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1.
Dev Cell ; 2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34256011

RESUMO

Cells counter DNA damage through repair or apoptosis, yet a direct mechanism for this choice has remained elusive. When facing interstrand crosslinks (ICLs), the ICL-repair protein FANCI heterodimerizes with FANCD2 to initiate ICL excision. We found that FANCI alternatively interacts with a pro-apoptotic factor, PIDD1, to enable PIDDosome (PIDD1-RAIDD-caspase-2) formation and apoptotic death. FANCI switches from FANCD2/repair to PIDD1/apoptosis signaling in the event of ICL-repair failure. Specifically, removing key endonucleases downstream of FANCI/FANCD2, increasing ICL levels, or allowing damaged cells into mitosis (when repair is suppressed) all suffice for switching. Reciprocally, apoptosis-committed FANCI reverts from PIDD1 to FANCD2 after a failed attempt to assemble the PIDDosome. Monoubiquitination and deubiquitination at FANCI K523 impact interactor selection. These data unveil a repair-or-apoptosis switch in eukaryotes. Beyond ensuring the removal of unrepaired genomes, the switch's bidirectionality reveals that damaged cells can offset apoptotic defects via de novo attempts at lesion repair.

2.
Acta Pharmacol Sin ; 2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34253875

RESUMO

Diabetic kidney disease (DKD) is one of the microvascular complications of diabetes mellitus and a major cause of end-stage renal disease with limited treatment options. Wogonin is a flavonoid derived from the root of Scutellaria baicalensis Georgi, which has shown a potent renoprotective effect. But the mechanisms of action in DKD are not fully elucidated. In this study, we investigated the effects of wogonin on glomerular podocytes in DKD using mouse podocyte clone 5 (MPC5) cells and diabetic mice model. MPC5 cells were treated with high glucose (30 mM). We showed that wogonin (4, 8, 16 µM) dose-dependently alleviated high glucose (HG)-induced MPC5 cell damage, accompanied by increased expression of WT-1, nephrin, and podocin proteins, and decreased expression of TNF-α, MCP-1, IL-1ß as well as phosphorylated p65. Furthermore, wogonin treatment significantly inhibited HG-induced apoptosis in MPC5 cells. Wogonin reversed HG-suppressed autophagy in MPC5 cells, evidenced by increased ATG7, LC3-II, and Beclin-1 protein, and decreased p62 protein. We demonstrated that wogonin directly bound to Bcl-2 in MPC5 cells. In HG-treated MPC5 cells, knockdown of Bcl-2 abolished the beneficial effects of wogonin, whereas overexpression of Bcl-2 mimicked the protective effects of wogonin. Interestingly, we found that the expression of Bcl-2 was significantly decreased in biopsy renal tissue of diabetic nephropathy patients. In vivo experiments were conducted in STZ-induced diabetic mice, which were administered wogonin (10, 20, 40 mg · kg-1 · d-1, i.g.) every other day for 12 weeks. We showed that wogonin administration significantly alleviated albuminuria, histopathological lesions, and p65 NF-κB-mediated renal inflammatory response. Wogonin administration dose-dependently inhibited podocyte apoptosis and promoted podocyte autophagy in STZ-induced diabetic mice. This study for the first time demonstrates a novel action of wogonin in mitigating glomerulopathy and podocytes injury by regulating Bcl-2-mediated crosstalk between autophagy and apoptosis. Wogonin may be a potential therapeutic drug against DKD.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34254638

RESUMO

Exosomes derived from human umbilical cord mesenchymal stem cells (hUMSC-Ex) play important roles in immune and inflammation diseases. However, the role of hUMSC-Ex in atherosclerosis has not been elucidated. In this study, the isolated exosomes were identified by transmission electron microscopy and nanoparticle tracking analysis. Exosome marker protein levels were increased in the hUMSC-Ex compared with those in hUMSC suspension, indicating that exosomes were successfully isolated from hUMSCs. Furthermore, eosinophils were treated with oxidized low-density lipoprotein (ox-LDL) to construct inflammation model and then incubated with hUMSC-Ex derived from hUMSCs which were transfected with miR-100-5p mimic or miR-100-5p inhibitor. We found that hUMSC-Ex increased miR-100-5p expression, inhibited cell migration, promoted cell apoptosis, and reduced inflammatory cytokine levels in ox-LDL-treated eosinophils, and miR-100-5p overexpression in hUMSCs enhanced these effects, while miR-100-5p inhibition reversed these effects. Moreover, frizzled 5 (FZD5) was a target gene of miR-100-5p. FZD5 overexpression reversed the inhibitory effects of hUMSC-Ex-miR-100-5p on cell progression and inflammation in eosinophils. Additionally, hUMSC-Ex-miR-100-5p decreased the expression of cyclin D1 and ß-catenin proteins. Wnt/ß-catenin pathway activator BML-284 effectively reversed the effects of hUMSC-Ex-miR-100-5p on cell progression and inflammation in eosinophils. ApoE-/- mice were fed with high-fat diet to construct an atherosclerosis mice model, and hUMSC-Ex was injected into mice. HUMSC-Ex reduced atherosclerotic plaque area and inflammation response in atherosclerosis mice. This study demonstrates that hUMSC-Ex-miR-100-5p inhibits cell progression and inflammatory response in eosinophils via the FZD5/Wnt/ß-catenin pathway, thereby alleviating atherosclerosis progression.

4.
Mol Nutr Food Res ; : e2100011, 2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34227225

RESUMO

SCOPE: The aim of the present study is to identify human milk pattern using multi-omics datasets and to explore association between patterns, infant growth, and allergy using data from the Chinese Human Milk Project (CHMP) study. METHODS AND RESULTS: Three patterns are identified from integrative analysis of proteome, lipidome, and glycome profiles of 143 mature human milk samples. Factor 1 is positively associated with 128 proteins, phospholipids, and human milk oligosaccharides (HMOs) including lacto N-neohexaose (LNnH) and lacto-N-difucohexaose II (LNDFH II); factor 2 is negatively associated with as1 -casein, phospholipids while positively associates with HMOs including LNnH, lactosialyl tetrasaccharide c (LSTc), and 2'-fucosyllactose (2'FL); factor 3 is positively associated with lysophospholipids while negatively associates with 27 proteins, triglycerides with two saturated fatty acids, 6'-sialyllactose (6'SL) and 2'FL. In general, factor 1 and factor 2 are associated with slower while factor 3 is associated with faster growth rate (p < 0.044). One unit higher in loadings of factor 2 is associated with 34% lower risk of allergies (p ≤ 0.017). Associations are not significant after adjustment for city except for factor 1. CONCLUSIONS: Three possible human milk patterns with varying degree of stability are identified. Future work is needed to understand these patterns in terms of generalization, biologic mechanisms, and genotype influences.

5.
Plant Physiol Biochem ; 166: 657-667, 2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34214776

RESUMO

To reveal the mechanism of photosynthesis inhibition by infection and the response of the MAPK signaling pathway to pathogen infection, tobacco leaves were inoculated with Pseudomonas syringae pv. tabaci (Pst), and the effects of Pst infection on photosynthesis of tobacco leaves were studied by physiological and proteomic techniques, with a focus on MAPK signaling pathway related proteins. Pst infection was observed to lead to the degradation of chlorophyll (especially Chl b) in tobacco leaves and the down-regulation of light harvesting antenna proteins expression, thus limiting the light harvesting ability. The photosystem II and I (PSII and PSI) activities were also decreased, and Pst infection inhibited the utilization of light and CO2. Proteomic analyses showed that the number of differentially expressed proteins (DEPs) under Pst infection at 3 d were significantly higher than at 1 d, especially the number of down-regulated proteins. The KEGG enrichment of DEPs was mainly enriched in the energy metabolism processes such as photosynthesis antenna proteins and photosynthesis. The down-regulation of chlorophyll a-b binding protein, photosynthetic electron transport related proteins (e.g., PSII and PSI core proteins, the Cytb6/f complex, PC, Fd, FNR), ATP synthase subunits, and key enzymes in the Calvin cycle were the key changes associated with Pst infection that may inhibit tobacco photosynthesis. The effect of Pst infection on the PSII electron acceptor side was significantly greater than that on the PSII donor side. The main factor that decreased the photosynthetic ability of tobacco leaves with Pst infection at 1 d may be the inhibition of photochemical reactions leading to an insufficient supply of ATP, rather than decreased expression of enzymes involved in the Calvin cycle. At 1 d into Pst infection, the PSII regulated energy dissipation yield Y(NPQ) may play a role in preventing photosynthetic inhibition in tobacco leaves, but the long-term Pst infection significantly inhibited Y(NPQ) and the expression of PsbS proteins. Proteins involved in the MAPK signaling pathway were up-regulated, suggesting the MAPK signaling pathway was activated to respond to Pst infection. However, at the late stage of Pst infection (at 3 d), MAPK signaling pathway proteins were degraded, and the defense function of the MAPK signaling pathway in tobacco leaves was damaged.

6.
Artigo em Inglês | MEDLINE | ID: mdl-34269703

RESUMO

ABSTRACT: Circular RNAs (circRNAs) act as vital regulators in diverse diseases. However, the investigation of circRNAs in sepsis-engendered acute kidney injury (AKI) remains dismal. We aimed to explore the effects of circPRKCI in lipopolysaccharide (LPS)-mediated HK2 cell injury. Sepsis in vitro model was established by LPS treatment. Quantitative real-time polymerase chain reaction (qRT-PCR) assay was conducted for determining the levels of circPRKCI, microRNA-106b-5p (miR-106b-5p) and growth factor receptor binding 2-associated binding protein 1 (GAB1). Cell viability and apoptosis were evaluated using Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis, respectively. The concentrations of interleukin-6 (IL-6), IL-1ß and tumor necrosis factor-α (TNF-α) were measured with Enzyme linked immunosorbent assay (ELISA) kits. The levels of oxidative stress markers were determined using relevant commercial kits. Western blot assay was conducted for B-cell lymphoma-2 (Bcl-2), BCL2-Associated X (Bax) and GAB1 protein levels. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were utilized to verify the association between miR-106b-5p and circPRKCI or GAB1. We found CircPRKCI level was decreased in sepsis patients and LPS-induced HK-2 cells. LPS exposure inhibited cell viability and facilitated apoptosis, inflammation and oxidative stress in HK-2 cells. CircPRKCI overexpression abrogated the effects of LPS on cell apoptosis, inflammation and oxidative stress in HK-2 cells. Furthermore, circPRKCI was identified as the sponge for miR-106b-5p to positively regulate GAB1 expression. Overexpression of circPRKCI relieved LPS-mediated HK-2 cell damage by sponging miR-106b-5p. MiR-106b-5p inhibition ameliorated the injury of HK-2 cells mediated by LPS, while GAB1 knockdown reversed the effect. Collectively, CircPRKCI overexpression attenuated LPS-induced HK-2 cell injury by regulating miR-106b-5p/GAB1 axis.

7.
Int J Mol Med ; 48(3)2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34278465

RESUMO

It has been previously reported that macrophages may be involved in diabetic nephropathy (DN) development. Furthermore, Bruton's tyrosine kinase (BTK) may participate in macrophage activation and lead to the release of inflammatory mediators. The main aim of the present study was to analyze the association between renal BTK expression and clinical indicators. Moreover, BTK knockout mice were used to establish a diabetic model for further research. The results demonstrated that BTK was activated in the kidneys of patients with DN and was associated with the progression of proteinuria, creatinine levels, estimated glomerular filtration rate and pathological changes in the kidneys of patients with DN. Furthermore, BTK knockout was observed to reduce urinary protein excretion, alleviate renal injury and decrease renal inflammation in diabetic mice. This protection may be attributed to BTK­induced suppression of the activation of the Nod­like receptor (NLR) family pyrin domain containing 3 inflammasome. Collectively, it has been demonstrated in the present study that BTK may be a potential target for DN treatment.

8.
PLoS Genet ; 17(7): e1009640, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34214075

RESUMO

Heterotrimeric G proteins were originally discovered through efforts to understand the effects of hormones, such as glucagon and epinephrine, on glucose metabolism. On the other hand, many cellular metabolites, including glucose, serve as ligands for G protein-coupled receptors. Here we investigate the consequences of glucose-mediated receptor signaling, and in particular the role of a Gα subunit Gpa2 and a non-canonical Gß subunit, known as Asc1 in yeast and RACK1 in animals. Asc1/RACK1 is of particular interest because it has multiple, seemingly unrelated, functions in the cell. The existence of such "moonlighting" operations has complicated the determination of phenotype from genotype. Through a comparative analysis of individual gene deletion mutants, and by integrating transcriptomics and metabolomics measurements, we have determined the relative contributions of the Gα and Gß protein subunits to glucose-initiated processes in yeast. We determined that Gpa2 is primarily involved in regulating carbohydrate metabolism while Asc1 is primarily involved in amino acid metabolism. Both proteins are involved in regulating purine metabolism. Of the two subunits, Gpa2 regulates a greater number of gene transcripts and was particularly important in determining the amplitude of response to glucose addition. We conclude that the two G protein subunits regulate distinct but complementary processes downstream of the glucose-sensing receptor, as well as processes that lead ultimately to changes in cell growth and metabolism.

9.
Infect Dis Ther ; 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34244957

RESUMO

INTRODUCTION: This study aimed to evaluate the utility of metagenomic next-generation sequencing (mNGS) for the diagnosis of Pneumocystis jirovecii pneumonia (PJP) in non-human immunodeficiency virus-infected patients. METHODS: We conducted a retrospective study. A total of 60 non-human immunodeficiency virus-infected PJP patients and 134 patients diagnosed with non-PJP pneumonia were included. P. jirovecii and other co-pathogens identified by mNGS in bronchoalveolar lavage fluid and/or blood samples were analyzed. Using clinical composite diagnosis as the reference standard, we compared the diagnostic performance of mNGS in PJP with conventional methods, including Gomori methenamine silver staining and serum (1,3)-ß-D-glucan. Modifications of antimicrobial treatment for PJP patients after the report of mNGS results were also reviewed. RESULTS: mNGS reached a sensitivity of 100% in diagnosing PJP, which was remarkably higher than Gomori methenamine silver staining (25.0%) and serum (1,3)-ß-D-glucan (67.4%). The specificity of mNGS (96.3%) significantly surpassed serum (1,3)-ß-D-glucan (81.4%). Simultaneous mNGS of bronchoalveolar lavage fluid and blood samples was performed in 21 out of 60 PJP patients, and it showed a concordance rate of 100% in detecting P. jirovecii. Besides, mNGS showed good performance in identifying co-pathogens of PJP patients, among which cytomegalovirus and Epstein-Barr virus were most commonly seen. Initial antimicrobial treatment was modified in 71.7% of PJP patients after the report of mNGS results. CONCLUSION: mNGS is a useful diagnostic tool with good performance for the diagnosis of PJP and the detection of co-pathogens. mNGS of bronchoalveolar lavage fluid and/or blood samples is suggested in patients with presumptive diagnosis of PJP. Blood samples may be a good alternative to bronchoalveolar lavage fluid for mNGS when bronchoscopic examination is not feasible.

10.
Aquat Toxicol ; 237: 105902, 2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34218114

RESUMO

There is concern about adverse effects of thyroid hormone (TH) disrupting chemicals on TH-dependent brain development. Bisphenol A (BPA) and its analogues, such as bisphenol F (BPF), are known to have the potential to interfere with TH signaling, but whether they affect TH-dependent brain development is not yet well documented. Here, we conducted the T3-induced Xenopus laevis metamorphosis assay, a model for studying TH signaling disruption, to investigate the effects of BPA and BPF (10-1000 nM) on TH signaling in brains and subsequent brain development. While 48-hr treatment with 1 nM T3 dramatically upregulated TH-response gene expression in X. laevis brains at stage 52, 1000 and/or 100 nM BPA also caused significant transcriptional up-regulation of certain TH-response genes, whereas BPF had slighter effects, suggesting limited TH signaling disrupting activity of BPF in brains relative to BPA at the lack of TH. In the presence of 1 nM T3, 1000 and/or 100 nM of BPF as well as BPA antagonized T3-induced TH-response gene expression, whereas lower concentrations agonized T3 actions on certain TH-response genes, displaying an apparently biphasic effect on TH signaling. After 96 h exposure, T3 induced brain morphological remodeling coupled with cell proliferation and neuronal differentiation, whereas both BPA and BPF generally antagonized T3-induced changes in a concentration-dependent manner, with weak or no effects of bisphenol exposure alone. Overall, all results show that BPA and BPF interfered with TH signaling in Xenopus brains, especially in the presence of TH, and subsequently affected TH-dependent brain development. Given the evolutionary conservation of TH-dependent brain development among vertebrates, our findings from X. laevis warrant further studies to reveal potential influences of bisphenols on TH-dependent brain development in higher vertebrates.

11.
J Agric Food Chem ; 69(28): 7910-7921, 2021 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-34241999

RESUMO

Today, we are seeking an efficient biotransformation of cellulosic material into sustainable biochemical products to meet the increasing global energy demand. Herein, we report the fabrication of multienzyme hybrid nanoflowers (ECG-NFs) by co-immobilizing three recombinant enzymes (cellobiohydrolase (CBH), endo-glucanase (EG), and ß-glucosidase (BG)) integrating a binary tag composed of elastin-like polypeptide (ELP) and His-tag to act as a tri-enzyme biocatalyst, which catalyzes the hydrolysis of cellulose into glucose. The prepared ECG-NFs exhibited excellent performance in terms of pH stability, thermal stability, storage stability, and catalytic efficiency compared to free multienzyme system. Notably, ECG-NFs could be recycled for up to eight consecutive runs. The Km and kcat/Km values for ECG-NFs were 9.33 g L-1 and 0.0051 L min-1 g-1, respectively, which were better than those of the free multienzyme system, indicating a better substrate affinity. Finally, the overall enzyme activity of ECG-NFs increased by 1.12 times and the degradation efficiency of ECG-NFs was superior to the free multienzyme system, which revealed that ECG-NFs could facilitate an effective one-pot hydrolysis of cellulose into glucose.

12.
Yi Chuan ; 43(7): 642-653, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-34284980

RESUMO

As a serine/threonine kinase, NIMA-related kinases (NEKs) play important roles in the regulation of cell cycle, and involve in several cellular activities such as centrosome separation, spindle assembly, chromatin condensation, nuclear envelope breakdown, spindle assembly checkpoint signaling, cytokinesis, cilia formation and DNA damage response. In this review, we summarize the component, structural characteristics and functions of NEK family in mitosis and meiosis based on the relevant researches in recent years, providing a reference for the further study on the roles of NEKs in the regulation of cell cycle and a theoretical basis for the clinical diagnosis and treatment of tumors.

13.
Se Pu ; 39(7): 686-694, 2021 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-34227365

RESUMO

N-Glycosylation of proteins, an important post-translational modification in eukaryotic cells, plays an essential role in the regulation of cell adhesion, migration, signal transduction, and apoptosis. Abnormal changes in protein glycosylation are closely related to the occurrence of many critical diseases, including diabetes, tumors, and neurological, kidney, and inflammatory diseases. A non-invasive type of liquid biopsy, urine sampling has the advantage of reducing the complexity of proteomic analysis. This facilitates the design of large-scale and continuous or multi-time point sampling strategies. However, the dynamic range of urinary protein abundance is relatively large, owing to individual differences and physiological conditions. Currently, there is a lack of specialized research on individual differences, physiological fluctuations, and physiological abundance ranges of urinary N-glycoproteins in large healthy populations. Therefore, it is difficult to accurately distinguish individual differences and normal physiological fluctuations from changes caused by disease; this poses a great challenge in disease marker research. Liquid chromatography-mass spectrometry (LC-MS) is an analytical technique widely used for the large-scale profiling of proteomes in biological systems, and the enrichment of N-glycopeptides is a prerequisite for their detection by MS.In this study, we established an approach based on hydrophilic interaction chromatography (HILIC) by optimizing the activation, cleaning, and elution processes of the enrichment method, for instance through the optimization of particle size and solvent composition, and investigated the identification number, selectivity, and stability of N-glycoprotein/N-glycopeptide enrichment under different experimental conditions. We found that N-glycoproteins and N-glycopeptides were highly enriched in a trifluoroacetic acid system with 5-µm filling particles in the HILIC column. On this basis, we analyzed the levels of N-glycoproteins/N-glycopeptides in urine samples. The consistency of N-glycoprotein/N-glycopeptide levels in urine samples taken from the same healthy person for five consecutive days was investigated by correlation analysis. This analysis revealed that the urinary N-glycoproteome of the same healthy person was relatively stable over a short period of time. Next, urinary samples from 20 healthy male volunteers and 20 healthy female volunteers were enriched for N-glycoproteins/N-glycopeptides, which were profiled by MS through qualitative and quantitative analyses. Screening and functional analysis of differential proteins were then carried out. A total of 1016 N-glycoproteins and 2192 N-glycopeptides were identified in the mid-morning urine samples of the 40 healthy volunteers. A label-free quantitation strategy was used to investigate the fluctuation range of the physiologically abundant urinary N-glycopeptides. The abundance of urinary N-glycopeptides spanned across approximately five orders of magnitude. Subsequently, gender differences in the N-glycosylation levels of urinary proteins were also explored in healthy people. Functional analysis of the N-glycoproteins that exhibited gender differences in abundance was performed. Based on multivariate statistical analysis, 206 differentially expressed proteins (p<0.05, fold change (FC)> 4) were identified. In females, we found 175 significantly down-regulated N-glycoproteins and 31 significantly up-regulated N-glycoproteins with respect to males. The expression levels of N-glycopeptides between the two groups suggested a clear gender difference. To investigate the biological processes and functions of these proteins, gene ontology (GO) analysis was performed on the N-glycoproteins/N-glycopeptides differentially expressed between males and females. Metabolic pathway analysis was also carried out based on the kyoto encyclopedia of genes and genomes (KEGG). Differentially expressed N-glycoproteins were mostly associated with platelet degranulation, extracellular region, and ossification. The top three relevant pathways were glycan biosynthesis and metabolism, metabolism of cofactors and vitamins, and lipid metabolism. Overall, sex may be an important factor for urinary N-glycoproteome differences among normal individuals and should be considered in clinical applications. This study provides relevant information regarding the function and mechanisms of the urinary glycoproteome and the screening of clinical biomarkers.

14.
Artigo em Inglês | MEDLINE | ID: mdl-34062173

RESUMO

Sliding window method is widely used to study the functional connectivity dynamics in brain networks. A key issue of this method is how to choose the window length and number of clusters across different window length. Here, we introduced a universal method to determine the optimal window length and number of clusters and applied it to study the dynamic functional network connectivity (FNC) in major depressive disorder (MDD). Specifically, we first extracted the resting-state networks (RSNs) in 27 medication-free MDD patients and 54 healthy controls using group independent component analysis (ICA), and constructed the dynamic FNC patterns for each subject in the window range of 10-80 repetition times (TRs) using sliding window method. Then, litekmeans algorithm was utilized to cluster the FNC patterns corresponding to each window length into 2-20 clusters. The optimal number of clusters was determined by voting method and the optimal window length was determined by identifying the most representative window length. Finally, 8 recurring FNC patterns regarded as FNC states were captured for further analyzing the dynamic attributes. Our results revealed that MDD patients showed increased mean dwell time and fraction of time spent in state #5, and the mean dwell time is correlated with depression symptom load. Additionally, compared with healthy controls, MDD patients had significantly reduced FNC within FPN in state #7. Our study reported a new approach to determine the optimal window length and number of clusters, which may facilitate the future study of the functional dynamics. These findings about MDD using dynamic FNC analyses provide new evidence to better understand the neuropathology of MDD.

15.
Artigo em Inglês | MEDLINE | ID: mdl-34142887

RESUMO

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide (NAM, SIRT1 inhibitor) simultaneously for four weeks. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2-/- mice without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced MMP2 upregulation via SIRT1-mediated YAP deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.

16.
Ecotoxicol Environ Saf ; 220: 112400, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34116331

RESUMO

The associations of bisphenol A exposure during pregnancy with risk of preterm birth (PTB) and changes in gestational age have remained controversial. To conduct the meta-analysis, the relevant studies were searched through PubMed, OVID, and Web of Science from inception through June 17, 2020. Data were independently extracted and analyzed using odds ratio (OR) or regression coefficient (ß) and their 95% confidence intervals (CIs). We identified 668 references and included 7 studies for preterm birth and 9 studies for gestational age. The included studies reported that the median or geometric mean (GM) of maternal urinary BPA ranged from 0.48 to 6.44 ng/ml. The meta-analysis estimated OR to be 1.36 (95% CI: 1.03, 1.69) for preterm birth associated with maternal urinary BPA exposure during pregnancy. In the subgroup analysis based on BPA exposure level, a significant association was observed between preterm birth and higher BPA exposure among the populations had BPA median or GM concentrations higher than 2.16 ng/ml (OR: 1.92; 95% CI: 1.38, 2.47). In the subgroup analyses by maternal urinary BPA exposure assessed in different trimesters, a significant association of preterm birth was only observed with BPA assessed in the third trimester (OR: 1.62; 95% CI: 1.15, 2.09). In addition, higher maternal urinary BPA exposure during pregnancy was associated with decreased gestational age by 0.50 (-0.87, -0.13) days, and the subgroup analyses also showed that only BPA exposure in the third trimester was associated with decreased gestational age by 1.36 (-2.21, -0.52) days. This meta-analysis demonstrated that higher BPA exposure was associated with an increased risk of preterm birth and decreased length of gestational age, and suggested that BPA exposure in the third trimester of pregnancy may be a critical susceptible period of preterm birth.


Assuntos
Compostos Benzidrílicos/efeitos adversos , Idade Gestacional , Exposição Materna/efeitos adversos , Fenóis/efeitos adversos , Trimestres da Gravidez , Nascimento Prematuro/etiologia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
17.
Nat Commun ; 12(1): 3720, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-34140524

RESUMO

Low levels of reactive oxygen species (ROS) are crucial for maintaining cancer stem cells (CSCs) and their ability to resist therapy, but the ROS regulatory mechanisms in CSCs remains to be explored. Here, we discover that prohibitin (PHB) specifically regulates mitochondrial ROS production in glioma stem-like cells (GSCs) and facilitates GSC radiotherapeutic resistance. We find that PHB is upregulated in GSCs and is associated with malignant gliomas progression and poor prognosis. PHB binds to peroxiredoxin3 (PRDX3), a mitochondrion-specific peroxidase, and stabilizes PRDX3 protein through the ubiquitin-proteasome pathway. Knockout of PHB dramatically elevates ROS levels, thereby inhibiting GSC self-renewal. Importantly, deletion or pharmacological inhibition of PHB potently slows tumor growth and sensitizes tumors to radiotherapy, thus providing significant survival benefits in GSC-derived orthotopic tumors and glioblastoma patient-derived xenografts. These results reveal a selective role of PHB in mitochondrial ROS regulation in GSCs and suggest that targeting PHB improves radiotherapeutic efficacy in glioblastoma.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioblastoma/metabolismo , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteínas Repressoras/metabolismo , Adulto , Idoso , Animais , Astrocitoma/metabolismo , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Técnicas de Inativação de Genes , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/radioterapia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Gradação de Tumores , Peroxirredoxinas/metabolismo , Prognóstico , Complexo de Endopeptidases do Proteassoma/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Análise Serial de Tecidos , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi ; 35(6): 761-768, 2021 Jun 15.
Artigo em Chinês | MEDLINE | ID: mdl-34142505

RESUMO

Objective: To investigate the effects of hypoxia inducible factor 1α (HIF-1α) overexpression on the differentiation of stem cells derived from human exfoliated deciduous teeth (SHED) into vascular endothelial cells. Methods: SHED was isolated from the retained primary teeth donated by healthy children by using collagenase digestion method. The third generation cells were identified by flow cytometry and alizarin red and alkaline phosphatase (ALP) staining after osteogenic differentiation culture. The SHED were divided into blank control group (SHED without any treatment), empty group (SHED infected with empty lentivirus), HIF-1α overexpression group (SHED infected with HIF-1α overexpression lentivirus), Wnt inhibitor group (SHED interfered by IWR-1), and combination group (HIF-1α overexpressed SHED interfered by IWR-1). Real-time fluorescence quantitative PCR (qRT-PCR) and Western blot were used to analyze the expressions of HIF-1α mRNA and protein in the SHED of blank control group, empty group, and HIF-1α overexpression group. Then the SHED in 5 groups were induced differentiation into vascular endothelial cells for 14 days. The expressions of cell surface marker molecule [von Willebrand factor (vWF) and CD31] were detected by flow cytometry. The mRNA expressions of vascular cell adhesion protein 1 (VCAM-1), KDR (Kinase-inserted domain containing receptor), and VE-cadherin (VE) were analyzed by qRT-PCR. The protein expressions of phosphate-glycogen synthasc kinase 3ß (p-GSK3ß) and ß-catenin were analyzed by Western blot. The tube forming ability of induced cells was detected by Matrigel tube forming experiment. The ability of endothelial cells to phagocytic lipid after differentiation was detected by DiI-labeled acetylated low density lipoprotein (DiI-Ac-LDL) phagocytosis. Results: After identification, the cells were SHED. After lentivirus transfection, compared with the blank control group and the empty group, the expressions of HIF-1α mRNA and protein in the HIF-1α overexpression group increased significantly ( P<0.05). Compared with the blank control group and the empty group, the expressions of VCAM-1, KDR, and VE mRNA, the percentages of vWF positive cells and CD31 positive cells, and the relative expression of ß-catenin protein were significantly higher ( P<0.05), the relative expression of p-GSK3ß protein was significantly lower ( P<0.05), the number of tubules formed and the ability to phagocytic lipids significantly increased ( P<0.05) in the HIF-1α overexpression group; while the indicators in the Wnt inhibitor group were opposite to those in the HIF-1α overexpression group ( P<0.05). Compared with the HIF-1α overexpression group, the expressions of VCAM-1, KDR, and VE mRNA, the percentages of vWF positive cells and CD31 positive cells, and the relative expression of ß-catenin protein were significantly lower ( P<0.05), the relative expression of p-GSK3ß protein was significantly higher, and the number of tubules formed and the ability of phagocytosis of lipids significantly reduced, showing significant differences between groups ( P<0.05). Conclusion: Overexpression of HIF-1α can promote SHED to differentiate into vascular endothelial cells by activating Wnt/ß-catenin signaling pathway.


Assuntos
Células Endoteliais , Subunidade alfa do Fator 1 Induzível por Hipóxia , Osteogênese , Diferenciação Celular , Criança , Humanos , Hipóxia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Células-Tronco , Dente Decíduo
19.
Ren Fail ; 43(1): 958-967, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34148499

RESUMO

OBJECTIVE: To investigate the relationship between preoperative proteinuria and postoperative acute kidney injury (AKI). METHODS: We performed a search on databases included PubMed, Embase, the Cochrane Library, and Web of Science, from December 2009 to September 2020. Data extracted from eligible studies were synthesized to calculate the odds ratio (OR) and 95% confidence interval (CI). A fixed or random effects model was applied to calculate the pooled OR based on heterogeneity through the included studies. RESULTS: This meta-analysis of 11 observational studies included 203,987 participants, of whom 21,621 patients suffered from postoperative AKI and 182,366 patients did not suffer from postoperative AKI. The combined results demonstrated that preoperative proteinuria is an independent risk factor for postoperative AKI (adjusted OR = 1.65, 95%CI:1.44-1.89, p < 0.001). Subgroup analysis showed that both preoperative mild proteinuria (adjusted OR = 1.30, 95%CI:1.24-1.36, p < 0.001) and preoperative heavy proteinuria (adjusted OR = 1.93, 95%CI:1.65-2.27, p < 0.001) were independent risk factors for postoperative AKI. The heterogeneity was combined because its values were lower. Further subgroup analysis found that preoperative proteinuria measured using dipstick was an independent risk factor for postoperative AKI (adjusted OR = 1.48, 95%CI:1.37-1.60, p < 0.001). Finally, preoperative proteinuria was an independent risk factor for postoperative AKI in the non-cardiac surgery group (adjusted OR = 2.06, 95%CI:1.31-3.24, p = 0.002) and cardiac surgery group (adjusted OR = 1.69, 95%CI:1.39-2.06, p < 0.001). CONCLUSION: Preoperative proteinuria is an independent risk factor for postoperative AKI and in instances when proteinuria is detected using dipsticks.

20.
Micron ; 148: 103103, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34134050

RESUMO

Nitrate has a wide temperature range, wide operating temperature, low vapor pressure, low cost, strong heat transfer and stable chemical properties. It is widely used in solar thermal power generation heat storage material. In this paper, the alkali salt NaNO3 was modified by solution combustion method with citric acid as fuel. The structure and thermal properties of the prepared salts were studied by field emission scanning electron microscopy (FE-SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The results show that the solution combustion process improves the structure and thermal properties of NaNO3, and the resulting product has a new phase. The particle size and microscopic morphology of the prepared salt were changed. As the proportion of fuel increases, the hollow cuboid structure gradually grows on the surface and inside of the modified salt. The microstructure obtained is different at different ignition temperatures, and a finer and even rod-like structure is obtained at an ignition temperature of 600 °C. The specific heat capacity of all modified samples has been improved, among which solid specific heat and liquid specific heat have increased the most, respectively 3.10 J/g·K and 3.19 J/g·K, which are 140.31% and 131.16% higher than the base salt, respectively. This work not only studies the specific heat capacity of NaNO3 modified by solution combustion, but also explores the effect of micromorphology and new phase formation on its performance, which provides innovative ideas for improving the specific heat capacity of molten salt heat storage materials.

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