ABSTRACT
Moyamoya disease (MMD) is a chronic, progressive cerebrovascular occlusive disease. Ring finger protein 213 (RNF213) is a susceptibility gene of MMD. Previous studies have shown that the expression levels of angiogenic factors increase in MMD patients, but the relationship between the susceptibility gene RNF213 and these angiogenic mediators is still unclear. The aim of the present study was to investigate the pathogenesis of MMD by examining the effect of RNF213 gene knockdown on the expression of matrix metalloproteinase-9 (MMP-9) and basic fibroblast growth factor (bFGF) in rat bone marrow-derived mesenchymal stem cells (rBMSCs). Firstly, 40 patients with MMD and 40 age-matched normal individuals (as the control group) were enrolled in the present study to detect the levels of MMP-9 and bFGF in serum by ELISA. Secondly, Sprague-Dawley male rat BMSCs were isolated and cultured using the whole bone marrow adhesion method, and subsequent phenotypic analysis was performed by flow cytometry. Alizarin red and oil red O staining methods were used to identify osteogenic and adipogenic differentiation, respectively. Finally, third generation rBMSCs were transfected with lentivirus recombinant plasmid to knockout expression of the RNF213 gene. After successful transfection was confirmed by reverse transcription-quantitative PCR and fluorescence imaging, the expression levels of bFGF and MMP-9 mRNA in rBMSCs and the levels of bFGF and MMP-9 protein in the supernatant of the culture medium were detected on the 7th and 14th days after transfection. There was no significant difference in the relative expression level of bFGF among the three groups on the 7th day. For the relative expression level of MMP-9, there were significant differences on the 7th day and 14th day. In addition, there was no statistically significant difference in the expression of bFGF in the supernatant of the RNF213 shRNA group culture medium, while there was a significant difference in the expression level of MMP-9. The knockdown of the RNF213 gene affects the expression of bFGF and MMP-9. However, further studies are needed to determine how they participate in the pathogenesis of MMD. The findings of the present study provide a theoretical basis for clarifying the pathogenesis and clinical treatment of MMD.
Subject(s)
Adenosine Triphosphatases , Fibroblast Growth Factor 2 , Matrix Metalloproteinase 9 , Mesenchymal Stem Cells , Moyamoya Disease , Rats, Sprague-Dawley , Ubiquitin-Protein Ligases , Adult , Animals , Female , Humans , Male , Middle Aged , Rats , Adenosine Triphosphatases/genetics , Adenosine Triphosphatases/metabolism , Bone Marrow Cells , Cells, Cultured , Fibroblast Growth Factor 2/genetics , Fibroblast Growth Factor 2/metabolism , Gene Knockdown Techniques , Genetic Predisposition to Disease , Matrix Metalloproteinase 9/metabolism , Matrix Metalloproteinase 9/genetics , Mesenchymal Stem Cells/metabolism , Moyamoya Disease/genetics , Moyamoya Disease/metabolism , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolism , Up-RegulationABSTRACT
Cancer-associated fibroblast (CAF) is an essential risk factor for ovarian cancer. Exosomes can mediate cellular communication in the tumour microenvironment, but the interaction of tumour cell exosomes with CAF is less studied in Ovarian cancer. This study identified H19/miR-29c-3p/LOXL2-COL1A1 as a ceRNA regulatory network involved in regulating tumour matrix-associated signaling pathways associated with CAF. Cellular assays demonstrated that exosomes from ovarian cancer cell line SKOV3 significantly promoted the proliferation and migration of CAF. The results of mixed transplantation tumour experiments in nude mice showed that exosomes of SKOV3 significantly promoted tumour growth. Ovarian cancer tumour-derived exosomes can regulate CAF proliferation and migration through H19/miR-29c-3p/LOXL2-COL1A1. This study reveals the regulatory role of tumour exosomes on CAF, which may provide a theoretical basis for the development of therapeutic regimens targeting fibroblasts in ovarian cancer.
ABSTRACT
Aiming at real-time detection of UAVs, small UAV targets are easily missed and difficult to detect in complex backgrounds. To maintain high detection performance while reducing memory and computational costs, this paper proposes the SEB-YOLOv8s detection method. Firstly, the YOLOv8 network structure is reconstructed using SPD-Conv to reduce the computational burden and accelerate the processing speed while retaining more shallow features of small targets. Secondly, we design the AttC2f module and replace the C2f module in the backbone of YOLOv8s with it, enhancing the model's ability to obtain accurate information and enriching the extracted relevant information. Finally, Bi-Level Routing Attention is introduced to optimize the Neck part of the network, reducing the model's attention to interfering information and filtering it out. The experimental results show that the mAP50 of the proposed method reaches 90.5% and the accuracy reaches 95.9%, which are improvements of 2.2% and 1.9%, respectively, compared with the original model. The mAP50-95 is improved by 2.7%, and the model's occupied memory size only increases by 2.5 MB, effectively achieving high-accuracy real-time detection with low memory consumption.
ABSTRACT
BACKGROUND & AIMS: The persistence of covalently closed circular DNA (cccDNA) in infected hepatocytes is the major barrier preventing viral eradication with existing therapies in patients with chronic hepatitis B. Therapeutic agents that can eliminate cccDNA are urgently needed to achieve viral eradication and thus HBV cure. METHODS: A phenotypic assay with HBV-infected primary human hepatocytes (PHHs) was employed to screen for novel cccDNA inhibitors. A HBVcircle mouse model and a uPA-SCID (urokinase-type plasminogen activator-severe combined immunodeficiency) humanized liver mouse model were used to evaluate the anti-HBV efficacy of the discovered cccDNA inhibitors. RESULTS: Potent and dose-dependent reductions in extracellular HBV DNA, HBsAg, and HBeAg levels were achieved upon the initiation of ccc_R08 treatment two days after the HBV infection of PHHs. More importantly, the level of cccDNA was specifically reduced by ccc_R08, while it did not obviously affect mitochondrial DNA. Additionally, ccc_R08 showed no significant cytotoxicity in PHHs or in multiple proliferating cell lines. The twice daily oral administration of ccc_R08 to HBVcircle model mice, which contained surrogate cccDNA molecules, significantly decreased the serum levels of HBV DNA and antigens, and these effects were sustained during the off-treatment follow-up period. Moreover, at the end of follow-up, the levels of surrogate cccDNA molecules in the livers of ccc_R08-treated HBVcircle mice were reduced to below the lower limit of quantification. CONCLUSIONS: We have discovered a small-molecule cccDNA inhibitor that reduces HBV cccDNA levels. cccDNA inhibitors potentially represent a new approach to completely cure patients chronically infected with HBV. IMPACT AND IMPLICATIONS: Covalently closed circular DNA (cccDNA) persistence in HBV-infected hepatocytes is the root cause of chronic hepatitis B. We discovered a novel small-molecule cccDNA inhibitor that can specifically reduce cccDNA levels in HBV-infected hepatocytes. This type of molecule could offer a new approach to completely cure patients chronically infected with HBV.
Subject(s)
Hepatitis B, Chronic , Humans , Animals , Mice , Hepatitis B, Chronic/drug therapy , Hepatitis B virus , DNA, Circular/therapeutic use , DNA, Viral/genetics , Virus Replication , Mice, SCID , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic useABSTRACT
MOTIVATION: An essential step in developing computational tools for the inference, optimization and simulation of biochemical reaction networks is gauging tool performance against earlier efforts using an appropriate set of benchmarks. General strategies for the assembly of benchmark models include collection from the literature, creation via subnetwork extraction and de novo generation. However, with respect to biochemical reaction networks, these approaches and their associated tools are either poorly suited to generate models that reflect the wide range of properties found in natural biochemical networks or to do so in numbers that enable rigorous statistical analysis. RESULTS: In this work, we present SBbadger, a python-based software tool for the generation of synthetic biochemical reaction or metabolic networks with user-defined degree distributions, multiple available kinetic formalisms and a host of other definable properties. SBbadger thus enables the creation of benchmark model sets that reflect properties of biological systems and generate the kinetics and model structures typically targeted by computational analysis and inference software. Here, we detail the computational and algorithmic workflow of SBbadger, demonstrate its performance under various settings, provide sample outputs and compare it to currently available biochemical reaction network generation software. AVAILABILITY AND IMPLEMENTATION: SBbadger is implemented in Python and is freely available at https://github.com/sys-bio/SBbadger and via PyPI at https://pypi.org/project/SBbadger/. Documentation can be found at https://SBbadger.readthedocs.io. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Metabolic Networks and Pathways , Software , Computer Simulation , Kinetics , WorkflowABSTRACT
Parkinson's disease (PD) is a kind of neurodegenerative disease that causes a huge burden to society. Previous studies have suggested the association between PD and multiple viruses. However, there is still a lack of a virome study about PD. This study systematically identified viruses from the public RNA-sequencing data of more than 700 samples from both PD patients and the control group (most were healthy people). Only nine viruses such as human betaherpesvirus 5 and Merkel cell polyomavirus have been detected in several human brain tissues of the central nervous system, the appendix, and blood of PD patients, and all of these viruses were also detected in the control group. Most viruses were observed to have low abundance in no more than three tissues. No statistically significant differences were observed between the virus abundance in the PD patients and the control group for all viruses. The positive rates of most viruses in PD patients were higher or similar to that in the control group, although those were less than 5% for most viruses. Overall, this is the first study to systematically investigate the virome in PD patients, and provides new insights into the association between viruses and PD.
Subject(s)
Merkel cell polyomavirus , Neurodegenerative Diseases , Parkinson Disease , Viruses , Humans , Virome , Viruses/geneticsABSTRACT
Endophytic bacteria residing within host plants can significantly impact on the host's growth, health, and overall relationship with its surrounding environment. However, the process that shape the community assembly of stem bacterial endophytes (SBEs) remains poorly understood. This study explored the community structure, co-occurrence patterns, and ecological processes of the SBEs inhabiting the shrub host, Mussaenda pubescens, across seven locations in southeastern China. We found that the absolute abundances, alpha diversity, and community composition of SBE communities exhibited notable differences among various host populations. Stem chemical characteristics were the most important factors influencing SBE community distribution, followed by geographic distance and climatic factors. The beta diversity decomposition analyses indicated that SBE community dissimilarities between sites were nearly equally driven by similarity, replacement diversity, and richness difference. The co-occurrence network analysis revealed that the keystone taxa were mostly observed in rare species, which may be essential for preserving the ecosystem's functions. Conditionally abundant taxa (CAT) showcased the highest closeness centrality, while exhibiting the lowest degree centrality and betweenness centrality as opposed to rare taxa. In addition, stochastic processes also played an important role in structuring SBE communities, with ecological drift being the dominant factor for both abundant and rare taxa. This study would deepen our understanding of the ecological dynamics and microbial interactions within plant endophytic microbiomes.
Subject(s)
Bacteria , Microbiota , Bacteria/genetics , Plants , ChinaABSTRACT
Rationale: The current understanding of human lung development derives mostly from animal studies. Although transcript-level studies have analyzed human donor tissue to identify genes expressed during normal human lung development, protein-level analysis that would enable the generation of new hypotheses on the processes involved in pulmonary development are lacking. Objectives: To define the temporal dynamic of protein expression during human lung development. Methods: We performed proteomics analysis of human lungs at 10 distinct times from birth to 8 years to identify the molecular networks mediating postnatal lung maturation. Measurements and Main Results: We identified 8,938 proteins providing a comprehensive view of the developing human lung proteome. The analysis of the data supports the existence of distinct molecular substages of alveolar development and predicted the age of independent human lung samples, and extensive remodeling of the lung proteome occurred during postnatal development. Evidence of post-transcriptional control was identified in early postnatal development. An extensive extracellular matrix remodeling was supported by changes in the proteome during alveologenesis. The concept of maturation of the immune system as an inherent part of normal lung development was substantiated by flow cytometry and transcriptomics. Conclusions: This study provides the first in-depth characterization of the human lung proteome during development, providing a unique proteomic resource freely accessible at Lungmap.net. The data support the extensive remodeling of the lung proteome during development, the existence of molecular substages of alveologenesis, and evidence of post-transcriptional control in early postnatal development.
Subject(s)
Gene Expression Regulation, Developmental/physiology , Lung/growth & development , Lung/metabolism , Proteins/genetics , Proteins/metabolism , Pulmonary Alveoli/growth & development , Pulmonary Alveoli/metabolism , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , ProteomicsABSTRACT
In order to monitor the diagnosis of mechanical equipment by monitoring the metal wear particles carried in large aperture lubricating oil tubes, the simulation optimization structure design was carried out based on the traditional three-coil inductance wear particle sensor. The numerical model of electromotive force induced by the wear particle sensor was established, and the coil distance and coil turns were simulated by finite element analysis software. When permalloy is covered on the surface of the excitation coil and induction coil, the background magnetic field at the air gap increases, and the induced electromotive force amplitude generated by wear particles is increased. The effect of alloy thickness on the induced voltage and magnetic field was analyzed to determine the optimum thickness, and increase the induction voltage of the alloy chamfer detection at the air gap. The optimal parameter structure was determined to improve the detection ability of the sensor. Ultimately, by comparing the extreme values of the induced voltage of various types of sensors, the simulation determined that the minimum allowable detection of the optimal sensor was 27.5 µm ferromagnetic particles.
ABSTRACT
Post-translational modifications (PTMs) are key regulatory mechanisms that can control protein function. Of these, phosphorylation is the most common and widely studied. Because of its importance in regulating cell signaling, precise and accurate measurements of protein phosphorylation across wide dynamic ranges are crucial to understanding how signaling pathways function. Although immunological assays are commonly used to detect phosphoproteins, their lack of sensitivity, specificity, and selectivity often make them unreliable for quantitative measurements of complex biological samples. Recent advances in Mass Spectrometry (MS)-based targeted proteomics have made it a more useful approach than immunoassays for studying the dynamics of protein phosphorylation. Selected reaction monitoring (SRM)-also known as multiple reaction monitoring (MRM)-and parallel reaction monitoring (PRM) can quantify relative and absolute abundances of protein phosphorylation in multiplexed fashions targeting specific pathways. In addition, the refinement of these tools by enrichment and fractionation strategies has improved measurement of phosphorylation of low-abundance proteins. The quantitative data generated are particularly useful for building and parameterizing mathematical models of complex phospho-signaling pathways. Potentially, these models can provide a framework for linking analytical measurements of clinical samples to better diagnosis and treatment of disease.
Subject(s)
Phosphoproteins , Signal Transduction , Phosphorylation , Mass Spectrometry , Protein Processing, Post-TranslationalABSTRACT
Tumors are serious threats to human health. The transcription factors are regarded as the potential targets for tumor treatment. As an important family of transcription factors, E2F family transcription factors (E2Fs) play vital roles in cell proliferation and regulation. However, the expression feature, gene functions, and molecular interactions of E2Fs in tumorigenesis are not clear. In this study, the transcriptome data, mutation data, and protein-protein interaction data of 10 high-incidence tumors in China from the TCGA database were integrated and analyzed to explore the expression, structure, function, mutation, and phylogenetic characteristics of E2Fs. The results showed that E2F1 and E2F7 were regularly upregulated in the tumor samples. Moreover, E2Fs participated in the regulation of the cell cycle, cell aging, and other signaling pathways. As an important regulator, E2F1 interacted with more proteins than other E2Fs. At the same time, the genetic mutation types of E2Fs varied in tumor type and patient sex, of which gene amplification accounts for the largest proportion. Phylogenetic analysis showed that E2Fs were conserved in 41 species, including fruit flies, nematodes, and humans. Meanwhile, E2Fs had a tendency for gene expansion during evolution. In conclusion, this study clarified the expression pattern, mutation characteristics, and evolutionary trend of E2Fs in high-incidence tumors in China, and suggested that E2F family transcription factors could be novel diagnostic markers for tumor diseases. Furthermore, this work can provide a theoretical basis for the development of anti-tumor-targeted drugs.
Subject(s)
Carcinogenesis , Transcription Factors , Humans , E2F Transcription Factors/genetics , E2F Transcription Factors/metabolism , Phylogeny , Transcription Factors/genetics , Cell Cycle , Carcinogenesis/geneticsABSTRACT
BACKGROUND: AKI is a significant public health problem with high morbidity and mortality. Unfortunately, no definitive treatment is available for AKI. RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. METHODS: We engineered red blood cell-derived extracellular vesicles (REVs) with targeting peptides and therapeutic siRNAs to treat experimental AKI in a mouse model after renal ischemia/reperfusion (I/R) injury and unilateral ureteral obstruction (UUO). Phage display identified peptides that bind to the kidney injury molecule-1 (Kim-1). RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets. RESULTS: REVs targeted with Kim-1-binding LTH peptide (REVLTH) efficiently homed to and accumulated at the injured tubules in kidney after I/R injury. We identified transcription factors P65 and Snai1 that drive inflammation and fibrosis as potential therapeutic targets. Taking advantage of the established REVLTH, siRNAs targeting P65 and Snai1 were efficiently delivered to ischemic kidney and consequently blocked the expression of P-p65 and Snai1 in tubules. Moreover, dual suppression of P65 and Snai1 significantly improved I/R- and UUO-induced kidney injury by alleviating tubulointerstitial inflammation and fibrosis, and potently abrogated the transition to CKD. CONCLUSIONS: A red blood cell-derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules.
Subject(s)
Acute Kidney Injury/therapy , Extracellular Vesicles , Genetic Therapy/methods , Hepatitis A Virus Cellular Receptor 1/genetics , Snail Family Transcription Factors/genetics , Transcription Factor RelA/genetics , Acute Kidney Injury/pathology , Animals , Disease Models, Animal , Erythrocytes , Fibrosis , Inflammation/therapy , Kidney Tubules/metabolism , Kidney Tubules/pathology , Male , Mice , Peptides , RNA Interference , RNA, Small Interfering/therapeutic use , Reperfusion Injury/complications , Snail Family Transcription Factors/metabolism , Transcription Factor RelA/metabolism , Ureteral Obstruction/complicationsABSTRACT
To investigate the characterization and function of a novel porous osteogenic material (PLLA / DDM) containing polylactic acid and demineralized dentin matrix. The surface morphology and composition of the material were observed by SEM and EDS. The physical characteristics of the material were detected by roughness and water contact angle analyses. The rate of weight loss and change in the pH value of the material were observed by scaffold degradation experiments. Four types of material were investigated: polylactic acid (PLLA) scaffold, demineralized dentin matrix (DDM) particles, PLLA/DDM scaffold and a blank control. The osteogenic effect and osteogenic characteristics of the new materials were explored through in vivo and in vitro osteogenic experiments. SEM analysis showed that DDM powder was uniformly distributed in the polylactic acid scaffold, and the water contact angle revealed that the water absorption of the porous scaffold was improved after the addition of DDM powder. The EDS results showed that the peak values of calcium and phosphorus were obviously increased after the addition of DDM powder, and the porosity test showed that the scaffold had higher porosity after the addition of DDM powder. Scaffold degradation experiments revealed that the scaffold gradually degraded with increasing time, and its pH value slightly increased. The results of cell culture and animal model experiments showed that the porous PLLA/DDM scaffold had good bio-compatibility and promoted cell proliferation and differentiation. In histological and micro-CT evaluations, the material showed good bio-compatibility, biodegradability and bone conductivity with host bone tissue in vivo. PLLA / DDM hybrid showed better performance than PLLA or DDM. The biocompatibility and cell growth promoting properties were stronger than those of single material.
Subject(s)
Osteogenesis , Tissue Scaffolds , Animals , Polyesters/pharmacology , Porosity , Powders , Tissue Engineering/methods , Tissue Scaffolds/chemistry , WaterABSTRACT
Soil column tests were conducted to investigate the effects of grass type on water infiltration in a three-layer landfill cover under drying and wetting conditions. Five soil columns were prepared, including one bare, two Bermuda grass-planted and the other two vetiver-planted. During the drying period, the suction of vetiver-planted soil column was the largest, while that of bare case was the lowest. During the wetting period, the infiltration rate shows a bimodal form due to the contrasting hydraulic properties of different soil layers. The infiltration rate of vetiver-planted soil column was the lowest, followed by Bermuda grass-planted and bare cases. Correspondingly, the vetiver-planted soil column retained the maximum suction and the deepest ponding depth during rainfall. This was likely due to the larger leaf area and deeper roots of vetiver than those of Bermuda grass, thus inducing the maximum initial suction by root water uptake before rainfall and reducing the water permeability by root occupations of soil pores. These results show that vetiver is more effective than Bermuda grass to reduce water percolation through the three-layer landfill cover.
Subject(s)
Soil Pollutants , Waste Disposal Facilities , Soil , Soil Pollutants/analysis , WaterABSTRACT
BACKGROUND: Representing biological networks as graphs is a powerful approach to reveal underlying patterns, signatures, and critical components from high-throughput biomolecular data. However, graphs do not natively capture the multi-way relationships present among genes and proteins in biological systems. Hypergraphs are generalizations of graphs that naturally model multi-way relationships and have shown promise in modeling systems such as protein complexes and metabolic reactions. In this paper we seek to understand how hypergraphs can more faithfully identify, and potentially predict, important genes based on complex relationships inferred from genomic expression data sets. RESULTS: We compiled a novel data set of transcriptional host response to pathogenic viral infections and formulated relationships between genes as a hypergraph where hyperedges represent significantly perturbed genes, and vertices represent individual biological samples with specific experimental conditions. We find that hypergraph betweenness centrality is a superior method for identification of genes important to viral response when compared with graph centrality. CONCLUSIONS: Our results demonstrate the utility of using hypergraphs to represent complex biological systems and highlight central important responses in common to a variety of highly pathogenic viruses.
Subject(s)
Algorithms , Models, Biological , Genomics , ProteinsABSTRACT
Oxygen homeostasis disturbances play a critical role in the pathogenesis of acute kidney injury (AKI). The transcription factor hypoxia-inducible factor-1 (HIF-1) is a master regulator of adaptive responses to hypoxia. Aside from posttranslational hydroxylation, the mechanism of HIF-1 regulation in AKI remains largely unclear. In this study, the mechanism of HIF-α regulation in AKI was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level in ischemia-reperfusion-, unilateral ureteral obstruction-, and sepsis-induced AKI models, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB, which plays a central role in the inflammation response, was involved in the increasing expression of HIF-1α in AKI, as evidenced by pharmacological modulation (NF-κB inhibitor BAY11-7082). Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription, which occurred not only under hypoxic conditions but also under normoxic conditions. Moreover, the induced HIF-1α by inflammation protected against tubular injury in AKI. Thus, our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.NEW & NOTEWORTHY Here, the mechanism of hypoxia-inducible factor-α (HIF-α) regulation in acute kidney injury (AKI) was investigated. We found that tubular HIF-1α expression significantly increased at the transcriptional level, which was closely associated with macrophage-dependent inflammation. Meanwhile, NF-κB was involved in the increasing expression of HIF-1α in AKI. Mechanistically, NF-κB directly bound to the HIF-1α promoter and enhanced its transcription. Our findings not only provide novel insights into HIF-1 regulation in AKI but also offer to understand the pathophysiology of kidney diseases.
Subject(s)
Acute Kidney Injury/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kidney/metabolism , NF-kappa B/metabolism , Acute Kidney Injury/genetics , Animals , Cells, Cultured , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Gene Expression Regulation/drug effects , Hypoxia-Inducible Factor 1, alpha Subunit/genetics , Inflammation/genetics , Inflammation/metabolism , Kidney/drug effects , Mice , NF-kappa B/antagonists & inhibitors , NF-kappa B/genetics , Nitriles/pharmacology , Sulfones/pharmacologyABSTRACT
Incomplete recovery from episodes of acute kidney injury (AKI) can predispose patients to develop chronic kidney disease (CKD). Although hypoxia-inducible factor-1α (HIF-1α) is a master regulator of the response to hypoxia/ischemia, the role of HIF-1α in CKD progression following incomplete recovery from AKI is poorly understood. Here, we investigated this issue using moderate and severe ischemia/reperfusion injury (I/RI) mouse models. We found that the outcomes of AKI were highly associated with the time course of tubular HIF-1α expression. Sustained activation of HIF-1α, accompanied by the development of renal fibrotic lesions, was found in kidneys with severe AKI. The AKI to CKD progression was markedly ameliorated when PX-478 (a specific HIF-1α inhibitor, 5 mg· kg-1·d-1, i.p.) was administered starting on day 5 after severe I/RI for 10 consecutive days. Furthermore, we demonstrated that HIF-1α C-terminal transcriptional activation domain (C-TAD) transcriptionally stimulated KLF5, which promoted progression of CKD following severe AKI. The effect of HIF-1α C-TAD activation on promoting AKI to CKD progression was also confirmed in in vivo and in vitro studies. Moreover, we revealed that activation of HIF-1α C-TAD resulted in the loss of FIH-1, which was the key factor governing HIF-1α-driven AKI to CKD progression. Overexpression of FIH-1 inhibited HIF-1α C-TAD and prevented AKI to CKD progression. Thus, FIH-1-modulated HIF-1α C-TAD activation was the key mechanism of AKI to CKD progression by transcriptionally regulating KLF5 pathway. Our results provide new insights into the role of HIF-1α in AKI to CKD progression and also the potential therapeutic strategy for the prevention of renal diseases progression.
Subject(s)
Acute Kidney Injury/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Kruppel-Like Transcription Factors/metabolism , Mixed Function Oxygenases/metabolism , Renal Insufficiency, Chronic/etiology , Signal Transduction/drug effects , Acute Kidney Injury/pathology , Animals , Disease Progression , Hypoxia/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors , Hypoxia-Inducible Factor 1, alpha Subunit/chemistry , Kidney/metabolism , Kidney/pathology , Male , Mice, Inbred C57BL , Mustard Compounds/therapeutic use , Phenylpropionates/therapeutic use , Protein Domains , Renal Insufficiency, Chronic/pathology , Up-Regulation/physiologyABSTRACT
OBJECTIVE: To study the change and significance of serum pentraxin-3 (PTX-3) and syndecan-4 in children with chronic heart failure (CHF). METHODS: A total of 40 children with CHF who were admitted to the Department of Pediatrics of the First Affiliated Hospital of Zhengzhou University were enrolled as the heart failure group, and 30 children who underwent physical examination in the outpatient service during the same period of time were enrolled as the control group. The serum levels of PTX-3, syndecan-4, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were compared between the two groups. RESULTS: The children with CHF had significant reductions in the serum levels of PTX-3, syndecan-4, and NT-proBNP after treatment. The levels of these markers in children with CHF were significantly higher than the control group before and after treatment (P < 0.05). The CHF children with grade II/III/IV cardiac function had significantly higher serum levels of PTX-3 and syndecan-4 than the control group (P < 0.05). The levels of PTX-3 and syndecan-4 were related to the severity of cardiac function. Compared with the grade II cardiac function group, the grade IV cardiac function group had significant increases in the serum levels of PTX-3 and syndecan-4 (P < 0.05). The serum level of PTX-3 was positively correlated with that of syndecan-4 in children with CHF (rs=0.999, P < 0.05); the serum level of PTX-3 was positively correlated with NT-proBNP, left ventricular mass index (LVMI), and cardiac function grade (rs=0.726, 0.736, and 0.934 respectively, P < 0.05) and was negatively correlated with left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) (rs=-0.852 and -0.767 respectively, P < 0.05); the serum level of syndecan-4 was positively correlated with NT-proBNP, LVMI, and cardiac function grade (rs=0.733, 0.743, and 0.934 respectively, P < 0.05) and was negatively correlated with LVEF and LVFS (rs=-0.856 and -0.771 respectively, P < 0.05). CONCLUSIONS: Serum PTX-3 and syndecan-4 may be involved in the development and progression of ventricular remodeling in children with CHF and may be used as markers for the diagnosis, cardiac function grading, and treatment outcome evaluation of children with heart failure.
Subject(s)
Heart Failure , Syndecan-4 , Biomarkers , C-Reactive Protein , Child , Chronic Disease , Humans , Natriuretic Peptide, Brain , Peptide Fragments , Serum Amyloid P-Component , Stroke Volume , Ventricular Function, LeftABSTRACT
This article summarizes and analyzes the clinical features and gene mutation characteristics of children with noncompaction of the ventricular myocardium (NVM). For the 6 children with NVM (4 boys and 2 girls), the age of onset ranged from 3 months to 12 years. Of the 6 children, 5 had arrhythmia, 3 had cardiac insufficiency, 1 had poor mental state, and 1 had chest distress and sighing. NVM-related gene mutations were detected in 4 children, among whom 2 had MYH7 gene mutation, 1 had PRDM16 gene mutation, and 1 had mutations in the ACTN2 and TNNT2 genes. Four children had improvement in cardiac function. The two children with no significant improvement in cardiac function had a younger age of onset, a greater reduction in systolic function on echocardiography, and greater increases in myocardial enzyme and N-terminal pro-brain natriuretic peptide. It is concluded that for children with the initial symptoms of chest distress, sighing, arrhythmia, enlarged heart shadow, and increased myocardial enzyme, echocardiography and cardiac magnetic resonance are recommended for the diagnosis of NVM. NVM can have various genetic mutations.
Subject(s)
Cardiomyopathies , Heart Ventricles , Child , Child, Preschool , Echocardiography , Female , Heart Ventricles/diagnostic imaging , Humans , Infant , Male , Mutation , MyocardiumABSTRACT
Emodin, an anthraquinone compound extracted from rhubarb and other traditional Chinese medicines, has been proven to have a wide range of pharmacological effects, such as anti-inflammatory, antiviral, and antitumor activities. Previous studies have confirmed that emodin has inhibitory effects on various solid tumors, such as osteosarcoma, liver cancer, prostate cancer and glioma. This study aimed to investigate the effects and mechanisms of emodin-induced necroptosis in the glioma cell line U251 by targeting the TNF-α/RIP1/RIP3 signaling pathway. We found that emodin could significantly inhibit U251 cell proliferation, and the viability of U251 cells treated with emodin was reduced in a dose- and time-dependent manner. Flow cytometry assays and Hoechst-PI staining assays showed that emodin induced apoptosis and necroptosis. Real-time PCR and western blot analysis showed that emodin upregulated the levels of TNF-α, RIP1, RIP3 and MLKL. Furthermore, the RIP1 inhibitor Nec-1 and the RIP3 inhibitor GSK872 attenuated the killing effect of emodin on U251 cells. In addition, emodin could increase the levels of TNF-α, RIP1, RIP3 and MLKL in vivo. The results demonstrate that emodin could induce necroptosis in glioma possibly through the activation of the TNF-α/RIP1/RIP3 axis. These studies provide novel insight into the induction of necroptosis by emodin and indicate that emodin might be a potential candidate for treating glioma through the necroptosis pathway.