The aberrant expression of hypoxia‐inducible factor 1 alpha (HIF1A)‐antisense RNA 2 (HIF1A‐AS2) was found in various human cancers including breast cancer. The aim of this study was to present more ...evidence about the role HIF1A‐AS2 on triple‐negative breast cancer (TNBC). In our results, HIF1A‐AS2 was also found to be upregulated in TNBC tissues compared with non‐TNBC tissues or adjacent normal tissues. Besides, HIF1A‐AS2 expression was also elevated in TNBC cell lines compared with the normal breast epithelial cell line. Moreover, high expression of HIF1A‐AS2 was associated with lymph node metastasis, distant metastasis and unfavorable histological grade in TNBC patients. Survival analysis showed a TNBC patient with high HIF1A‐AS2 expression had shorter overall survival than patients with low HIF1A‐AS2 expression, and HIF1A‐AS2 high expression acted as an independent poor prognostic factor for overall survival in TNBC patients. The cell migration and invasion assays suggested inhibition of HIF1A‐AS2 obviously depressed TNBC cell migration and invasion. In conclusion, HIF1A‐AS2 serves as a novel biomarker for predicting clinical progression and prognosis in TNBC.
Hypoxia‐inducible factor 1 alpha (HIF1A)‐antisense RNA 2 (HIF1A‐AS2) expression is associated with clinical progression and poor prognosis in patients with triple‐negative breast cancer (TNBC). Inhibition of HIF1A‐AS2 depresses TNBC cell migration and invasion.
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•Etomidate causes POCD in mice.•Downregulation of HIF1A alleviates POCD in mice.•PGK1 promotes oxidative stress in the hippocampus of mice with POCD.•HIF1A regulates PGK1 ...transcriptional activation.•PGK1 overturns the effects of KD-HIF1A on oxidative stress in HT-22 cells.
Etomidate (ETO), a hypnotic agent used for anesthesia induction, has been shown to induce long-lasting cognitive deficits. In the present study, we investigated whether ETO could activate the HIF1A/PGK1 pathway to antagonize oxidative damage in mice with postoperative cognitive dysfunction (POCD). A mouse model of ETO-mediated POCD was established, and pathological changes, apoptosis, and inflammatory factors in mouse hippocampal tissues were analyzed by HE staining, TUNEL assay, and ELISA. ETO was revealed to cause cognitive dysfunction in mice. Integrated database mining was conducted to screen out transcription factors that are both related to ETO and POCD. Hypoxia-inducible factor 1-alpha (HIF1A) was overexpressed in mice with POCD, and downregulation of HIF1A alleviated cognitive dysfunction in mice. HIF1A downregulation inhibited the transcription of phosphoglycerate kinase 1 (PGK1). Overexpression of PGK1 abated the alleviating effects of HIF1A knockdown on oxidative stress in mice with POCD. In addition, HIF1A activation of PGK1 induced oxidative stress and apoptosis in HT-22 cells while inhibiting cell viability. Taken together, we demonstrated that HIF1A activation of PGK1 induced oxidative stress in ETO-mediated POCD.
Extracellular vesicles (EVs) possess great potential in the modulation of cardiovascular diseases. Our current work intended to assay the clinical significance of endothelial cell (EC)‐derived EVs in ...atherosclerosis (AS). Expression of HIF1A‐AS2, miR‐455‐5p, and ESRRG in plasma from AS patients and mice and EVs from ox‐LDL‐treated ECs was measured. Interactions among HIF1A‐AS2, miR‐455‐5p, ESRRG, and NLRP3 were analyzed. Next, EVs were co‐cultured with ECs, and ectopic expression and depletion experimentations of HIF1A‐AS2, miR‐455‐5p, ESRRG, and/or NLRP3 were carried out to assay their roles in pyroptosis and inflammation of ECs in AS. At last, the effects of HIF1A‐AS2 shuttled by EC‐derived EVs on EC pyroptosis and vascular inflammation in AS were verified in vivo. HIF1A‐AS2 and ESRRG were highly expressed, while miR‐455‐5p was poorly expressed in AS. HIF1A‐AS2 could sponge miR‐455‐5p to elevate the expression of ESRRG and NLRP3. Both in vitro and in vivo experiments revealed that ECs‐derived EVs carrying HIF1A‐AS2 induced the pyroptosis and vascular inflammation of ECs to promote the progression of AS by sponging miR‐455‐5p via ESRRG/NLRP3. HIF1A‐AS2 shuttled by ECs‐derived EVs can accelerate the progression of AS by downregulating miR‐455‐5p and upregulating ESRRG and NLRP3.
The molecular mechanism by which ECs‐derived EVs delivering HIF1A‐AS2 affect the pyroptosis and vascular inflammation of ECs in AS via the miR‐455‐5p/ESRRG/NLRP3 axis.
BACKGROUND:Myocarditis can develop into dilated cardiomyopathy, which may require heart transplantation. The immunological network of myocarditis phases remains unknown. This study aimed to ...investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis.
METHODS:Mice were treated with myosin heavy chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing analysis of Cd45 cells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory, and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone heart transplantation.
RESULTS:We identified 26 cell subtypes among 34 665 cells. Macrophages constituted the main immune cell population at all disease phases (>60%), and an inflammation-associated macrophage cluster was identified in which the expression of Hif1a-regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then released Il-1 to participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. T-helper 17 cells, in which the expression of Hif1a-regulated genes was upregulated, constituted the main T-cell population detected at the acute inflammatory phase, whereas regulatory T cells were the main T-cell population detected at the subacute inflammatory phase, and γδ T cells releasing Il-17 were the main T-cell population observed at the myopathy phase. Moreover, the Hif1a expression level correlated with the extent of inflammation. In addition, PX-478 could alleviate the inflammatory responses of the different EAM phases. Last, HIF1A was expressed at higher levels in patients with acute autoimmune myocarditis than in patients with dilated cardiomyopathy and healthy control subjects.
CONCLUSIONS:We present here a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidate the contribution of Hif1a to the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and T-helper 17 cells. Moreover, an Hif1a inhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.
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•This is the first report about the effects of glycolysis and HSPs on the hypoxia adaptation of Tibetan sheep at different altitudes.•HIF1A and PDK4 expression level and ...glycolysis-related enzymes content were significantly increased with altitude, and reached the highest level in Tibetan sheep at 4,500 m altitude.•Expression divergence between HSP27 and HSP60 in response to altitude-related hypoxia indicates their different regulatory functions.•Glycolysis and HSPs became upregulated to ensure energy supply and proteostasis in Tibetan sheep under hypoxia condition.
Glycolysis and heat shock proteins (HSPs) play an important role in mediating the physiological response to hypoxia. The changes of glycolysis and HSPs with altitude would provide important information regarding ways to prevent hypoxia-related sickness in both animals and humans. In this study, the expression pattern of HIF1A, PDK4, HSP27 and HSP60, indexes activity and content of glucose metabolism were detected in heart, lung, brain, and quadriceps femoris taken from Tibetan sheep (Ovis aries) that were raised at different altitudes (2,500 m, 3,500 m and 4,500 m). The expression of HIF1A and PDK4 was increased with increasing altitude in all of the tissues. The lactate dehydrogenase (LDH) activities and adenosine triphosphate (ATP), nicotinamide adenine dinucleotide (NADH (redox state), NAD+), lactic acid (LA), pyruvic acid (PA) contents were all increased with increasing altitude in all of the tissues. The ratio of NADH/NAD+ and LA/PA were higher in sheep at an altitude of 4,500 m than of 3,500 m and 2,500 m in all tissues, except for the NADH/NAD+ ratio in lung and quadriceps femoris. An increase in the protein and mRNA expression of ATP-independent HSP27 during hypoxia condition was detected. The expression of ATP-dependent HSP60 mRNA and protein was increased in all of the tissues at an altitude of 3,500 m than of 2,500 m, but was decreased at an altitude of 4,500 m. These results suggest that glycolysis and HSPs are upregulated to ensure energy supply and proteostasis during hypoxia, but energy conservation may be prioritized over cytoprotective protein chaperoning in Tibetan sheep tissues during extreme hypoxia.
AIM: To investigate the effect of long non-coding RNA-HIF1A-AS1(lncRNA HIF1A-AS1)on the chemotherapy sensitivity of vincristine(VCR)-resistant in retinoblastoma(RB)cells by regulating the expression ...of hypoxia-inducible factor-1α(HIF-1α).METHODS: The human RB VCR-resistant cell line SO-RB50/VCR was established, expression of lncRNA HIF1A-AS1 in SO-RB50 and SO-RB50/VCR cells were detected by reverse transcription-quantitative real-time PCR(RT-qPCR); inhibition of lncRNA HIF1A-AS1 expression or simultaneous overexpression of HIF-1α in SO-RB50/VCR cells, and then median inhibitory concentration(IC50)of VCR and cell proliferation and apoptosis were detected in SO-RB50/VCR cells; the protein expressions of HIF-1α, multidrug resistance associate protein(MRP)and P-glycoprotein(P-gp)were measured by Western blot.RESULTS: Compared with SO-RB50 cells, the expression levels of lncRNA HIF1A-AS1 and HIF-1α protein in SO-RB50/VCR cells were increased(P<0.05); after inhibiting the expression of lncRNA HIF1A-AS1 in SO-RB50/VCR cells, the apoptosis rate was significantly increased(P<0.05), optical density(OD450), the IC50 value of VCR on cells and the expression levels of HIF-1α, MRP and P-gp proteins were significantly reduced(P<0.05); overexpression of HIF-1α attenuates the inhibitory effect of down-regulated lncRNA HIF1A-AS1 expression on drug resistance in SO-RB50/VCR cells.CONCLUSION: The lncRNA HIF1A-AS1 was highly expressed in SO-RB50/VCR cells, and inhibition of lncRNA HIF1A-AS1 expression reduced VCR resistance in SO-RB50/VCR cells by down-regulating HIF-1α expression.
Preeclampsia affects 5%–8% of pregnancies and is the leading worldwide cause of maternal and fetal morbidity and mortality. Preeclampsia is associated with shallow trophoblast invasion and inadequate ...spiral artery remodeling, which are widely believed to lead to placental hypoxia, the putative culprit initiating the cascade of events that ultimately results in the maternal manifestations of the disease. Despite extensive research, however, the pathophysiology of this disease remains poorly understood, no effective prevention exists, and treatment is limited to symptomatic therapy. Recent research has introduced exciting new theories regarding the pathogenesis of preeclampsia. Clinical and experimental evidence implicating the circulating antiangiogenic molecules soluble Fms-like tyrosine kinase-1 (sFLT-1) and soluble endoglin (sENG), as well as endothelin-1 and the angiotensin II receptor type I autoimmune antibody (AT-1AA), have been especially promising. This review collates evidence for a role of hypoxia and hypoxia-inducible factor-1alpha (HIF1A; referred to as HIF-1α throughout) in the pathogenesis of preeclampsia and discusses possible molecular links between hypoxia and the newly reported potential mediators of the disease's manifestations.
Angiogenesis serves as an important protective mechanism against ischemic stroke, because angiogenesis promotes the generation of collateral circulation and consequently improves the blood supply to ...cerebral infraction areas. Long noncoding RNAs (lncRNAs), which can act as a competing endogenous RNA, mediate protein-coding gene expression by sponging miRNA. Based on previous studies, the present study hypothesized that lncRNAs HIF1A-AS2 by sponging to miR-153-3p might regulate expression of HIF-1α and its down-stream targets, thereby influencing angiogenesis in hypoxia. Permanent middle cerebral artery occlusion (pMCAO) model was established in SD rats to explore the association between angiogenesis and expression profiles of miR-153-3p and HIF-1α in infraction areas. The effect of HIF1A-AS2 on angiogenesis was investigated in an in vitro study by using human umbilical vein endothelial cells (HUVECs). Results showed that angiogenesis was induced during pMCAO. pMCAO decreased miR-153-3p RNA level in infraction areas, but increased protein levels of HIF-1α, VEGFA and Notch1. HIF1A-AS2 was up-regulated in HUVECs in hypoxia. Luciferase reporter assay indicated that HIF1A-AS2 serves as a ‘sponge’ to miR-153-3p, which decreased the post-transcriptional silencing of HIF-1α by miR-153-3p. This function of HIF1A-AS2 facilitated the activation of HIF-1α/VEGFA/Notch1 cascades, by which HUVECs viability, migration ability and tube formation were promoted. These results suggest an enhanced angiogenesis in HUVECs. In short, HIF1A-AS2 facilitates the up-regulation of HIF-1α by sponging to miR-153-3p, whereby promoting angiogenesis in HUVECs in hypoxia. The present study revealed an important mechanism for understanding angiogenesis in hypoxia, thus laid theoretical basis for developing new strategy for the treatment of ischemic stroke.
Mitochondria are at the basis of various cellular functions ranging from metabolism and redox homeostasis to inflammation and cell death regulation. Mitochondria therefore constitute an attractive ...target for invading pathogens to fulfil their infectious cycle. This involves the modulation to their advantage of mitochondrial metabolism and dynamics, including the controlled degradation of mitochondria through mitophagy. Mitophagy might for instance be beneficial for bacterial survival as it can clear bactericidal mitochondrial ROS produced by damaged organelle fragments from the intracellular niche. In the case of the bacterial pathogen Brucella abortus, mitophagy induction has another role in the intracellular lifecycle of the bacteria. Indeed, in our study, we showed that B. abortus triggers an iron-dependent BNIP3L-mediated mitophagy response required for proper bacterial egress and infection of neighboring cells. These results highlight the diversity of mitophagy processes that might be crucial for several stages of cellular infection.
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