Endothelial cell death is linked to vascular diseases such as atherosclerosis and tissue ischemia. miRNA-17-92 (miR-17–92) is a multiple functional oncogenic miRNA cluster which plays vital roles in ...tumor angiogenesis and tissue development. However, its role in regulation of endothelial cell ferroptosis remains unclear. In this study, we revealed that miR-17–92 protects endothelial HUVEC cells from erastin-induced ferroptosis. miR-17-92 overexpression significantly reduced erastin-induced growth inhibition and ROS generation of HUVEC cells. Furthermore, Zinc lipoprotein A20, a validated target of miR-17-92, was identified as a novel regulator of endothelial cell ferroptosis. Lentivirus mediated A20 overexpression increased ROS generation and enhanced erastin-induced ferroptosis, whereas A20 knockdown inhibited erastin-induced ferroptosis. Mechanistic studies revealed that erastin-induced ferroptosis is associated with GPX4 downregulation and ACSL4 upregulation. miR-17-92 overexpression or A20 inhibition increased the ACSL4 expression in HUVEC cells. A20 was identified to directly with and regulate ACSL4 expression by immunoprecipitation. It suggests that the A20-ACSL4 axis plays important roles in erastin-induced endothelial ferroptosis. In conclusion, this study revealed a novel mechanism through which miR-17-92 protects endothelial cells from erastin-induced ferroptosis by targeting the A20-ACSL4 axis.
•miR-17-92 protects endothelial cells from erastin-induced ferroptosis.•Zinc lipoprotein A20 is identified as a novel regulator of ferroptosis.•A20 regulates ACSL4 by their directly interaction in endothelial cells.•miR-17-92 targets the A20-ACSL4 axis in endothelial cells.
Here, we introduce the 3D Genome Browser, http://3dgenome.org , which allows users to conveniently explore both their own and over 300 publicly available chromatin interaction data of different ...types. We design a new binary data format for Hi-C data that reduces the file size by at least a magnitude and allows users to visualize chromatin interactions over millions of base pairs within seconds. Our browser provides multiple methods linking distal cis-regulatory elements with their potential target genes. Users can seamlessly integrate thousands of other omics data to gain a comprehensive view of both regulatory landscape and 3D genome structure.
Conventional lithium‐ion batteries (LIBs) with graphite anodes are approaching their theoretical limitations in energy density. Replacing the conventional graphite anodes with high‐capacity Si‐based ...anodes represents one of the most promising strategies to greatly boost the energy density of LIBs. However, the inherent huge volume expansion of Si‐based materials after lithiation and the resulting series of intractable problems, such as unstable solid electrolyte interphase layer, cracking of electrode, and especially the rapid capacity degradation of cells, severely restrict the practical application of Si‐based anodes. Over the past decade, numerous reports have demonstrated that polymer binders play a critical role in alleviating the volume expansion and maintaining the integrity and stable cycling of Si‐based anodes. In this review, the state‐of‐the‐art designing of polymer binders for Si‐based anodes have been systematically summarized based on their structures, including the linear, branched, crosslinked, and conjugated conductive polymer binders. Especially, the comprehensive designing of multifunctional polymer binders, by a combination of multiple structures, interactions, crosslinking chemistries, ionic or electronic conductivities, soft and hard segments, and so forth, would be promising to promote the practical application of Si‐based anodes. Finally, a perspective on the rational design of practical polymer binders for the large‐scale application of Si‐based anodes is presented.
Polymer binders play a crucial role in alleviating the volume expansion and maintaining the integrity and stable cycling of Si‐based anodes. This review presents the state‐of‐the‐art designing of polymer binders for Si‐based anodes based on the linear, branched, crosslinked, conjugated polymer structures. Besides, the multifunctional design of polymer binders for the practical application of Si‐based anodes has been discussed.
MicroRNAs (miRNAs) have been shown to anticipate great cancer diagnostic potential. Recently, circulating miRNAs have been reported as promising biomarkers for various pathologic conditions. The ...objective of this study was to investigate the potential of serum miRNAs as novel biomarkers for hepatocellular carcinoma (HCC).
This study was divided into four phases: (I) Ten candidate serum miRNAs were detected by using real-time RT-PCR, corresponding 10 HCC patients with chronic hepatitis B virus (HBV) infection and 10 age- and sex-matched healthy subjects. (II) Marker validation by real-time RT-PCR on HBV patients with (n = 48) or without HCC (n = 48), and healthy subjects (n = 24). (III) Marker detection by real-time RT-PCR in sera from another 14 HCC patients before and 1 month after surgical resection. (IV) We examined the correlation between the expressions of candidate serum miRNAs with clinical parameters of HCC patients. Although miR-222, miR-223 or miR-21 were significantly up- or down-regulated between HCC patients and healthy controls, no significant difference was observed in the levels of these miRNAs between HBV patients without and with HCC. MiR-122 in serum was significantly higher in HCC patients than healthy controls (p<0.001). More importantly, it was found that the levels of miR-122 were significantly reduced in the post-operative serum samples when compared to the pre-operative samples. Although serum miR-122 was also elevated in HBV patients with HCC comparing with those without HCC, the difference was at the border line (p = 0.043).
Our results suggest that serum miR-122 might serve as a novel and potential noninvasive biomarker for detection of HCC in healthy subjects, moreover, it might serve as a novel biomarker for liver injury but not specifically for detection of HCC in chronic HBV infection patients.
L-type amino acid transporters (LATs) uptake neutral amino acids including L-leucine into cells, stimulating mammalian target of rapamycin complex 1 signaling and protein synthesis. LAT1 and LAT3 are ...overexpressed at different stages of prostate cancer, and they are responsible for increasing nutrients and stimulating cell growth.
We examined LAT3 protein expression in human prostate cancer tissue microarrays. LAT function was inhibited using a leucine analog (BCH) in androgen-dependent and -independent environments, with gene expression analyzed by microarray. A PC-3 xenograft mouse model was used to study the effects of inhibiting LAT1 and LAT3 expression. Results were analyzed with the Mann-Whitney U or Fisher exact tests. All statistical tests were two-sided.
LAT3 protein was expressed at all stages of prostate cancer, with a statistically significant decrease in expression after 4-7 months of neoadjuvant hormone therapy (4-7 month mean = 1.571; 95% confidence interval = 1.155 to 1.987 vs 0 month = 2.098; 95% confidence interval = 1.962 to 2.235; P = .0187). Inhibition of LAT function led to activating transcription factor 4-mediated upregulation of amino acid transporters including ASCT1, ASCT2, and 4F2hc, all of which were also regulated via the androgen receptor. LAT inhibition suppressed M-phase cell cycle genes regulated by E2F family transcription factors including critical castration-resistant prostate cancer regulatory genes UBE2C, CDC20, and CDK1. In silico analysis of BCH-downregulated genes showed that 90.9% are statistically significantly upregulated in metastatic castration-resistant prostate cancer. Finally, LAT1 or LAT3 knockdown in xenografts inhibited tumor growth, cell cycle progression, and spontaneous metastasis in vivo.
Inhibition of LAT transporters may provide a novel therapeutic target in metastatic castration-resistant prostate cancer, via suppression of mammalian target of rapamycin complex 1 activity and M-phase cell cycle genes.
Si has been recognized as a next-generation anode alternative to graphite for high-energy-density lithium-ion batteries. However, the most intractable problem of previous Si-based anodes is the ...relatively low compressive strength of particles because of excess voids and porous structures, thus leading to poor structural integrity and electrochemical performance under high pressure of the rolling procedure in practical application. Therefore, a rational design of robust Si/C microspheres with a compact nano/microstructure is an effective strategy to address the above-mentioned issues. In this ingenious structure, Si nanoparticles are homogeneously dispersed and anchored on flake graphite and then the composites self-assemble into microspheres via polycondensation and surface tension of pitch under high temperature and high pressure. Benefitting from this innovative approach and rational design, the obtained robust Si/C microspheres not only present high compressive property and high tap density (1.0 g cm–3) but also demonstrate high initial Coulombic efficiency (90.5%) and cycling stability with areal capacity (4 mA h cm–2) under a compaction density of 1.3 g cm–3. Furthermore, the full cell assembled with LiNi0.8Co0.1Mn0.1O2 and the resultant Si/C microsphere anode also displays good cycling performance and rate capabilities. Owing to these aspects, the proposed rational design of encapsulating Si nanoparticles in high-tap-density microspheres could be extended to load other nanomaterials for advanced batteries.
The tree shrew (Tupaia belangeri chinensis), a small animal widely distributed in Southeast Asia and southwest China, has the potential to be developed as an animal model for hepatitis C. To ...determine the susceptibility of the tree shrew to hepatitis C virus (HCV) infection in vitro and in vivo, a well-established HCV, produced from the J6/JFH1-Huh7.5.1 culture system, was used to infect cultured primary tupaia hepatocytes (PTHs) and tree shrews. The in vitro results showed that HCV genomic RNA and HCV-specific nonstructural protein 5A (NS5A) could be detected in the PTH cell culture from days 3-15 post-infection, although the viral load was lower than that observed in Huh7.5.1 cell culture. The occurrence of five sense mutations S391A, G397A, L402F and M405T in the hypervariable region 1 (HVR1) of envelope glycoprotein 2 and I2750M in NS5B suggested that HCV undergoes genetic evolution during culture. Fourteen of the 30 experimental tree shrews (46.7 %) were found to be infected, although the HCV viremia was intermittent in vivo. A positive test for HCV RNA in liver tissue provided stronger evidence for HCV infection and replication in tree shrews. The results of an immunohistochemistry assay also demonstrated the presence of four HCV-specific proteins (Core, E2, NS3/4 and NS5A) in the hepatocytes of infected tree shrews. The pathological changes observed in the liver tissue of infected tree shrews could be considered to be representative symptoms of mild hepatitis. These results revealed that the tree shrew can be used as an animal model supporting the infection and replication of HCV in vitro and in vivo.
Mesenchymal stem cells (MSCs) are a population of pluripotent cells that have been tested for the treatment of many inflammatory diseases. It remains unclear whether MSCs were effective in treating ...mice with alcoholic hepatitis (AH) and its underlying mechanism. In the present study, MSCs were isolated from bone marrow of 4-6 week-old C57BL/6N male mice. AH was induced in female mice by chronic-binge ethanol feeding for 10 days. Intraperitoneal (i.p.) transplantation of MSCs or saline were performed in mice on day 10. Blood samples and hepatic tissues were harvested on day 11. Biochemical, liver histological and flow cytometric analyses were performed. Compared to the control mice, the AH mice had significantly increased liver/body weight ratio, serum alanine aminotransferase (ALT) and aspartate aminotransferases (AST), hepatic total cholesterol (TC), triglyceride (TG), malondialdehyde (MDA), hepatic neutrophil and macrophage infiltration (P<0.001), which were markedly reduced by i.p. transplantation of MSCs (P<0.01). Compared to the control mice, the hepatic glutathione (GSH) was prominently lower in the AH mice (P<0.001), which was markedly enhanced after i.p. injection of MSCs (P<0.001). MSCs were effective for the treatment of AH mice, which might be associated with their ability in inhibiting hepatic neutrophil and macrophage infiltration, and alleviating oxidative stress.
Circular RNAs (circRNAs), a novel class of poorly conserved non-coding RNAs that regulate gene expression, are highly enriched in the human brain. Despite increasing discoveries of circRNA function ...in human neurons, the circRNA landscape and function in developing human oligodendroglia, the myelinating cells that govern neuronal conductance, remains unexplored. Meanwhile, improved experimental and computational tools for the accurate identification of circRNAs are needed.
We adopt a published experimental approach for circRNA enrichment and develop CARP (CircRNA identification using A-tailing RNase R approach and Pseudo-reference alignment), a comprehensive 21-module computational framework for accurate circRNA identification and quantification. Using CARP, we identify developmentally programmed human oligodendroglia circRNA landscapes in the HOG oligodendroglioma cell line, distinct from neuronal circRNA landscapes. Numerous circRNAs display oligodendroglia-specific regulation upon differentiation, among which a subclass is regulated independently from their parental mRNAs. We find that circRNA flanking introns often contain cis-regulatory elements for RNA editing and are predicted to bind differentiation-regulated splicing factors. In addition, we discover novel oligodendroglia-specific circRNAs that are predicted to sponge microRNAs, which co-operatively promote oligodendroglia development. Furthermore, we identify circRNA clusters derived from differentiation-regulated alternative circularization events within the same gene, each containing a common circular exon, achieving additive sponging effects that promote human oligodendroglia differentiation.
Our results reveal dynamic regulation of human oligodendroglia circRNA landscapes during early differentiation and suggest critical roles of the circRNA-miRNA-mRNA axis in advancing human oligodendroglia development.
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