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Aims Novel cancer therapies leading to increased survivorship of cancer patients have been negated by a concomitant rise in cancer therapies-related cardiovascular toxicities. Sunitinib, a first line multi-receptor tyrosine kinase inhibitor, has been reported to cause vascular dysfunction although the initiating mechanisms contributing to this side effect remain unknown. Long non-coding RNAs (lncRNAs) are emerging regulators of biological processes in endothelial cells (ECs); however, their roles in cancer therapies-related vascular toxicities remain underexplored. Methods and results We performed lncRNA expression profiling to identify potential lncRNAs that are dysregulated in human-induced pluripotent stem cell-derived ECs (iPSC-ECs) treated with sunitinib. We show that the lncRNA hyaluronan synthase 2 antisense 1 (HAS2-AS1) is significantly diminished in sunitinib-treated iPSC-ECs. Sunitinib was found to down-regulate HAS2-AS1 by an epigenetic mechanism involving hypermethylation. Depletion of HAS2-AS1 recapitulated sunitinib-induced detrimental effects on iPSC-ECs, whereas CRISPR-mediated activation of HAS2-AS1 reversed sunitinib-induced dysfunction. We confirmed that HAS2-AS1 stabilizes the expression of its sense gene HAS2 via an RNA/mRNA heteroduplex formation. Knockdown of HAS2-AS1 led to reduced synthesis of hyaluronic acid (HA) and up-regulation of ADAMTS5, an enzyme involved in extracellular matrix degradation, resulting in disruption of the endothelial glycocalyx which is critical for ECs. In vivo , sunitinib-treated mice showed reduced coronary flow reserve, accompanied by a reduction in Has2os and degradation of the endothelial glycocalyx. Finally, we identified that treatment with high molecular-weight HA can prevent the deleterious effects of sunitinib both in vitro and in vivo by preserving the endothelial glycocalyx. Conclusions Our findings highlight the importance of lncRNA-mediated regulation of the endothelial glycocalyx as an important determinant of sunitinib-induced vascular toxicity and reveal potential novel therapeutic avenues to attenuate sunitinib-induced vascular dysfunction. [ABSTRACT FROM AUTHOR]

Resource, environmental, and ecological issues have become major constraints to the development of many regions. The Yellow River Basin is an important barrier for maintaining ecological security in northern China, but it has been impacted by problems such as severe soil erosion and declining biodiversity. The rational construction of ecological security patterns is important to enhance ecosystem functions and maintain regional ecological security. In this study, a comprehensive ecological security assessment system was constructed by selecting ecosystem service importance, ecological sensitivity, and landscape connectivity to assess the ecological security of Xiliu Ditch, an ecologically fragile region of the Inner Mongolia section of the Yellow River Basin in China. The assessment results showed significant spatial heterogeneity, with medium- and low-security value areas dominating, while high-security value areas accounted for only 18.7% of the study area. Seventeen ecological sources were identified from the high-security areas, which were mainly composed of grassland, woodland, and water bodies, most of which are distributed in the southern part of the study area. Twenty ecological corridors were selected by the minimum cumulative resistance model and gravity model and classified into 15 construction corridors and 5 potential corridors. Forty-six ecological nodes were defined, including twenty strategic points, nine potential strategic points, and seventeen break points. On this basis, we constructed an ecological security pattern of "two belts, three cores, six zones, multiple corridors and multiple nodes" and proposed corresponding ecological governance measures. This study explores the ecological security pattern at the small watershed scale, which helps to realize the fine management of the Xiliu Ditch basin and, on this basis, can provide scientific support for the ecological protection and sustainable development of the Yellow River basin. In addition, the ecological security assessment system proposed in this study can provide new ideas for the construction of ecological security patterns in similar ecologically fragile areas around the globe. [ABSTRACT FROM AUTHOR]

Equitable distribution of urban park green space benefits public health and improves quality of life. From the perspective of landscape justice, this study establishes a subjective and objective comprehensive fairness evaluation method and analyzes the fairness of the spatial distribution of park green space in the Daxing part of Yizhuang New Town, Beijing and its relationship with the economic level of residents. The results show that: (1) the green space in the Daxing part of Yizhuang New Town is concentrated in the town center and distributed more sparsely in surrounding areas; (2) urban park green space is not equitable in quantity, area, disaster prevention and avoidance, or accessibility; (3) high-grade apartment complexes have higher quality of services than low-grade apartment complexes, and the number of parks, per capita park area, disaster prevention and avoidance, and park accessibility are all higher for high-grade than for low-grade apartment complexes. Medium-grade apartment complexes have a high level of green space services, and the number of parks, total area, and accessibility are 1.06, 2.58, and 1.13 times higher than those of high-grade apartment complexes, respectively. Conversely, disaster prevention and avoidance and park area per capita of medium-grade apartment complexes are lower than in high-grade apartment complexes, at 0.81 and 0.12 times, respectively. This study provides a new perspective for exploring society and landscape equity and concludes with suggestions for improving park green space public services. [ABSTRACT FROM AUTHOR]

Cardiomyocytes differentiated from human‐induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo‐YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo‐YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi‐based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP‐TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo‐YAP signal in cardiovascular lineage commitment. [ABSTRACT FROM AUTHOR]

Melatonin, a hormone secreted by the pineal gland, possesses multiple biological activities such as antitumor, antioxidant, and anti-ischemia. C-kit+ cardiac progenitor cells ( CPCs) have emerged as a promising tool for the treatment of heart diseases. However, the senescence of CPCs due to pathological stimuli leads to the decline of CPCs' functions and regenerative potential. This study was conducted to demonstrate whether melatonin antagonizes the senescence of CPCs in response to oxidative stress. Here, we found that the melatonin treatment markedly inhibited the senescent characteristics of CPCs after exposed to sublethal concentration of H2O2, including the increase in senescence-associated β-galactosidase ( SA- β-gal)-positive CPCs, senescence-associated heterochromatin loci ( SAHF), secretory IL-6 level, and the upregulation of p53 and p21 proteins. Senescence-associated proliferation reduction was also attenuated by melatonin in CPCs. Luzindole, the melatonin membrane receptor blocker, may block the melatonin-mediated suppression of premature senescence in CPCs. Interestingly, we found that long noncoding RNA H19 and its derived miR-675 were downregulated by H2O2 in CPCs, but melatonin treatment could counter this alteration. Furthermore, knockdown of H19 or miR-675 blocked antisenescence actions of melatonin on H2O2-treated CPCs. It was further verified that H19-derived miR-675 targeted at the 3′ UTR of USP10, which resulted in the downregulation of p53 and p21 proteins. In summary, melatonin antagonized premature senescence of CPCs via H19/miR-675/ USP10 pathway, which provides new insights into pharmacological actions and potential applications of melatonin on the senescence of CPCs. [ABSTRACT FROM AUTHOR]

Background: This study aimed to characterize the N 6 -methyladenosine epitranscriptomic profile induced by mono(2-ethylhexyl) phthalate (MEHP) exposure using a human-induced pluripotent stem cell-derived endothelial cell model. Methods: A multiomic approach was employed by performing RNA sequencing in parallel with an N 6 -methyladenosine-specific microarray to identify mRNAs, lncRNAs, and miRNAs affected by MEHP exposure. Results: An integrative multiomic analysis identified relevant biological features affected by MEHP, while functional assays provided a phenotypic characterization of these effects. Transcripts regulated by the epitranscriptome were validated with quantitative PCR and methylated RNA immunoprecipitation. Conclusion: The authors' profiling of the epitranscriptome expands the scope of toxicological insights into known environmental toxins to under surveyed cellular contexts and emerging domains of regulation and is, therefore, a valuable resource to human health.

N6-methyladenosine (m 6 A), as the most abundant modification of mammalian messenger RNAs, is essential for tissue development and pathogenesis. However, the biological significance of m 6 A methylation in cardiac differentiation and development remains largely unknown. Here, we identify that the downregulation of m 6 A demethylase ALKBH5 is responsible for the increase of m 6 A methylation and cardiomyocyte fate determination of human embryonic stem cells (hESCs) from mesoderm cells (MESs). In contrast, ALKBH5 overexpression remarkably blocks cardiomyocyte differentiation of hESCs. Mechanistically, KDM5B and RBBP5, the components of H3K4 modifying enzyme complexes, are identified as downstream targets for ALKBH5 in cardiac-committed hESCs. Loss of function of ALKBH5 alters the expression of KDM5B and RBBP5 through impairing stability of their mRNAs, which in turn promotes the transcription of GATA4 by enhancing histone H3 Lys4 trimethylation (H3K4me3) at the promoter region of GATA4. Taken together, we reveal a previously unidentified role of m 6 A demethylase ALKBH5 in determining cardiac lineage commitment of hESCs., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)