribution of noncoding RNAs to NLRP3 inflammasome activation-associated endothelial dysfunction, and outlined potential clinical drugs targeting NLRP3 inflammasome involved in endothelial dysfunction. Collectively, this summary provides recent developments and perspectives on how NLRP3 inflammasome interferes with endothelial dysfunction and the potential research value of NLRP3 inflammasome as a potential mediator of endothelial dysfunction.

Recent Advances: Molecular Mechanism of RNA Oxidation and Its Role in Various Diseases.

Compared with the research on DNA damage, there are fewer studies on RNA damage, and the damage mechanism remains mostly unknown. Recent studies have shown that RNA is more vulnerable to damage than DNA when the cells are exposed to endogenous and exogenous insults. RNA injury may participate in a variety of disease occurrence and development. RNA not only has important catalytic functions and other housekeeping functions, it also plays a decisive role in the translation of genetic information and protein biosynthesis. Various kinds of stressors, such as ultraviolet, reactive oxygen species and nitrogen, can cause damage to RNA. It may involve in the development and progression of diseases. In this review, we focused on the relationship between the RNA damage and disease as well as the research progress on the mechanism of RNA damage, which is of great significance for the pathogenesis, diagnosis, and treatment of related diseases.

Role of RNA Oxidation in Neurodegenerative Diseases.

In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.

Combined detection of miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 for screening of early heart failure diseases.

The use of circulating microRNAs as biomarkers opens up new opportunities for the diagnosis of cardiovascular diseases because of their specific expression profiles. The aim of the present study was to identify circulating microRNAs in human plasma as potential biomarkers of heart failure and related diseases. We used real-time quantitative PCR to screen microRNA in plasma samples from 62 normal controls and 62 heart failure samples. We found that circulating miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 expressed differently between healthy controls and heart failure patients. Plasma levels of miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 were unaffected by hemolysis. Correlation analysis showed any two of these miRNAs possess a strong correlation, indicating a possibility of combined analysis. MiR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 could be combined in two or three or more combinations. The results suggest that miR-21-5p, miR-30a-3p, miR-30a-5p, miR-155-5p, miR-216a and miR-217 may be a new diagnostic biomarker for heart failure and related diseases.

The involvement of post-translational modifications in cardiovascular pathologies: Focus on SUMOylation, neddylation, succinylation, and prenylation.

Cardiovascular disease (CVD) is one of the most threatening diseases to human health and life, and the number of patients is increasing year by year. Thus, it is of great significance to study the pathogenesis, prevention and treatment of CVDs. The occurrence and development of CVDs involve dynamic, complex and delicate intracellular processes and the pathogenesis is not entirely clear. In contrast to genetic mutations, most of the protein post-translational modifications (PTMs) are reversible, and can affect the activity, stability, subcellular localization, protein-protein interaction etc., of the substrate targets, emerging as key mediators of a number of CVD progression. Under pathological conditions, the PTMs undergo aberrant balances which cause changes of the substrate target proteins in expression level, localization and capacity to activate downstream signaling pathways. Therefore, new approaches can be created aiming to correct the abnormal PTM alterations in treating CVDs. This review summarizes some of the more recent advances in PTMs, focusing on SUMOylation, neddylation, succinylation, and prenylation, and the effect of these modifications on cardiovascular function and progression, which may provide potential targets for future therapeutics.

Role of apoptosis repressor with caspase recruitment domain (ARC) in cancer.

Apoptosis repressor with caspase recruitment domain (ARC) is a potent inhibitor of apoptosis. Under physiological conditions, ARC is abundantly expressed in terminally differentiated cells, including cardiomyocytes, skeletal muscles and neurons. ARC serves a key role in determining cell fate, and abnormal ARC expression has been demonstrated to be associated with abnormal cell growth. Previous studies have revealed that ARC was upregulated in several different types of solid tumor, where it suppressed tumor cell apoptosis. Furthermore, the increased expression levels of ARC in cancer cells contributed to the development of therapeutic resistance and adverse clinical outcomes in patients with leukemia. However, the exact role of ARC, as well as the underlying molecular mechanisms involved, remain poorly understood. The present review summarizes the characteristics of ARC and its cytoprotective role under different conditions and describes the potential ARC as a new target for cancer therapy.

miR-23a binds to p53 and enhances its association with miR-128 promoter.

Apoptosis plays an important role in cardiac pathology, but the molecular mechanism by which apoptosis regulated remains largely elusive. Here, we report that miR-23a promotes the apoptotic effect of p53 in cardiomyocytes. Our results showed that miR-23a promotes apoptosis induced by oxidative stress. In exploring the molecular mechanism by which miR-23a promotes apoptosis, we found that it sensitized the effect of p53 on miR-128 regulation. It promoted the association of p53 to the promoter region of miR-128, and enhanced the transcriptional activation of p53 on miR-128 expression. miR-128 can downregulate prohibitin expression, and subsequently promote apoptosis. Our data provides novel evidence revealing that miR-23a can stimulate transcriptional activity of p53.

Interactions of several genetic polymorphisms and alcohol consumption on blood pressure levels.

This study aimed to detect the interactions of several single nucleotide polymorphisms (SNPs) and alcohol consumption on blood pressure levels. Genotypes of 10 SNPs in the ATP-binding cassette transporter A1 (ABCA-1), acyl-CoA:cholesterol acyltransferase-1 (ACAT-1), low density lipoprotein receptor (LDLR), hepatic lipase gene (LIPC), endothelial lipase gene (LIPG), methylenetetrahydrofolate reductase (MTHFR), the E3 ubiquitin ligase myosin regulatory light chain-interacting protein (MYLIP), proprotein convertase subtilisin-like kexin type 9 (PCSK9), peroxisome proliferator-activated receptor delta (PPARD), and Scavenger receptor class B type 1 (SCARB1) genes were determined in 616 nondrinkers and 608 drinkers. The genotypic frequencies of LDLR rs5925, LIPC rs2070895, MTHFR rs1801133, and MYLIP rs3757354 SNPs were significantly different between nondrinkers and drinkers. The levels of systolic blood pressure (ABCA-1 rs2066715 and rs2070895), diastolic blood pressure (rs2070895), and pulse pressure (PP) (rs2066715, ACAT-1 rs1044925, and rs1801133) in nondrinkers, and systolic blood pressure (rs1044925 and SCARB1 rs5888), diastolic blood pressure (rs1044925 and LIPG rs2000813), and PP (PCSK9 rs505151 and rs5888) in drinkers were different among the genotypes (P < 0.005-0.001). The interactions of several SNPs and alcohol consumption on systolic blood pressure (rs2066715, rs1044925, rs5925, rs2070895, rs1801133, rs3757354, PPARD rs2016520, and rs5888), diastolic blood pressure (rs2066715, rs1044925, rs5925, rs2000813, rs3757354, and rs2016520), and PP (rs1044925, rs2070895, rs1801133, rs3757354, rs505151, and rs5888) were observed (P < 0.005-0.001). The differences in blood pressure levels between the nondrinkers and drinkers might be partially attributed to the interactions of these SNPs and alcohol consumption.

Association between the MLX interacting protein-like, BUD13 homolog and zinc finger protein 259 gene polymorphisms and serum lipid levels.

This study aimed to detect the association between the MLX interacting protein-like (MLXIPL), BUD13 homolog (BUD13) and zinc finger protein 259 (ZNF259) single nucleotide polymorphisms (SNPs) and serum lipid levels in the Chinese Mulao and Han populations. Genotyping of 9 SNPs was performed in 825 Mulao and 781 Han participants. The genotype and allele frequencies of ZNF259 rs2075290 and rs964184, and BUD13 rs10790162 SNPs were different between the Mulao and Han populations (P < 0.001). The SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum total cholesterol levels; ZNF259 rs2075290 and rs964184, BUD13 rs10790162, and MLXIPL rs3812316 and rs13235543 were associated with triglyceride (TG); and MLXIPL rs35332062 was associated with apolipoprotein (Apo) A1 in the Mulaos (P < 0.006-0.001). However, in the Hans, the SNPs of ZNF259 rs2075290 and BUD13 rs10790162 were associated with serum TG levels; ZNF259 rs2075290 was associated with low-density lipoprotein cholesterol and the ApoA1/ApoB ratio (P < 0.006-0.001). Significant linkage disequilibria were noted among ZNF259 rs2075290 and rs964184 and BUD13 rs10790162, and between MLXIPL rs3812316 and rs13235543 (r(2) > 0.05, P < 0.001). The haplotypes of A-C-G-A-C (rs2075290A-rs964184C-rs10790162G-rs17119975A-rs11556024C) and C-C-C-C (rs799161C-rs35332062C-rs3812316C-rs13235543C) accounted for over half of the % haplotype of each ethnic group.

Adiponectin is associated with increased mortality in patients with already established cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND: The overall quantitative estimate on the possible association of adiponectin concentrations with mortality in patients with cardiovascular diseases (CVD) has not been reported. METHODS: We performed a systematic review and meta-analysis of prospective studies to evaluate the overall quantitative estimates on the adiponectin levels for risk of mortality in patients with CVD. MEDLINE, EMBASE, CINAHL, and the Cochrane Library (up to Mar 22, 2014) were used to search for studies evaluating the effect of adiponectin levels on mortality in patients with CVD. Random-effect models were selected to estimate overall effect estimates. RESULTS: Data from 14063 CVD patients enrolled in 15 prospective cohort and 1 nested case control studies were collated. The meta-analyses showed strong positive association of adiponectin with all-cause (n=14 studies, overall pooled effect estimate=1.45 [95% CI, 1.17-1.79]) and cardiovascular (n=11 studies, overall pooled effect estimate=1.69 [1.35-2.10]) mortality, for the highest tertile of adiponectin levels versus the lowest tertile. Subgroup analyses show study characteristics (including effect estimate, mean age, study location, sample sizes, gender, durations of follow-up, types of primary event, and acute or chronic CVD) did not substantially influence these positive associations. CONCLUSIONS: Our results showed that increased baseline plasma adiponectin levels are significantly associated with elevated risk of all-cause and cardiovascular mortality in subjects with CVD. These positive associations may have been amplified by adjustment for potential intermediates or residual confounding, and their basis requires further investigation.