Novel insights into sevoflurane-induced developmental neurotoxicity mechanisms.

Aim: This study explores Sevoflurane (Sevo)-induced neurotoxicity mechanisms in neonates through transcriptome sequencing and models.Methods: Seven-day-old mice were exposed to 3% Sevo, and hippocampal tissue was collected for analysis of differentially expressed lncRNAs and mRNAs compared with normal mice. MiR-152-3p was selected, and the interaction between H19, USP30, and miR-152-3p was explored in BV2 microglial cells and mouse hippocampal neurons.Results: Sevo disrupts mitochondrial autophagy via USP30 upregulation, exacerbating neurotoxicity and activating NLRP1 inflammasome-mediated inflammation.Conclusion: Sevo neurotoxicity is mediated through the H19/miR-152-3p/USP30 axis, implicating microglial regulation of neuronal pyroptosis.

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lncRNA H19 plays a role in multiple myeloma via interacting with hnRNPA2B1 to stabilize BET proteins by targeting osteoclasts and osteoblasts.

BACKGROUND: Multiple myeloma (MM), characterized with bone marrow microenvironment disorder, accounts for about 20% of hematological cancer deaths globally. Tissue extracellular communication, especially extracellular vesicles, has been defined as important mediator among cell-to-cell cross-talk. Our previous study revealed an elevated level of H19 in MM, whereas, its role in MM exosomes in the development of osteolysis remains largely unknown. METHOD: MM exosomes referring to 5TGM1 cells were isolated and characterized using transmission electron microscopy (TEM), nanoparticle tracking and western blot analysis. The biological effects of blocking H19 were examined on osteolysis in vivo of C57Bl6/KalwRij mice, as well as on the osteoclast differentiation in vitro of RAW264.7 cells, by the application of TRAP, either with osteogenic differentiation in vitro of bone marrow mesenchymal stem cells (BMSCs), by the detection of alkaline phosphatase (ALP), alizarin red dye staining (ARS). The targeted relationships among H19/hnRNPA2B1/BET proteins were validated through RNA immunoprecipitation (RIP) and RNA pull-down assays. RESULTS: 5TGM1 cells derived-exosomes lacking H19 dramatically blocked osteolysis and boosted osteogeneis in C57Bl6/KalwRij mice, either with osteoclastic differentiation of RAW264.7 cells and osteogenic differentiation of BMSCs, thereby enhancing their resorptive activity. Physically, H19 interacted with hnRNPA2B1 by preferentially adhering to it and enhancing its nuclear-cytoplasmic translocation. Further mechanistic research validated that H19 promoted the stabilization of BET proteins through hnRNA2B1 to be involved in osteoclast differentiation for contributing to MM progression. CONCLUSION: Altogether, our findings suggest that H19, serving as an essential role for exosomes in the bone marrow environment, might be a viable diagnostic and therapeutic target for MM therapy.

Influence of H19 polymorphisms on breast cancer: risk assessment and prognostic implications via LincRNA H19/miR-675 and downstream pathways.

Introduction: Breast cancer, as the most prevalent malignancy among women globally, continues to exhibit rising incidence rates, particularly in China. The disease predominantly affects women aged 40 to 60 and is influenced by both genetic and environmental factors. This study focuses on the role of H19 gene polymorphisms, investigating their impact on breast cancer susceptibility, clinical outcomes, and response to treatment. Methods: We engaged 581 breast cancer patients and 558 healthy controls, using TaqMan assays and DNA sequencing to determine genotypes at specific loci (rs11042167, rs2071095, rs2251375). We employed in situ hybridization and immunohistochemistry to measure the expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in formalin-fixed, paraffin-embedded samples. Statistical analyses included chi-squared tests, logistic regression, and Kaplan-Meier survival curves to evaluate associations between genetic variations, gene expression, and clinical outcomes. Results: Genotypes AG at rs11042167, GT at rs2071095, and AC at rs2251375 were significantly associated with increased risk of breast cancer. Notably, the AA genotype at rs11042167 and TT genotype at rs2071095 were linked to favorable prognosis. High expression levels of LincRNA H19, miR-675, MRP3, HOXA1, and MMP16 in cancer tissues correlated with advanced disease stages and poorer survival rates. Spearman correlation analysis revealed significant positive correlations between the expression of LincRNA H19 and miR-675 and specific genotypes, highlighting their potential regulatory roles in tumor progression. Discussion: The study underscores the critical roles of LincRNA H19 and miR-675 as prognostic biomarkers in breast cancer, with their overexpression associated with disease progression and adverse outcomes. The H19/LincRNA H19/miR-675/MRP3-HOXA1-MMP16 axis offers promising targets for new therapeutic strategies, reflecting the complex interplay between genetic markers and breast cancer pathology. Conclusion: The findings confirm that certain H19 SNPs are associated with heightened breast cancer risk and that the expression profiles of related genetic markers can significantly influence prognosis and treatment response. These biomarkers hold potential as targets for personalized therapy and early detection strategies in breast cancer, underscoring the importance of genetic research in understanding and managing this disease.

ART altered DNA methylation of the imprinted gene H19 in fetal tissue after multifetal pregnancy reduction.

PURPOSE: This study aimed to assess whether assisted reproductive technology alters DNA methylation levels at the H19 promoter and H19 imprinting control element (ICE) in fetal tissues obtained after multifetal pregnancy reduction. METHODS: Fetal tissues from multiple pregnancies were obtained, including fresh and frozen-thawed embryos: nine from conventional in vitro fertilization (c-IVF), four from intracytoplasmic sperm injection (ICSI), ten from cryopreserved IVF embryos (cryo-IVF), and six from cryopreserved ICSI (cryo-ICSI) embryos. Next-generation sequencing-based bisulfite PCR was used to determine the DNA methylation status of three CpG islands (H19-1, H19-2, and H19-3) in the H19 promoter and H19 ICE. The primary outcome was H19-1 DNA methylation status, whereas secondary outcomes assessed H19-2, H19-3, and ICE methylation. RESULTS: The ICSI (ß = -3.189, 95% CI = -5.034 to -1.345, p = 0.0026), cryo-IVF (ß = -2.150, 95% CI = -3.706 to -0.593, p = 0.0129), and cryo-ICSI (ß = -2.238, 95% CI = -3.817 to -0.659, p = 0.0110) groups exhibited significantly lower methylation levels in the primary outcome H19-1 region than the c-IVF group after adjustment. For the secondary outcome H19-2 region, significant decreases were observed in the cryo-IVF (ß = -2.132, 95% CI = -4.071 to -0.192, p = 0.0425) and cryo-ICSI groups (ß = -2.598, 95% CI = -4.566 to -0.630, p = 0.0168). CONCLUSIONS: These findings further indicate that embryo cryopreservation and potentially ICSI can lower the methylation level of the H19 promoter, advocating for careful use of these techniques when necessary.

lncRNA H19 facilitates vascular neointima formation by targeting miR-125a-3p/FLT1 axis.

The aberrant proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of neointima formation in vascular restenosis. This study aims to explore the function of the long noncoding RNA H19 in neointima formation. A mouse carotid ligation model was established, and human vascular smooth muscle cells (VSMCs) were used as a cell model. lncRNA H19 overexpression promoted VSMC proliferation and migration. Moreover, miR-125a-3p potentially bound to lncRNA H19, and Fms-like tyrosine kinase-1 (FLT1) might be a direct target of miR-125a-3p in VSMCs. Upregulation of miR-125a-3p alleviated lncRNA H19-enhanced VSMC proliferation and migration. Furthermore, rescue experiments showed that enhanced expression of miR-125a-3p attenuated lncRNA H19-induced FLT1 expression in VSMCs. In addition, the overexpression of lncRNA H19 significantly exacerbated neointima formation in a mouse carotid ligation model. In summary, lncRNA H19 stimulates VSMC proliferation and migration by acting as a competing endogenous RNA (ceRNA) of miR-125a-3p. lncRNA H19 may be a therapeutic target for restenosis.

The Role of Long Non-Coding RNAs in Ovarian Cancer Cells.

Among the most deadly malignancies that strike women worldwide, ovarian cancer is still one of the most common. The primary factor affecting a patient's survival is early lesion discovery. Unfortunately, because ovarian cancer is a sneaky illness that usually manifests as nonspecific symptoms only in advanced stages, its early detection and screening are challenging. A lot of research is being conducted on effective methods of diagnosing and treating ovarian cancer. Recently, non-coding RNAs (ncRNAs) have gained great popularity, which are considered to be the main regulators of many cellular processes, especially those occurring in cancer. LncRNAs are also being studied for their therapeutic use in the treatment of ovarian cancer and their use in diagnostics and as indicators of poor prognosis. In this article, we reviewed lncRNAs described in the literature that may play an important role in ovarian cancer.

Inflammatory markers and noncoding-RNAs responses to low and high compressions of HIIT with or without berberine supplementation in middle-aged men with prediabetes.

This study compared the capacity of two different models of HIIT [high-(HC) and low-(LC) compression], with or without the use of berberine (BBR), on NOD-like receptor pyrin domain-containing protein-3 (NLRP3), H19, interleukin (IL)-1ß, high-sensitivity C-reactive protein (hs-CRP), and insulin resistance markers. Fifty-four middle-aged men with overweight or obesity and prediabetes [fasting blood glucose (FBG) 110-180 mg/dL] were randomly and equally assigned to the HC, LC, HC + BBR, LC + BBR, BBR, and non-exercising control (CON) groups. The HC (2:1 work-to-rest) and LC (1:1 work-to-rest) home-based training programs included 2-4 sets of 8 exercises at 80%-95% HRmax, twice a week for 8 weeks. Participants in the berberine groups received approximately 1000 mg daily. All exercise interventions led to a significant reduction in hs-CRP, IL-1ß, insulin, FBG, and insulin resistance index (HOMA-IR) versus CON. Notably, there was a significant reduction in FBG and HOMA-IR with the BBR group compared to the baseline. Both NLRP3 and H19 experienced a significant drop only with LC in comparison to the baseline. While both exercise protocols were beneficial overall, LC uniquely exhibited more anti-inflammatory effects, as indicated by reductions in H19 and NLRP3. However, the addition of berberine to the exercise programs did not demonstrate additional benefits.

Long noncoding RNA H19 knockdown promotes angiogenesis via IMP2 after ischemic stroke.

AIMS: This study aimed to explore the effects of long noncoding RNA (lncRNA) H19 knockdown on angiogenesis and blood-brain barrier (BBB) integrity following cerebral ischemia/reperfusion (I/R) and elucidate their underlying regulatory mechanisms. METHODS: A middle cerebral artery occlusion/reperfusion model was used to induce cerebral I/R injury. The cerebral infarct volume and neurological impairment were assessed using 2,3,5-triphenyl-tetrazolium chloride staining and neurobehavioral tests, respectively. Relevant proteins were evaluated using western blotting and immunofluorescence staining. Additionally, a bioinformatics website was used to predict the potential target genes of lncRNA H19. Finally, a rescue experiment was conducted to confirm the potential mechanism. RESULTS: Silencing of H19 significantly decreased the cerebral infarct volume, enhanced the recovery of neurological function, mitigated BBB damage, and stimulated endothelial cell proliferation following ischemic stroke. Insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) is predicted to be a potential target gene for lncRNA H19. H19 knockdown increased IMP2 protein expression and IMP2 inhibition reversed the protective effects of H19 inhibition. CONCLUSION: Downregulation of H19 enhances angiogenesis and mitigates BBB damage by regulating IMP2, thereby alleviating cerebral I/R injury.

Long Non-Coding H19 in Lymphocytes: Prognostic Value in Acute Ischemic Stroke Patients.

Acute ischemic stroke (AIS) is a cerebrovascular disease that seriously affects the physical and mental health and quality of life of patients. However, there is a lack of reliable prognostic prediction methods. The main objective of this study was to investigate the prognostic value of long non-coding RNA (lncRNA) H19 in lymphocytes of patients with AIS, and to construct a prognostic prediction model for AIS including lncRNA H19 in lymphocytes, which would provide new ideas for the prognostic evaluation of AIS. Poor prognosis was defined when the patient's modified Rankin scale (mRS) score at 3 months after AIS onset was greater than 2. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the level of lncRNA H19 in lymphocytes. Spearman correlation analysis revealed a positive correlation between lncRNA H19 and mRS score at 3 months after AIS onset (r = 0.1977, p = 0.0032), while lncRNA H19 was negatively correlated with white blood cells counts, lymphocytes counts, and neutrophils counts. Logistic regression analysis identified lncRNA H19 as an independent predictor of poor prognosis (OR = 3.062 [1.69-5.548], p < 0.001). Moreover, a nomogram prediction model incorporating lncRNA H19 in lymphocytes demonstrated effective discrimination, calibration, and clinical applicability in predicting AIS outcomes. The findings suggest that lncRNA H19 in lymphocytes could be a valuable prognostic indicator and a potential pharmacological target for AIS patients, and might be a novel pathway for enhanced prognostic evaluation and targeted therapeutic strategies.

LncRNA H19 accelerates renal fibrosis by negatively regulating the let-7b-5p/TGF-ßR1/COL1A1 axis.

BACKGROUND: Transforming growth factor-beta1 (TGF-ß1)-mediated renal fibrosis is a critical pathological process of chronic kidney disease worsening to end-stage renal disease. Recent studies have shown that long noncoding RNA H19 (lncRNA H19) is widely involved in the formation and progression of fibrosis in multiple organs. However, its molecular events in renal fibrosis remain to be elucidated. METHODS: Rats were treated with adenine intragastrically and HK-2 cells were induced by TGF-ß1 to construct renal fibrosis models in vivo and in vitro, respectively. Renal histopathological examination was performed using HE and Masson staining. Gene expression levels of interleukin-1beta (IL-1ß), tumor necrosis factor-alpha (TNF-α), TGF-ß1, fibronectin (Fn), alpha-smooth muscle actin (α-SMA), H19, let-7b-5p, TGF-ß receptor 1 (TGF-ßR1), and type I collagen (COL1A1) were detected by qRT-PCR. Immunohistochemistry, immunofluorescence, and western blot analysis were used to evaluate the expression of renal fibrosis biomarkers. Dual-luciferase reporter assay was used to verify the presence of binding sites between H19 and let-7b-5p, and between let-7b-5p and TGF-ßR1 and COL1A1. RESULTS: H19 was overexpressed in both in vivo and in vitro renal fibrosis models. H19 knockdown significantly reversed TGF-ß1-induced upregulation of fibronectin, COL1A1, and α-SMA and downregulation of E-cadherin in HK-2 cells, accompanied by an increase in let-7b-5p. Let-7b-5p was bound to H19 in HK-2 cells, and its overexpression inhibited TGF-ß1-induced HK-2 cell fibrosis. Further experiments determined that let-7b-5p directly targets TGF-ßR1 and COL1A1 in HK-2 cells. In addition, inhibition of let-7b-5p reversed the reduction in HK-2 cell fibrosis induced by H19 knockdown. Finally, knockdown of H19 alleviated renal fibrosis in vivo and was associated with regulation of the let-7b-5p/TGF-ßR1/COL1A1 axis. CONCLUSION: Our results indicate that knockdown of H19 inhibits renal tubular epithelial fibrosis by negatively regulating the let-7b-5p/TGF-ßR1/COL1A1 axis, which may provide new mechanistic insights into CRF progression.

Extracellular vesicle transfer of lncRNA H19 splice variants to cardiac cells.

The delivery of therapeutic long non-coding RNAs (lncRNA) to the heart by extracellular vesicles (EVs) is promising for heart repair. H19, a lncRNA acting as a major regulator of gene expression within the cardiovascular system, is alternatively spliced, but the loading of its different splice variants into EVs and their subsequent uptake by recipient cardiac cells remain elusive. Here, we dissected the cellular expression of H19 splice variants and their loading into EVs secreted by Wharton-Jelly mesenchymal stromal/stem cells (WJ-MSCs). We demonstrated that overexpression of the mouse H19 gene in WJ-MSCs induces the expression of H19 splice variants at different levels. Interestingly, EVs isolated from the H19-transfected WJ-MSCs (EV-H19) showed similar expression levels for all tested splice variant sets. In vitro, we further demonstrated that EV-H19 was taken up by cardiomyocytes, fibroblasts, and endothelial cells (ECs). Finally, analysis of EV tropism in living rat myocardial slices indicated that EVs were internalized mostly by cardiomyocytes and ECs. Collectively, our results indicated that EVs can be loaded with different lncRNA splice variants and successfully internalized by cardiac cells.

LncRNAH19 acts as a ceRNA of let-7 g to facilitate endothelial-to-mesenchymal transition in hypoxic pulmonary hypertension via regulating TGF-ß signalling pathway.

BACKGROUND: Hypoxic pulmonary hypertension (HPH) is a challenging lung arterial disorder with remarkably high incidence and mortality rates, and the efficiency of current HPH treatment strategies is unsatisfactory. Endothelial-to-mesenchymal transition (EndMT) in the pulmonary artery plays a crucial role in HPH. Previous studies have shown that lncRNA-H19 (H19) is involved in many cardiovascular diseases by regulating cell proliferation and differentiation but the role of H19 in EndMT in HPH has not been defined. METHODS: In this research, the expression of H19 was investigated in PAH human patients and rat models. Then, we established a hypoxia-induced HPH rat model to evaluate H19 function in HPH by Echocardiography and hemodynamic measurements. Moreover, luciferase reporter gene detection, and western blotting were used to explore the mechanism of H19. RESULTS: Here, we first found that the expression of H19 was significantly increased in the endodermis of pulmonary arteries and that H19 deficiency obviously ameliorated pulmonary vascular remodelling and right heart failure in HPH rats, and these effects were associated with inhibition of EndMT. Moreover, an analysis of luciferase activity indicated that microRNA-let-7 g (let-7 g) was a direct target of H19. H19 deficiency or let-7 g overexpression can markedly downregulate the expression of TGFßR1, a novel target gene of let-7 g. Furthermore, inhibition of TGFßR1 induced similar effects to H19 deficiency. CONCLUSIONS: In summary, our findings demonstrate that the H19/let-7 g/TGFßR1 axis is crucial in the pathogenesis of HPH by stimulating EndMT. Our study may provide new ideas for further research on HPH therapy in the near future.

Emerging roles of long noncoding RNA H19 in human lung cancer.

Lung cancer holds the position of being the primary cause of cancer-related fatalities on a global scale. Furthermore, it exhibits the highest mortality rate among all types of cancer. The survival rate within a span of 5 years is less than 20%, primarily due to the fact that the disease is often diagnosed at an advanced stage, resulting in less effective treatment options compared to earlier stages. There are two main types of primary lung cancer: nonsmall-cell lung cancer, which accounts for approximately 80%-85% of all cases, and small-cell lung cancer, which is categorized based on the specific type of cells in which the cancer originates. The understanding of the biology of this disease and the identification of oncogenic driver alterations have significantly transformed the landscape of therapeutic approaches. Long noncoding RNAs (lncRNAs) play a crucial role in regulating various physiological and pathological processes through diverse molecular mechanisms. Among these lncRNAs, lncRNA H19, initially identified as an oncofetal transcript, has garnered significant attention due to its elevated expression in numerous tumors. Extensive research has confirmed its involvement in tumorigenesis and malignant progression by promoting cell growth, invasion, migration, epithelial-mesenchymal transition, metastasis, and therapy resistance. This comprehensive review aims to provide an overview of the aberrant overexpression of lncRNA H19 and the molecular pathways through which it contributes to the advancement of lung cancer. The findings of this review highlight the potential for further investigation into the diagnosis and treatment of this disease, offering promising avenues for future research.

H19 lncRNA triggers ferroptosis, exacerbating ox-LDL-induced artery endothelial cell damage in vitro.

BACKGROUND: The precise association between lncRNA H19 and ferroptosis in the context of atherosclerosis remains uncertain. OBJECTIVE: This study is to clarify the underlying process and propose novel approaches for the advancement of therapeutic interventions targeting atherosclerosis. METHODS: Assessment of ferroptosis, which entails the evaluation of cell viability using CCK-8 and the quantification of intracellular MDA, GSH, and ferrous ions. Simultaneously, the protein expression levels of assessed by western blot analysis, while the expression level of lncRNA H19 was also determined. Furthermore, HAECs that were cultured with ox-LDL were subjected to Fer-1 interference. HAECs were exposed to ox-LDL and then transfected with H19 shRNA and H19 overexpression vector pcDNA3.1. The level of ferroptosis in the cells was then measured. Then, HAECs were subjected to incubation with ox-LDL, followed by transfection with H19 shRNA and treated with Erastin to assess the levels of ferroptosis, cell viability, and inflammatory factor production. and the ability for blood vessel development. RESULTS: The survival rate of HAECs in the ox-LDL group was much lower. Ox-LDL resulted in an upregulation of ACSL4 expression in HAECs, while the expression of SLC7A11 and GPX4 decreased. CONCLUSIONS: lncRNA H19 enhances ferroptosis and exacerbates arterial endothelial cell damage induced by LDL.

Up-regulation of long non-coding RNA H19 ameliorates renal tubulointerstitial fibrosis by reducing lipid deposition and inflammatory response through regulation of the microRNA-130a-3p/long-chain acyl-CoA synthetase 1 axis.

Long non-coding RNA (lncRNA) H19 is an extensively studied lncRNA that is related to numerous pathological changes. Our previous findings have documented that serum lncRNA H19 levels are decreased in patients with chronic kidney disorder and lncRNA H19 reduction is closely correlated with renal tubulointerstitial fibrosis, an essential step in developing end-stage kidney disease. Nonetheless, the precise function and mechanism of lncRNA H19 in renal tubulointerstitial fibrosis are not fully comprehended. The present work utilized a mouse model of unilateral ureteral obstruction (UUO) and transforming growth factor-ß1 (TGF-ß1)-stimulated HK-2 cells to investigate the possible role and mechanism of lncRNA H19 in renal tubulointerstitial fibrosis were investigated. Levels of lncRNA H19 decreased in kidneys of mice with UUO and HK-2 cells stimulated with TGF-ß1. Up-regulation of lncRNA H19 in mouse kidneys remarkably relieved kidney injury, fibrosis and inflammation triggered by UUO. Moreover, the increase of lncRNA H19 in HK-2 cells reduced epithelial-to-mesenchymal transition (EMT) induced by TGF-ß1. Notably, up-regulation of lncRNA H19 reduced lipid accumulation and triacylglycerol content in kidneys of mice with UUO and TGF-ß1-stimulated HK-2 cells, accompanied by the up-regulation of long-chain acyl-CoA synthetase 1 (ACSL1). lncRNA H19 was identified as a sponge of microRNA-130a-3p, through which lncRNA H19 modulates the expression of ACSL1. The overexpression of microRNA-130a-3p reversed the lncRNA H19-induced increases in the expression of ACSL1. The suppressive effects of lncRNA H19 overexpression on the EMT, inflammation and lipid accumulation in HK-2 cells were diminished by ACSL1 silencing or microRNA-130a-3p overexpression. Overall, the findings showed that lncRNA H19 ameliorated renal tubulointerstitial fibrosis by reducing lipid deposition via modulation of the microRNA-130a-3p/ACSL1 axis.

LncRNA H19 knockdown promotes neuropathologic and functional recovery via the Nrf2/HO-1 axis after traumatic brain injury.

AIMS: Traumatic brain injury (TBI) stands as a significant concern in public health, frequently leading to enduring neurological deficits. Long non-coding RNA H19 (lncRNA H19) exerts a potential regulator role in the pathology of brain injury. This study investigates the effects of lncRNA H19 knockdown (H19-KD) on the pathophysiology of TBI and its potential neuroprotective mechanisms. METHODS: Controlled cortical impact was employed to establish a stable TBI mouse model. The expression levels of various genes in perilesional cortex and striatum tissue after TBI was detected by RT-qPCR. AAV9-shRNA-H19 was injected into the lateral ventricle of mice to knockdown the expression of lncRNA H19. Various behavioral tests were performed to evaluate sensorimotor and cognitive functions after TBI. Immunofluorescence and Nissl staining were performed to assess brain tissue damage and neuroinflammation. The Nrf2 and HO-1 expression was performed by Western blot. RESULTS: After TBI, the expression of lncRNA H19 was elevated in perilesional tissue and gradually reverted to baseline. Behavioral tests demonstrated that H19-KD significantly promoted the recovery of sensorimotor and cognitive functions after TBI. Besides, H19-KD reduced brain tissue loss, preserved neuronal integrity, and ameliorated white matter damage at the histological level. In addition, H19-KD restrained the pro-inflammatory and facilitated anti-inflammatory phenotypes of microglia/macrophages, attenuating the neuroinflammatory response after TBI. Furthermore, H19-KD promoted activation of the Nrf2/HO-1 axis after TBI, while suppression of Nrf2 partially abolished the neuroprotective effect. CONCLUSION: H19-KD exerts neuroprotective effects after TBI in mice, partially mediated by the activation of the Nrf2/HO-1 axis.

In vitro and in vivo evaluation of biohybrid tissue-engineered vascular grafts with transformative 1H/19F MRI traceable scaffolds.

Biohybrid tissue-engineered vascular grafts (TEVGs) promise long-term durability due to their ability to adapt to hosts' needs. However, the latter calls for sensitive non-invasive imaging approaches to longitudinally monitor their functionality, integrity, and positioning. Here, we present an imaging approach comprising the labeling of non-degradable and degradable TEVGs' components for their in vitro and in vivo monitoring by hybrid 1H/19F MRI. TEVGs (inner diameter 1.5 mm) consisted of biodegradable poly(lactic-co-glycolic acid) (PLGA) fibers passively incorporating superparamagnetic iron oxide nanoparticles (SPIONs), non-degradable polyvinylidene fluoride scaffolds labeled with highly fluorinated thermoplastic polyurethane (19F-TPU) fibers, a smooth muscle cells containing fibrin blend, and endothelial cells. 1H/19F MRI of TEVGs in bioreactors, and after subcutaneous and infrarenal implantation in rats, revealed that PLGA degradation could be faithfully monitored by the decreasing SPIONs signal. The 19F signal of 19F-TPU remained constant over weeks. PLGA degradation was compensated by cells' collagen and α-smooth-muscle-actin deposition. Interestingly, only TEVGs implanted on the abdominal aorta contained elastin. XTT and histology proved that our imaging markers did not influence extracellular matrix deposition and host immune reaction. This concept of non-invasive longitudinal assessment of cardiovascular implants using 1H/19F MRI might be applicable to various biohybrid tissue-engineered implants, facilitating their clinical translation.

H19 influenza A virus exhibits species-specific MHC class II receptor usage.

Avian influenza A virus (IAV) surveillance in Northern California, USA, revealed unique IAV hemagglutinin (HA) genome sequences in cloacal swabs from lesser scaups. We found two closely related HA sequences in the same duck species in 2010 and 2013. Phylogenetic analyses suggest that both sequences belong to the recently discovered H19 subtype, which thus far has remained uncharacterized. We demonstrate that H19 does not bind the canonical IAV receptor sialic acid (Sia). Instead, H19 binds to the major histocompatibility complex class II (MHC class II), which facilitates viral entry. Unlike the broad MHC class II specificity of H17 and H18 from bat IAV, H19 exhibits a species-specific MHC class II usage that suggests a limited host range and zoonotic potential. Using cell lines overexpressing MHC class II, we rescued recombinant H19 IAV. We solved the H19 crystal structure and identified residues within the putative Sia receptor binding site (RBS) that impede Sia-dependent entry.

LncRNA H19/miR-107 regulates endothelial progenitor cell pyroptosis and promotes flow recovery of lower extremity ischemia through targeting FADD.

BACKGROUND: Peripheral artery disease (PAD) is an ischemic disease with a rising incidence worldwide. The lncRNA H19 (H19) is enriched in endothelial progenitor cells (EPCs), and transplantation of pyroptosis-resistant H19-overexpressed EPCs (oe-H19-EPCs) may promote vasculogenesis and blood flow recovery in PAD, especially with critical limb ischemia (CLI). METHODS: EPCs isolated from human peripheral blood was characterized using immunofluorescence and flow cytometry. Cell proliferation was determined with CCK8 and EdU assays. Cell migration was assessed by Transwell and wound healing assays. The angiogenic potential was evaluated using tube formation assay. The pyroptosis pathway-related protein in EPCs was detected by western blot. The binding sites of H19 and FADD on miR-107 were analyzed using Luciferase assays. In vivo, oe-H19-EPCs were transplanted into a mouse ischemic limb model, and blood flow was detected by laser Doppler imaging. The transcriptional landscape behind the therapeutic effects of oe-H19-EPCs on ischemic limbs were examined with whole transcriptome sequencing. RESULTS: Overexpression of H19 in EPCs led to an increase in proliferation, migration, and tube formation abilities. These effects were mediated through pyroptosis pathway, which is regulated by the H19/miR-107/FADD axis. Transplantation of oe-H19-EPCs in a mouse ischemic limb model promoted vasculogenesis and blood flow recovery. Whole transcriptome sequencing indicated significant activation of vasculogenesis pathway in the ischemic limbs following treatment with oe-H19-EPCs. CONCLUSIONS: Overexpression of H19 increases FADD level by competitively binding to miR-107, leading to enhanced proliferation, migration, vasculogenesis, and inhibition of pyroptosis in EPCs. These effects ultimately promote the recovery of blood flow in CLI.

Maternal perceived stress and green spaces during pregnancy are associated with adult offspring gene (NR3C1 and IGF2/H19) methylation patterns in adulthood: A pilot study.

BACKGROUND: Changes in NR3C1 and IGF2/H19 methylation patterns have been associated with behavioural and psychiatric outcomes. Maternal mental state has been associated with offspring NR3C1 promotor and IGF2/H19 imprinting control region (ICR) methylation patterns. However, there is a lack of prospective studies with long-term follow-up. METHODS: 52 mother-offspring pairs were studied from 12 to 22 weeks of pregnancy and offspring was followed-up until 28-29 years-of-age. During pregnancy, mothers filled in a Life Event Scale and a Daily Hassles Scale measuring perceived stress; i.e., appraisal or subjectively experienced severity of impact of important life events and of daily hassles in several life domains during pregnancy, respectively. Green space was quantified around the residence, using high-resolution (1 m2) map data. Saliva and blood samples were obtained from the adult offspring. Absolute DNA methylation levels were determined in blood and saliva on four NR3C1 amplicons, and one IGF2/H19 ICR amplicon using a bisulfite PCR and sequencing method. Linear mixed effect models were used to test the associations between perceived stress and green spaces during pregnancy, and adult offspring methylation patterns. RESULTS: We found associations between maternal perceived stress during pregnancy and methylation patterns on two out of the four NR3C1 amplicons, measured in blood, from offspring in adulthood, but not with IGF2/H19 methylation. For an interquartile-range (IQR) increase in maternal perceived life event or daily hassles stress scores, absolute methylation levels on several NR3C1 CpG sites were significantly changed (-1.62 % to +5.89 %, p<0.05). Maternal perceived stress scores were not associated with IGF2/H19 methylation, neither in blood nor in saliva. Maternal exposure to green spaces surrounding the residence during the pregnancy was associated with IGF2/H19 ICR methylation (-0.80 % to -1.04 %, p<0.05) in saliva, but not with NR3C1 promotor methylation. CONCLUSION: We observed significant long-term effects of maternal perceived stress during pregnancy on the methylation patterns of the NR3C1 promotor in offspring well into adulthood. This may imply that maternal psychological distress during pregnancy may influence the regulation of the HPA-axis well into adulthood. Additionally, maternal proximity to green spaces was associated with IGF2/H19 ICR methylation patterns, which is a novel finding.