Bronchopulmonary dysplasia (BPD) is characterized by abnormal development of the blood vessels and alveoli in lungs, which largely occurs in premature infants. Exosomes (EXO) from very preterm ...infants (VPI) with BPD (BPD-EXO) impair angiogenic activities of human umbilical vein endothelial cells (HUVECs) via EXO-miRNAs cargo. This study aimed to determine whether and how BPD-EXO affect the development of BPD in a mouse model. We showed that treating BPD mice with BPD-EXO chronically and irreversibly aggravated lung injury. BPD-EXO up-regulated 139 and down-regulated 735 genes in the mouse lung tissue. These differentially expressed genes were enriched to the MAPK pathway (e.g., Fgf9 and Cacna2d3), which is critical to angiogenesis and vascular remodeling. BPD-EXO suppressed expression of Fgf9 and Cacna2d3 in HUVECs and inhibited migration, tube formation, and increased cell apoptosis in HUVECs. These data demonstrate that BPD-EXO aggravate lung injury in BPD mice and impair lung angiogenesis, plausibly leading to adverse outcomes of VPI with BPD. These data also suggest that BPD-EXO could serve as promising targets for predicting and treating BPD.
The conversion of biomass waste into economical and high-performance energy storage devices receives significant attention. Herein, a facile and green method to prepare porous active carbon from ...walnut septum is applied to the electrode materials of supercapacitors. The effect of chemical etching reagent (KOH) on the microstructure and specific capacitance of the porous carbon are explored. The modified BC-2.0, with a KOH/walnut septum mass ratio of 2:1, exhibits large specific surface area of 1003.9 m
2
·g
−1
with hierarchical micro-mesoporous structures. BC-2.0 reveals a superior specific capacitance of 457 F·g
−1
at 1 A·g
−1
. The flexible symmetric supercapacitor in gel electrolyte (KOH/PVA) exhibits considerable synergetic energy–power output performance. The results indicate that walnut septum is a better precursor to obtain activated carbons relative to other biomass carbon sources. The large mesoporosity after activation effectively boosts the electrochemical properties of supercapacitor. Consequently, the walnut septum has potential to be a superior electrode material for supercapacitors.
Graphical abstract
Purpose
Necroptosis is an important form of cell death following myocardial ischemia/reperfusion (I/R) and phosphoglycerate mutase 5 (PGAM5) functions as the convergent point for multiple necrosis ...pathways. This study aims to investigate whether inhibition of PGAM5 could reduce I/R-induced myocardial necroptosis and the underlying mechanisms.
Methods
The SD rat hearts (or H9c2 cells) were subjected to 1-h ischemia (or 10-h hypoxia) plus 3-h reperfusion (or 4-h reoxygenation) to establish the I/R (or H/R) injury model. The myocardial injury was assessed by the methods of biochemistry, H&E (hematoxylin and eosin), and PI/DAPI (propidium iodide/4′,6-diamidino-2-phenylindole) staining, respectively. Drug interventions or gene knockdown was used to verify the role of PGAM5 in I/R (or H/R)-induced myocardial necroptosis and possible mechanisms.
Results
The I/R-treated heart showed the injuries (increase in infarct size and creatine kinase release), upregulation of PGAM5, dynamin-related protein 1 (Drp1), p-Drp1-S616, and necroptosis-relevant proteins (RIPK1/RIPK3, receptor-interacting protein kinase 1/3; MLKL, mixed lineage kinase domain-like); these phenomena were attenuated by inhibition of PGAM5 or RIPK1. In H9c2 cells, H/R treatment elevated the levels of PGAM5, RIPK1, RIPK3, MLKL, Drp1, and p-Drp1-S616 and induced mitochondrial dysfunctions (elevation in mitochondrial membrane potential and ROS level) and cellular necrosis (increase in LDH release and the ratio of PI
+
/DAPI
+
cells); these effects were blocked by inhibition or knockdown of PGAM5.
Conclusions
Inhibition of PGAM5 can reduce necroptosis in I/R-treated rat hearts through suppression of Drp1; there is a positive feedback between RIPK1 and PGAM5, and PGAM5 might serve as a novel therapeutic target for prevention of myocardial I/R injury.
The dehydration responsive element binding (DREB) transcription factors play an important role in regulating stress-related genes. OsDREB2A, a member of the DREBP subfamily of AP2/ERF transcription ...factors in rice (Oryza sativa), is involved in the abiotic stress response. OsDREB2A expression is induced by drought, low-temperature and salt stresses. Here, we report the ability of OsDREB2A to regulate high-salt response in transgenic soybean. Overexpressing OsDREB2A in soybeans enhanced salt tolerance by accumulating osmolytes, such as soluble sugars and free proline, and improving the expression levels of some stress-responsive transcription factors and key genes. The phenotypic characterization of transgenic soybean were significantly better than those of wild-type (WT). Electrophoresis mobility shift assay (EMSA) revealed that the OsDREB2A can bind to the DRE core element in vitro. These results indicate that OsDREB2A may participate in abiotic stress by directly binding with DRE element to regulate the expression of downstream genes. Overexpression of OsDREB2A in soybean might be used to improve tolerance to salt stress.
Endoscopy is the primary modality for detecting asymptomatic esophageal squamous cell carcinoma (ESCC) and precancerous lesions. Improving detection rate remains challenging. We developed a system ...based on deep convolutional neural networks (CNNs) for detecting esophageal cancer and precancerous lesions high-risk esophageal lesions (HrELs) and validated its efficacy in improving HrEL detection rate in clinical practice (trial registration ChiCTR2100044126 at www.chictr.org.cn). Between April 2021 and March 2022, 3117 patients ≥50 years old were consecutively recruited from Taizhou Hospital, Zhejiang Province, and randomly assigned 1:1 to an experimental group (CNN-assisted endoscopy) or a control group (unassisted endoscopy) based on block randomization. The primary endpoint was the HrEL detection rate. In the intention-to-treat population, the HrEL detection rate 28 of 1556 (1.8%) was significantly higher in the experimental group than in the control group 14 of 1561 (0.9%),
= 0.029, and the experimental group detection rate was twice that of the control group. Similar findings were observed between the experimental and control groups 28 of 1524 (1.9%) versus 13 of 1534 (0.9%), respectively;
= 0.021. The system's sensitivity, specificity, and accuracy for detecting HrELs were 89.7, 98.5, and 98.2%, respectively. No adverse events occurred. The proposed system thus improved HrEL detection rate during endoscopy and was safe. Deep learning assistance may enhance early diagnosis and treatment of esophageal cancer and may become a useful tool for esophageal cancer screening.
Receptor-interacting protein kinase 1/3 (RIPK1/3) and mixed lineage kinase domain-like (MLKL)-mediated necroptosis contributes to brain injury after ischemic stroke. Ligustroflavone is an ingredient ...of
common privet
with activities of anti-inflammation and complement inhibition. This study aims to explore the effect of ligustroflavone on ischemic brain injury in stroke rat and the underlying mechanisms. A rat model of ischemic stroke was established by middle cerebral artery occlusion (MCAO), which showed ischemic injury (increase in neurological deficit score and infarct volume) and upregulation of necroptosis-associated proteins (RIPK1, RIPK3 and MLKL/p-MLKL). Administration of ligustroflavone (30 mg/kg, i.g.) 15 min before ischemia evidently improved neurological function, reduced infarct volume, and decreased the levels of necroptosis-associated proteins except the RIPK1. Consistently, hypoxia-cultured PC12 cells (O
2
/N2/CO
2
, 1:94:5, 8 h) caused cellular injury (LDH release and necroposis) concomitant with up-regulation of necroptosis-associated proteins, and these phenomena were blocked in the presence of ligustroflavone (25 μM) except the elevated RIPK1 levels. Using the Molecular Operating Environment (MOE) program, we identified RIPK1, RIPK3, and MLKL as potential targets of ligustroflavone. Further studies showed that the interaction between RIPK3 and RIPK1 or MLKL was significantly enhanced, which was blocked in the presence of ligustroflavone. Based on these observations, we conclude that ligustroflavone protects rat brain from ischemic injury, and its beneficial effect is related to the prevention of necroptosis through a mechanism involving targeting RIPK1, RIPK3, and/or MLKL.
Ethylene/polar monomer coordination copolymerization offers an attractive way of making functionalized polyolefins. However, ethylene copolymerization with industrially relevant short chain length ...alkenoic acid remain a big challenge. Here we report the efficient direct copolymerization of ethylene with vinyl acetic acid by tetranuclear nickel complexes. The protic monomer can be extended to acrylic acid, allylacetic acid, ω-alkenoic acid, allyl alcohol, and homoallyl alcohol. Based on X-ray analysis of precatalysts, control experiments, solvent-assisted electrospray ionization-mass spectrometry detection of key catalytic intermediates, and density functional theory studies, we propose a possible mechanistic scenario that involves a distinctive vinyl acetic acid enchainment enabled by Ni···Ni synergistic effects. Inspired by the mechanistic insights, binuclear nickel catalysts are designed and proved much more efficient for the copolymerization of ethylene with vinyl acetic acid or acrylic acid, achieving the highest turnover frequencies so far for both ethylene and polar monomers simultaneously.
Blood-brain barrier (BBB) dysfunction causing edema and hemorrhagic transformation is one of the pathophysiological characteristics of stroke. Protection of BBB integrity has shown great potential in ...improving stroke outcome. Here, we assessed the efficacy of exosomes extracted from healthy rat serum in protection against ischemic stroke
and
. Exosomes were isolated by gradient centrifugation and ultracentrifugation and exosomes were characterized by transmission electron microscopy (TEM) and nanoparticle tracking video microscope. Exosomes were applied to middle cerebral artery occlusion (MCAO) rats or brain microvascular endothelial cell line (bEnd.3) subjected to oxygen-glucose deprivation (OGD) injury. Serum-derived exosomes were injected intravenously into adult male rats 2 h after transient MCAO. Infarct volume and gross cognitive function were assessed 24 h after reperfusion. Poststroke rats treated with serum-derived exosomes exhibited significantly reduced infarct volumes and enhanced neurological function. Apoptosis was assessed via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) staining and the expression of B-cell lymphoma-2 (Bcl-2), Bax, and cleaved caspase-3 24 h after injury. Our data showed that serum exosomes treatment strikingly decreased TUNEL
cells in the striatum, enhanced the ratio of Bcl-2 to Bax, and inhibited cleaved caspase-3 production in MCAO rats and OGD/reoxygenation insulted bEnd.3 cells. Under the consistent treatment, the expression of microtubule-associated protein 1 light chain 3B-II (LC3B-II), LC3B-I, and Sequestosome-1 (SQSTM1)/p62 was detected by Western blotting. Autolysosomes were observed via TEM. We found that serum exosomes reversed the ratio of LC3B-II to LC3B-I, prevented SQSTM1/p62 degradation, autolysosome formation, and autophagic flux. Together, these results indicated that exosomes isolated from healthy serum provided neuroprotection against experimental stroke partially via inhibition of endothelial cell apoptosis and autophagy-mediated BBB breakdown. Intravenous serum-derived exosome treatment may, therefore, provide a novel clinical therapeutic strategy for ischemic stroke.
Gasdermin E (GSDME), also called DFNA5, is a member of the gasdermin family. GSDME is involved in the regulation of apoptosis and necrosis. The N-terminal domain of GSDME displays an ...apoptosis-inducing activity while the C-terminal domain may serve as an apoptosis-inhibiting regulator by shielding the N-terminal domain. Besides its function in the regulation of apoptosis, GSDME was recently reported to be a substrate of caspase-3 and cleavage of GSDME by caspase-3 into necrotic N-terminal fragment leads to the induction of secondary necrosis.
GSDME
was first identified as a deafness gene because its mutation was associated with a specific form of autosomal dominant progressive sensorineural hearing loss. Furthermore, GSDME has been considered a tumor suppressor implicated in several types of cancer. This mini-review summarized recent reports relevant to the functions of GSDME in the regulation of apoptosis and necrosis as well as its clinical relevance.
The rat is an important animal model in biomedical research, but practical limitations to genetic manipulation have restricted the application of genetic analysis. Here we report the derivation of ...rat androgenetic haploid embryonic stem cells (RahESCs) as a tool to facilitate such studies. Our approach is based on removal of the maternal pronucleus from zygotes to generate androgenetic embryos followed by derivation of ESCs. The resulting RahESCs have 21 chromosomes, express pluripotency markers, differentiate into three germ layer cells, and contribute to the germline. Homozygous mutations can be introduced by both large-scale gene trapping and precise gene targeting via homologous recombination or the CRISPR-Cas system. RahESCs can also produce fertile rats after intracytoplasmic injection into oocytes and are therefore able to transmit genetic modifications to offspring. Overall, RahESCs represent a practical tool for functional genetic studies and production of transgenic lines in rat.
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•Derivation of rat haploid embryonic stem cells from androgenetic embryos•RahESCs are pluripotent and able to differentiate into various cell types•Homozygous mutations can be introduced to RahESCs using a variety of strategies•RahESCs can produce fertile rats after intracytoplasmic injection into oocytes
Li et al. show here that androgenetic rat haploid embryonic stem cells can be used for genetic screening, random or homologous mutagenesis, and CRISPR-Cas-mediated gene editing.
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