No abstract

The epigenetic modification of nucleic acids represents one of the most significant areas of study in the field of nucleic acids because it makes gene regulation more complex and heredity more complicated, thus indicating its profound impact on aspects of heredity, growth, and diseases. The recent characterization of epigenetic modifications of DNA and RNA using chemical labelling strategies has promoted the discovery of these modifications, and the newly developed single-base or single-cell resolution mapping strategies have enabled large-scale epigenetic studies in eukaryotes. Due to these technological breakthroughs, several new epigenetic marks have been discovered that have greatly extended the scope and impact of epigenetic modifications in nucleic acids over the past few years. Because epigenetics is reversible and susceptible to environmental factors, it could potentially be a promising direction for clinical medicine research. In this review, we have comprehensively discussed how these epigenetic marks are involved in disease, including the pathogenesis, prevention, diagnosis and treatment of disease. These findings have revealed that the epigenetic modification of nucleic acids has considerable significance in various areas from methodology to clinical medicine and even in biomedical applications.

ObjectivesTo investigate vascular flow density in pathological myopia with optical coherence tomography (OCT) angiography.DesignA prospective comparative study was conducted from December 2015 to March 2016.SettingParticipants were recruited in Beijing Tongren Hospital.ParticipantsA total of 131 eyes were enrolled, which were divided into three groups: 45 eyes with emmetropia (EM; mean spherical equivalent (MSE) 0.50D to −0.50D), 41 eyes with high myopia (HM; MSE ≤−6.00D, without pathological changes), and 45 eyes with pathological myopia (PM; MSE ≤−6.00D and axial length (AL) ≥26.5 mm, and with pathological changes).Main outcome measuresMacular, choriocapillaris and radial peripapillary capillary (RPC) flow densities were measured and compared between groups, and their relationships with AL and best corrected visual acuity (BCVA) were analysed.ResultsSignificant differences were found in macular, choriocapillaris and RPC flow densities among the three groups (p<0.05). Multiple comparisons revealed that, compared with the EM and HM groups, macular and RPC flow densities of the PM group were significantly decreased (p<0.05), but no significant difference in choriocapillaris flow density was found between the PM and HM groups (p=0.731). Compared with the EM group, retinal flow density in the macular and arcuate fibre region was not decreased in the HM group. In addition, there was a negative correlation between AL and superficial macular flow density (β=−0.542, p<0.001), deep macular flow density (β=−0.282, p=0.002) and RPC flow density (β=−0.522, p<0.001); and a positive correlation between BCVA and superficial macular flow density (β=0.194, p=0.021), deep macular flow density (β=0.373, p<0.001), and choriocapillaris flow density (β=0.291, p=0.001).ConclusionsMacular and RPC flow densities decreased in pathological myopia compared with high myopia and emmetropia. No significant decrease of retinal flow density in the macular and arcuate fibre region was found in high myopic eyes compared with emmetropic eyes. Moreover, macular and RPC flow densities were negatively related to AL, and macular flow density was positively related to BCVA.

Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson’s disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP-responsive element-binding protein, glial cell line-derived neurotrophic factor and Wnt/β-catenin pathway have the potential to enhance the effects of Nurr1-based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.

BackgroundAn increasing number of extremely preterm (EP) infants have survived worldwide. However, few data have been reported from China. This study was designed to investigate the short-term outcomes of EP infants at discharge in Guangdong province.MethodsA total of 2051 EP infants discharged from 26 neonatal intensive care units during 2008–2017 were enrolled. The data from 2008 to 2012 were collected retrospectively, and from 2013 to 2017 were collected prospectively. Their hospitalization records were reviewed.ResultsDuring 2008–2017, the mean gestational age (GA) was 26.68 ± 1.00 weeks and the mean birth weight (BW) was 935 ± 179 g. The overall survival rate at discharge was 52.5%. There were 321 infants (15.7%) died despite active treatment, and 654 infants (31.9%) died after medical care withdrawal. The survival rates increased with advancing GA and BW (p < 0.001). The annual survival rate improved from 36.2% in 2008 to 59.3% in 2017 (p < 0.001). EP infants discharged from hospitals in Guangzhou and Shenzhen cities had a higher survival rate than in others (p < 0.001). The survival rate of EP infants discharged from general hospitals was lower than in specialist hospitals (p < 0.001). The major complications were neonatal respiratory distress syndrome, 88.0% (1804 of 2051), bronchopulmonary dysplasia, 32.3% (374 of 1158), retinopathy of prematurity (any grade), 45.1% (504 of 1117), necrotizing enterocolitis (any stage), 10.1% (160 of 1588), intraventricular hemorrhages (any grade), 37.4% (535 of 1431), and blood culture-positive nosocomial sepsis, 15.7% (250 of 1588). The multivariate logistic regression analysis indicated that improved survival of EP infants was associated with discharged from specialist hospitals, hospitals located in high-level economic development region, increasing gestational age, increasing birth weight, antenatal steroids use and a history of premature rupture of membranes. However, twins or multiple births, Apgar ≤7 at 5 min, cervical incompetence, and decision to withdraw care were associated with decreased survival.ConclusionsOur study revealed the short-term outcomes of EP infants at discharge in China. The overall survival rate was lower than the developed countries, and medical care withdrawal was a serious problem. Nonetheless, improvements in care and outcomes have been made annually.

Melanoma is the least common but most serious form of skin cancer. The leading cause of death in melanoma patients is widespread metastasis caused by increased cell motility and a rich blood supply for tumor cells. A unique form of microcirculation called vasculogenic mimicry, which efficiently supplies blood to tumor cells, has been reported recently. Apoptosis-related protein performs a nonapoptotic function to promote migration and invasion of tumor cells. This study focuses on the nonapoptotic role of caspase-3 in melanoma and its effects on the migration, invasion, and vasculogenic mimicry formation of melanoma cells. Human melanoma samples were used to detect active caspase-3 expression and determine its relationship with clinicopathologic parameters. In addition, a human melanoma A375 cell line was used to determine the role of caspase-3 in migration and invasion using z-DEVD-fmk, a selective caspase-3 inhibitor, to inhibit caspase-3 activity. The findings suggest that active caspase-3 is expressed in nonapoptotic melanoma cells and is related to metastasis and vasculogenic mimicry formation in patients with melanoma. Low doses of caspase-3 inhibitor reduced caspase-3 activity without affecting cell apoptosis. Inhibition of caspase-3 activity using low-dose z-DEVD-fmk decreased the migration, invasion, and vasculogenic mimicry formation of melanoma cells in vitro. Similarly, downregulation of caspase-3 by specific small interfering RNA also inhibited the migratory, invasive, and tube-forming potential of melanoma cells. The caspase-3-mediated promotion of melanoma cell motility may be because of the cleavage of matrix metalloproteinase-2.

Vasculogenic mimicry (VM) refers to the unique ability of highly aggressive tumor cells to mimic the pattern of embryonic vasculogenic networks. Hypoxia plays a pivotal role in the formation of VM. Hypoxia-induced Bcl-2 overexpression is observed in many types of tumors including melanoma, in which it is associated with tumorigenicity and angiogenesis. VE-cadherin, the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation, is also overexpressed in melanoma. Despite these connections, whether hypoxia induces VM formation via VE-cadherin regulation by Bcl-2 is not confirmed. We used human melanoma cells to upregulate or knockdown the expression of Bcl-2 to investigate the possible molecular mechanism of VM formation under hypoxia. Bcl-2 overexpression increased VE-cadherin expression and VM formation under normoxia, whereas Bcl-2 siRNA significantly decreased VE-cadherin expression and VM formation under hypoxia. We then demonstrated that Bcl-2 regulated VE-cadherin transcription activity by Western blot, three-dimensional cultures, reporter gene assay, and clinical analysis. Therefore, Bcl-2-dependent VE-cadherin overexpression may be an important mechanism by which hypoxia induces VM.

N6-methyladenosine (m 6 A) is rapidly being studied and uncovered to play a significant role in various biological processes as well as in RNA fate and functions, while the effects of defined m 6 A sites are rarely characterized for the lack of convenient tools. To provide an applicable method to remove m 6 A modification at specific loci, an m 6 A editing system called "targeted RNA demethylation by SunTag system (TRADES)" is engineered. In this system, the targeting element dCas13b is fused to ten copies of GCN4 peptides which can recruit multiple scFv-fusion RNA demethylase to demethylate the target m 6 A site. Owing to this design, TRADES is more flexible to the indistinct m 6 A sites for its wide editing window. By site-specific demethylation of messenger RNA (mRNA) SON A2699, the lifetime of SON RNA is successfully prolonged in HeLa cells. Meanwhile, TRADES negligibly influences the lifetime of other non-targeted transcripts. TRADES also can regulate the gene expression of target transcript in an m 6 A-dependent manner. Moreover, the interference occuring for HBV and HIV replications demonstrates that the TRADES system holds potential in viral life cycle regulation and clinical applications.