ABSTRACT
BACKGROUND: This study aimed to investigate the association between estimated pulse wave velocity (ePWV) and mortality outcomes among individuals with hypertension. METHODSâANDâRESULTS: Based on the National Health and Nutrition Examination Survey (NHANES) 1999-2018, a total of 14,396 eligible participants with hypertension were enrolled. The ePWV was calculated using the equation based on blood pressure and age. The mortality outcomes of included participants were directly acquired from the National Death Index database. The multivariable Cox regression analysis was used to examine the relationship between ePWV and mortality outcomes. Moreover, the restricted cubic spline (RCS) was also used to explore this relationship. Receiver operating characteristics curves (ROC) were adopted to evaluate the prognostic ability of ePWV for predicting mortality outcomes of patients with hypertension. The median follow-up duration was 10.8 years; individuals with higher an ePWV had higher risks of mortality from both all causes (HR: 2.79, 95% CI: 2.43-3.20) and cardiovascular diseases (HR: 3.41, 95% CI: 2.50-4.64). After adjusting for confounding factors, each 1 m/s increase in ePWV was associated with a 43% increase in all-cause mortality risk (HR: 1.43, 95% CI: 1.37-1.48) and a 54% increase in cardiovascular mortality risk (HR: 1.54, 95% CI: 1.43-1.66). CONCLUSIONS: This study indicates that ePWV is a novel prognostic indicator for predicting the risks of mortality among patients with hypertension.
Subject(s)
Cardiovascular Diseases , Cardiovascular System , Hypertension , Humans , Nutrition Surveys , Pulse Wave AnalysisABSTRACT
Epicardial adipose tissue (EAT) is a metabolically active organ which generates inflammatory cytokines. Thickness of EAT is associated with onset and development of heart failure with preserved ejection fraction (HFpEF). However, it is still unclear the specific mechanisms and pharmacological targets on EAT induced inflammation in HFpEF. A two-hit protocol with western diet and Nω-nitrol-arginine methyl ester (L-NAME) was used to establish HFpEF mouse model. In HFpEF mice, inflammatory biomarkers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and von willebrand factor (vWF) elevated in myocardium compared to control. Inflammatory cell infiltration in myocardium was increased. In HFpEF mice, inflammasome-mediated pyroptosis pathway was activated in the EAT. Suppression of pyroptosis-related protein gasdermin D (GSDMD) in cultured EAT could lower cardiomyocyte inflammation and autophagy. Furthermore, spironolactone and rosuvastatin, the two-hit anti-inflammatory agents, reduced NLR family pyrin domain containing 3 (NLRP3)/GSDMD pyroptosis in EAT and autophagy in myocardium of HFpEF mouse. The combination treatment also enhanced exercise tolerance and appeased inflammatory injuries in HFpEF mice. CONCLUSION: Pyroptosis signaling is involved in EAT-myocardium axis in mouse model of HFpEF. Targeting adipocyte-derived inflammation in EAT bears potential to treatment HFpEF.
Subject(s)
Heart Failure , Pyroptosis , Mice , Animals , Heart Failure/metabolism , Stroke Volume , Inflammasomes/metabolism , Myocardium/metabolism , Adipose Tissue/metabolism , Inflammation/pathology , Disease Models, Animal , NLR Family, Pyrin Domain-Containing 3 Protein/metabolismABSTRACT
Stolon is an important organ for reproduction and regeneration of Amana edulis. Previous analysis of transcriptome showed that MYB was one of the most active transcription factor families during the development of A. edulis stolon. In order to study the possible role of MYB transcription factors in stolon development, the authors screened out an up-regulated MYB gene named AeMYB4 was by analyzing the expression profile of MYB transcription factors. In the present study, sequence analysis demonstrated that AeMYB4 contained an open reading frame of 756 bp encoding 251 amino acids, and domain analysis revealed that the predicted amino acids sequence contained two highly conserved SANT domains and binding sites for cold stress factor CBF. By multiple sequence alignment and phylogenetic analysis, it is indicated that AeMYB4 clustered with AtMYB15 from Arabidopsis thaliana, belonging to subgroup S2 of R2 R3-MYB. And most of the transcription factors in this subfamily are related to low temperature stress. The GFP-AeMYB4 fusion protein expression vector for subcellular localization was constructed and transferred into Agrobacterium tumefaciens to infect the leaves of Nicotiana benthamiana, and the results showed the protein was located in the nucleus. To investigate the transcriptional activation, the constructed pGBKT7-AeMYB4 fusion expression vector was transferred into Y2 H Gold yeast cells, which proved that AeMYB4 was a transcription activator with strong transcriptional activity. Real-time quantitative PCR was used to detect the expression of AeMYB4 gene in three different development stages of stolon and in leaves, flowers, and bulbs of A. edulis, which indicated that AeMYB4 transcription factor was tissue-specific in expression, mainly in the stolon development stage, and that the expression was the most active in the middle stage of stolon development, suggesting that AeMYB4 gene may play an important role in stolon development. This study contributes to the further research on the function of AeMYB4 transcription factor in stolon development of A. edulis.
Subject(s)
Arabidopsis , Plant Proteins , Amino Acid Sequence , Arabidopsis/genetics , Arabidopsis/metabolism , Cloning, Molecular , Gene Expression Regulation, Plant , Humans , Phylogeny , Plant Proteins/genetics , Plant Proteins/metabolismABSTRACT
Amana edulis is a traditional Chinese medicinal plant with low propagation coefficient. In recent years, the increasing demands of A. edulis lead to a shortage of its wild resources. In order to analyze the expression of related functional genes in A. edulis, the selection of suitable internal reference genes is crucial to improve the accuracy of experimental results. Eight genes(ACT, TUA, CYP, GAPDH, UBQ, UBI, EF1a, UBC)were chosen as candidate reference genes based on the RNA-Seq. Real-time fluorescence quantitative technique was used to detect the expression level of candidate internal reference genes in different organs(bulb, leaf, flo-wer) and stolons at different development stages of A. edulis. Then GeNorm, NormFinder, BestKeeper softwares and RefFinder website were used for a comprehensive analysis of the expression stability of the candidate genes.The results showed that among the 8 candidate reference genes, the variation range of Ct value of UBC was the smallest, and the expression level was stable, which was suitable for an reference gene. GeNorm and NormFinder software analysis showed that UBC and UBI were the optimal reference genes. BestKeeper analysis showed that CYP and UBC expression were relatively stable. Comprehensive evaluation of RefFinder website showed that UBC and UBI were the most stable genes, and ACT displayed the lowest stability in all software evaluation, indicating UBC and UBI were suitable for reference genes. Additionally, the most stable UBC, UBI and the most unstable ACT were used as internal reference genes to detect the expression of GBSS gene in A. edulis, and expression pattern of GBSS gene was the same under the calibration of UBC and UBI. The expression data of GBSS gene confirmed that UBC and UBI genes were reliable for A. edulis qRT-PCR as internal reference genes. The results would benefit future studies on related gene expression of A. edulis.
Subject(s)
Gene Expression Regulation, Plant , Genes, Plant , Gene Expression Profiling , Genes, Plant/genetics , Real-Time Polymerase Chain Reaction , Reference StandardsABSTRACT
Helicobacter pylori is an important risk factor for gastric ulcers. However, antibacterial therapies increase the resistance rate and decrease the eradication rate of H. pylori Inspired by the microaerophilic characteristics of H. pylori, we aimed at effectively establishing an oxygen-enriched environment to eradicate and prevent the recurrence of H. pylori The effect and the mechanism of an oxygen-enriched environment in eradicating H. pylori and preventing the recurrence were explored in vitro and in vivo During oral administration and after drug withdrawal, H. pylori counts were evaluated by Giemsa staining in animal cohorts. An oxygen-enriched environment in which H. pylori could not survive was successfully established by adding hydrogen peroxide into several solutions and rabbit gastric juice. Hydrogen peroxide effectively killed H. pylori in Columbia blood agar and special peptone broth. Minimum inhibition concentrations and minimum bactericidal concentrations of hydrogen peroxide were both relatively stable after promotion of resistance for 30 generations, indicating that hydrogen peroxide did not easily promote resistance in H. pylori In models of Mongolian gerbils and Kunming mice, hydrogen peroxide has been shown to significantly eradicate and effectively prevent the recurrence of H. pylori without toxicity and damage to the gastric mucosa. The mechanism of hydrogen peroxide causing H. pylori death was related to the disruption of bacterial cell membranes. The oxygen-enriched environment achieved by hydrogen peroxide eradicates and prevents the recurrence of H. pylori by damaging bacterial cell membranes. Hydrogen peroxide thus provides an attractive candidate for anti-H. pylori treatment.
Subject(s)
Anti-Bacterial Agents/pharmacology , Helicobacter Infections/drug therapy , Helicobacter pylori/drug effects , Hydrogen Peroxide/pharmacology , Oxygen/pharmacology , Animals , Anti-Ulcer Agents/pharmacology , Cell Membrane/drug effects , Drug Resistance, Bacterial/physiology , Female , Gastric Mucosa/drug effects , Gerbillinae , Male , Mice , Microbial Sensitivity Tests , Rabbits , Stomach Ulcer/microbiology , Stomach Ulcer/prevention & controlABSTRACT
Uncoupled endothelial nitric oxide synthase (eNOS) produces O2- instead of nitric oxide (NO). Earlier, we reported rapamycin, an autophagy inducer and inhibitor of cellular proliferation, attenuated low shear stress (SS) induced O2- production. Nevertheless, it is unclear whether autophagy plays a critical role in the regulation of eNOS uncoupling. Therefore, this study aimed to investigate the modulation of autophagy on eNOS uncoupling induced by low SS exposure. We found that low SS induced endothelial O2- burst, which was accompanied by reduced NO release. Furthermore, inhibition of eNOS by L-NAME conspicuously attenuated low SS-induced O2- releasing, indicating eNOS uncoupling. Autophagy markers such as LC3 II/I ratio, amount of Beclin1, as well as ULK1/Atg1 were increased during low SS exposure, whereas autophagic degradation of p62/SQSTM1 was markedly reduced, implying impaired autophagic flux. Interestingly, low SS-induced NO reduction could be reversed by rapamycin, WYE-354 or ATG5 overexpression vector via restoration of autophagic flux, but not by N-acetylcysteine or apocynin. eNOS uncoupling might be ascribed to autophagic flux blockade because phosphorylation of eNOS Thr495 by low SS or PMA stimulation was also regulated by autophagy. In contrast, eNOS acetylation was not found to be regulated by low SS and autophagy. Notably, although low SS had no influence on eNOS Ser1177 phosphorylation, whereas boosted eNOS Ser1177 phosphorylation by rapamycin were in favor of the eNOS recoupling through restoration of autophagic flux. Taken together, we reported a novel mechanism for regulation of eNOS uncoupling by low SS via autophagy-mediated eNOS phosphorylation, which is implicated in geometrical nature of atherogenesis.
Subject(s)
Atherosclerosis/genetics , Autophagy/genetics , Nitric Oxide Synthase Type III/genetics , Stress, Mechanical , Animals , Autophagy/drug effects , Cell Proliferation/drug effects , Cell Proliferation/genetics , Endothelial Cells/metabolism , Humans , NG-Nitroarginine Methyl Ester/pharmacology , Nitric Oxide/biosynthesis , Nitric Oxide/chemistry , Nitric Oxide Synthase Type III/chemistry , Oxygen/metabolism , Phosphorylation , Signal TransductionABSTRACT
We designed a series of novel phenothiazine-1,2,3-triazole hybrids by the molecular hybridization strategy and evaluated their antiproliferative activity against three cancer cell lines (MDA-MB-231, MDA-MB-468 and MCF-7). For the structure-activity relationships, the importance of 1,2,3-triazole and substituents on phenyl ring was explored. Among these phenothiazine-1,2,3-triazole hybrids, compound 9f showed the most potent inhibitory effect against MCF-7 cells, with an IC50 value of 0.8 µM. Importantly, compound 9f could induce apoptosis against MCF-7 cells by regulating apoptosis-related proteins (Bcl-2, Bax, Bad, Parp, and DR5). These potent phenothiazine-1,2,3-triazole hybrids as novel apoptosis inducers might be used as antitumor agents in the future.
Subject(s)
Antineoplastic Agents/chemical synthesis , Apoptosis Regulatory Proteins/genetics , Breast Neoplasms/genetics , Phenothiazines/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Breast Neoplasms/drug therapy , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Female , Gene Expression Regulation, Neoplastic/drug effects , Humans , MCF-7 Cells , Molecular Structure , Phenothiazines/chemistry , Phenothiazines/pharmacology , Structure-Activity RelationshipABSTRACT
In this paper, carboxyl groups were introduced by liquid oxidation methods onto multi-walled carbon nanotubes (MWCNTs) to improve the MWCNTs' electrocatalytic properties. A platinum wire microelectrode (ME) was corroded using aqua regia and subsequently embedded with MWCNTs to achieve more active sites, producing a so-called powder microelectrode (PME). Compared with conventional MEs, the PME has a larger specific surface area and more active sites. When PME was used to detect ascorbic acid (AA), the AA oxidation potential shifted negatively and current peak was visibly increased. The calibration curve obtained for AA was in a range of 5.00 × 10-6~9.50 × 10-4 mol·L-1: Ipa(µA) = 3.259 × 10-2+ 1.801 × 10² C (mol·L-1) under the optimum testing conditions. Moreover, the detection and quantitation limits were confirmed at 4.89 × 10-7 mol·L-1 and 1.63 × 10-7 mol·L-1, respectively. When the fabricated PME was practically applied to detect AA, it was shown a recovery rate of 94~107% with relative standard deviation (RSD) <5%. The proposed strategy thus offers a promising, rapid, selective and low-cost approach to effective analysis of AA.
ABSTRACT
Amyloid-ß peptides (Aß) exist in several forms and are known as key modulators of Alzheimer's disease (AD). Fibrillary Aß (fAß) has been found to disrupt the blood-brain barrier (BBB) by triggering and promoting inflammation. In this study, luteolin, a naturally occurring flavonoid that has shown beneficial properties in the central nervous system, was evaluated as a potential agent to preserve barrier function and inhibit inflammatory responses at the BBB that was injured by fAß1-40. We established an in vitro BBB model by co-culturing human brain microvascular endothelial cells (hBMECs) and human astrocytes (hAs) under fAß1-40-damaged conditions and investigated the effect of luteolin by analyzing cellular toxicity, barrier function, cytokine production and inflammation-related intracellular signaling pathways. Our results demonstrated that, in cells injured by fAß1-40, luteolin increased cell viability of hBMECs and hAs. The cytoprotection of the co-culture against the damage induced by fAß1-40 was also increased at both the apical and basolateral sides. Luteolin protected the barrier function by preserving transendothelial electrical resistance and relieving aggravated permeability in the human BBB model after being exposed to fAß1-40. Moreover, in both the apical and basolateral sides of the co-culture, luteolin reduced fAß1-40-induced inflammatory mediator and cytokine production, including cyclooxygenase-2 (COX-2), tumor necrosis factor α (TNF-α), interleukin 1 ß (IL-1ß), interleukin 6 (IL-6), and interleukin 8 (IL-8), however it did not show sufficient effects on scavenging intracellular reactive oxygen species (ROS) in hBMECs and hAs. The mechanism of BBB protection against fAß1-40-induced injury may be related to the regulation of inflammatory signal transduction, which involves inhibition of p38 mitogen-activated protein kinase (MAPK) activation, downregulation of phosphorylated inhibitory κB kinase (phosphor-IKK) levels, relief of inhibitory κB α (IκBα) degradation, blockage of nuclear factor κB (NF-κB) p65 nuclear translocation, and reduction of the release of inflammatory cytokines. Moreover, the employment of p38 MAPK and NF-κB inhibitors reversed luteolin-mediated barrier function and cytokine release. Taken together, luteolin may serve as a potential therapeutic agent for BBB protection by inhibiting inflammation following fAß1-40-induced injury.
Subject(s)
Amyloid beta-Peptides/adverse effects , Blood-Brain Barrier/drug effects , Luteolin/pharmacology , MAP Kinase Signaling System/drug effects , NF-kappa B/metabolism , Neuroprotective Agents/pharmacology , Peptide Fragments/adverse effects , Apoptosis/drug effects , Astrocytes/cytology , Astrocytes/drug effects , Astrocytes/immunology , Blood-Brain Barrier/immunology , Brain/blood supply , Brain/cytology , Brain/immunology , Cell Survival , Cells, Cultured , Coculture Techniques , Cytokines/metabolism , Endothelial Cells/drug effects , Endothelial Cells/immunology , Gene Expression Regulation/drug effects , Humans , Models, BiologicalABSTRACT
UNLABELLED: OCTOBER: To explore the effects of the glucagon-like peptide 1 (GLP-1) liraglutide on the penile erectile function of rats with diabetic erectile dysfunction (DED) by observing the impact of liraglutide on the expression of eNOS in the corpus cavernosum of diabetic rats. METHODS: We randomly divided 30 six-week-old male SD rats into a normal control (n = 10) and an experimental group (n = 20) , established models of diabetes mellitus (DM) in the experimental rats, and subdivided them into a DM (n = 8) and a GLP-1 group (n = 8) to receive intramuscular injection of normal saline and liraglutide at 5 mg per kg of the body weight per day, respectively. After 12 weeks of intervention, we obtained the levels of FPG, FINS, TG, TC, HDL-C, LDL-C, testosterone, and IL-6 and the indexes of Homa-IR and Homa-ß, detected the expressions of Akt/p-Akt and eNOS/p-eNOS in the corpus cavernosum by Western blot, and compared the erectile function between different groups. RESULTS: The frequency and rate of penile erection were significantly lower in the DM group than in the GLP-1 and normal control groups (P < 0.05) and also lower in the GLP-1 group than in the normal controls (P < 0.05). Immunofluorescence staining showed the expression of eNOS mainly in the cytoplasm of the cavernosal vessels and sinusoidal endothelial cells, markedly lower in the DM and GLP-1 groups than in the normal rats (P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05). The level of eNOS/p-eNOS in the penile tissue was significantly decreased in the DM and GLP-1 groups in comparison with the normal controls (P < 0.01 or P < 0.05), while that of p-eNOS was markedly increased in the GLP-1 group as compared with the DM group (P < 0.05). No statistically significant differences were observed in the Akt level among the three groups of animals (P > 0.05). The expression of p-Akt was remarkably reduced in the DM and GLP-1 groups in comparison with the control rats (P < 0.01 or P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05). CONCLUSION: GLP-1 can protect the function of endothelial cells in the corpus cavernosum and improve the erectile function of DED rats by regulating the Akt/ eNOS signaling pathway, which indicates that GLP-1 could be an important option for the treatment and prevention of DED.
Subject(s)
Hypoglycemic Agents/pharmacology , Liraglutide/pharmacology , Nitric Oxide Synthase Type III/metabolism , Penile Erection/drug effects , Penis/drug effects , Animals , Blotting, Western , Diabetes Mellitus, Experimental , Erectile Dysfunction/drug therapy , Erectile Dysfunction/enzymology , Male , Penis/enzymology , Penis/physiopathology , Random Allocation , Rats , Rats, Sprague-Dawley , Testosterone/bloodABSTRACT
MicroRNAs (miRNAs) are single-stranded, 18- to 23-nt RNA molecules that function as regulators of gene expression. Previous studies have shown that microRNAs play important roles in human cancers, including gliomas. Here, we found that expression levels of miR-181b were decreased in gliomas, and we identified IGF-1R as a novel direct target of miR-181b. MiR-181b overexpression inhibited cell proliferation, migration, invasion, and tumorigenesis by targeting IGF-1R and its downstream signaling pathways, PI3K/AKT and MAPK/ERK1/2. Overexpression of IGF-1R rescued the inhibitory effects of miR-181b. In clinical specimens, IGF-1R was overexpressed, and its protein levels were inversely correlated with miR-181b expression. Taken together, our results indicate that miR-181b functions in gliomas to suppress growth by targeting the IGF-1R oncogene and that miR-181b may serve as a novel therapeutic target for gliomas.
Subject(s)
Cell Proliferation , Cell Transformation, Neoplastic , Glioma/metabolism , Glioma/pathology , MicroRNAs/metabolism , Receptor, IGF Type 1/metabolism , Angiogenesis Inhibitors/metabolism , Animals , Cell Movement , Genes, Tumor Suppressor , Humans , Male , Mice , Mice, Nude , MicroRNAs/genetics , Signal TransductionABSTRACT
Fenofibrate, a fibric acid derivative, is known to possess lipid-lowering effects. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcriptional activity has been reported to exhibit anticancer effects, the underlying mechanisms are poorly understood. In this study, we investigated the mechanisms behind the antiproliferative effects of fenofibrate in U87MG cells (human glioma cell line) using the WST-8 Cell Proliferation Assay Kit. Furthermore, we examined genome-wide gene expression profiles and molecular networks using the DAVID online software. Fenofibrate reduced the expression of 405 genes and increased the expression of 2280 genes. DAVID analysis suggested that fenofibrate significantly affected cell cycle progression and pathways involved in cancer, including the mTOR signaling pathway and insulin signaling pathway. Results of flow cytometry analysis indicated that fenofibrate induced cell cycle G0/G1 arrest in U87MG cells. Furthermore, we identified the FoxO1-p27(kip) signaling axis to be involved in fenofibrate-induced cell cycle arrest. Our findings suggest that in addition to its known lipid-lowering effects, fenofibrate may be used as an antitumor agent in glioma therapy.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Fenofibrate/administration & dosage , Forkhead Transcription Factors/biosynthesis , Glioblastoma/drug therapy , PPAR alpha/biosynthesis , Cell Cycle Checkpoints/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Forkhead Box Protein O1 , Gene Expression Regulation, Neoplastic/drug effects , Genome, Human , Glioblastoma/genetics , Glioblastoma/pathology , Humans , Neoplasm Proteins/biosynthesis , Signal Transduction/drug effects , TOR Serine-Threonine Kinases/biosynthesisABSTRACT
The dysregulation of miR-1224-5p has been reported in several human cancers. However, the expression and function of miR-1224-5p in glioma remains unknown. The aim of our study was to investigate the effect of miR-1224-5p on glioma cells and to determine its functional signaling mediators. Using 198 glioma samples within the Chinese Glioma Genome Atlas expression dataset, we demonstrated that miR-1224-5p expression is decreased in high-grade gliomas when compared with low-grade gliomas. Differential miR-1224-5p expression in 50 randomly selected samples was verified by in situ hybridization. The expression of miR-1224-5p was shown to positively correlate with overall survival in 82 glioblastoma patients. Exogenous expression of miR-1224-5p in glioma cells suppressed proliferation and invasion and promoted apoptosis. Target prediction algorithms identified a consensus miR-1224-5p recognition site in the 3'UTR of the cAMP response element-binding protein (CREB1) gene, and this sequence was shown to directly confer miR-1224-5p repression in luciferase reporter assays. Furthermore, exogenous miR-1224-5p expression was shown to down-regulate CREB1, as well as its downstream target genes matrix metalloproteinase-9 and B-cell lymphoma-2. Conversely, over-expression of CREB1 reversed the effect of miR-1224-5p on the proliferation, invasion, and apoptosis of glioma cells. These data indicate that miR-1224-5p may inhibit tumor-associated activity in malignant gliomas by targeting CREB1.
Subject(s)
Brain Neoplasms/genetics , Cyclic AMP Response Element-Binding Protein/metabolism , Genes, Tumor Suppressor , Glioma/genetics , MicroRNAs/metabolism , Apoptosis , Base Sequence , Brain Neoplasms/pathology , Cell Line, Tumor , Cell Proliferation , Down-Regulation/genetics , Gene Expression Regulation, Neoplastic , Glioma/pathology , Humans , MicroRNAs/genetics , Molecular Sequence Data , Neoplasm Invasiveness , Prognosis , Survival AnalysisABSTRACT
BACKGROUND: Epidermal growth factor receptor (EGFR) is amplified in 40% of human glioblastomas. However, most glioblastoma patients respond poorly to anti-EGFR therapy. MicroRNAs can function as either oncogenes or tumor suppressor genes, and have been shown to play an important role in cancer cell proliferation, invasion and apoptosis. Whether microRNAs can impact the therapeutic effects of EGFR inhibitors in glioblastoma is unknown. METHODS: miR-566 expression levels were detected in glioma cell lines, using real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays and Western blots were used to validate VHL as a direct target gene of miR-566. Cell proliferation, invasion, cell cycle distribution and apoptosis were also examined to confirm whether miR-566 inhibition could sensitize anti-EGFR therapy. RESULTS: In this study, we demonstrated that miR-566 is up-regulated in human glioma cell lines and inhibition of miR-566 decreased the activity of the EGFR pathway. Lentiviral mediated inhibition of miR-566 in glioblastoma cell lines significantly inhibited cell proliferation and invasion and led to cell cycle arrest in the G0/G1 phase. In addition, we identified von Hippel-Lindau (VHL) as a novel functional target of miR-566. VHL regulates the formation of the ß-catenin/hypoxia-inducible factors-1α complex under miR-566 regulation. CONCLUSIONS: miR-566 activated EGFR signaling and its inhibition sensitized glioblastoma cells to anti-EGFR therapy.
Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , ErbB Receptors/genetics , Glioblastoma/genetics , MicroRNAs/genetics , Signal Transduction , Animals , Blotting, Western , Cell Line, Tumor , ErbB Receptors/metabolism , Fluorescent Antibody Technique , Glioblastoma/metabolism , Heterografts , Humans , Immunoblotting , Immunoprecipitation , Mice , Mice, Nude , Real-Time Polymerase Chain Reaction , Signal Transduction/genetics , Transfection , Von Hippel-Lindau Tumor Suppressor Protein/geneticsABSTRACT
BACKGROUND: Evidences concerning the predictive value of baseline inflammatory biomarkers after drug-eluting stent (DES) placement are controversial, mainly because the use of statin was not precisely defined. OBJECTIVES: The aim was to compare the differences between interleukin (IL)-6 and high-sensitivity C-reactive protein (hs-CRP) in predicting cardiovascular events 2 years after stenting in patients with unstable angina (UA) who had not received statin pretreatment. METHODS: There were 1,896 patients included in this study. The primary end-point was the occurrence of cardiac death or myocardial infarction (MI). Secondary endpoints included all-cause death, stent thrombosis (ST), target lesion revascularization (TLR), target vessel revascularization (TVR), or a composite of major adverse cardiac events (MACE) at 2 years after the procedure. RESULTS: During the median follow-up of 2.77 years, 96 patients experienced cardiac death (n = 37, 1.95%) or MIs (n = 70, 3.69%), 94 TLRs, 123 TVRs, 215 MACEs, and 21 definite or probable STs. In multivariable Cox proportional-hazards models and discrimination analysis, elevated IL-6 levels were superior to hs-CRP in predicting the occurrence not only of cardiac death or MI (HR 1.337, 95% CI 1.234-1.449, P < 0.001), but also of MACE and late-occurring definite/probable ST. Incorporation of IL-6 into conventional variables resulted in significantly increased c statistic for the prediction of end-points, with the exception of TLR and TVR. CONCLUSION: Elevated IL-6 levels were independent predictors of cardiac death or MI, MACE, and late ST in patients with UA who had not received statin pretreatment, suggesting a role for IL-6 in the inflammatory risk assessment. Pathological studies have confirmed that atherosclerosis is a chronic inflammatory disease. Serum levels of high-sensitivity C-reactive protein (hs-CRP), matrix metalloproteinase, plasminogen activator inhibitor-1, the complement components C3a or C5a, and interleukin(IL)-6 were reported to provide strong and independent indications of the risk for future cardiovascular (CV) events, even among individuals who are thought to be free of vascular disease.
Subject(s)
Angina, Unstable/therapy , C-Reactive Protein/analysis , Cardiovascular Diseases/blood , Drug-Eluting Stents , Interleukin-6/blood , Aged , Death , Female , Forecasting , Humans , MaleABSTRACT
Systemic inflammation and reciprocal organ interactions are associated with the pathophysiology of heart failure with preserved ejection fraction (HFpEF). However, the clinical value, especially the diagnositc prediction power of inflammation and extra-cardiac organ dysfunction for HfpEF is not explored. In this cross-sectional study, 1808 hospitalized patients from January 2014 to June 2022 in ChiHFpEF cohort were totally enrolled according to inclusion and exclusion criteria. A diagnostic model with markers from routine blood test as well as liver and renal dysfunction for HFpEF was developed using data from ChiHFpEF-cohort by logistic regression and assessed by receiver operating characteristic curve (ROC) and Brier score. Then, the model was validated by the tenfold cross-validation and presented as nomogram and a web-based online risk calculator as well. Multivariate and LASSO regression analysis revealed that age, hemoglobin, neutrophil to lymphocyte ratio, AST/ALT ratio, creatinine, uric acid, atrial fibrillation, and pulmonary hypertension were associated with HFpEF. The predictive model exhibited reasonably accurate discrimination (ROC, 0.753, 95% CI 0.732-0.772) and calibration (Brier score was 0.200). Subsequent internal validation showed good discrimination and calibration (AUC = 0.750, Brier score was 0.202). In additoin to participating in pathophysiology of HFpEF, inflammation and multi-organ interactions have diagnostic prediction value for HFpEF. Screening and optimizing biomarkers of inflammation and multi-organ interactions stand for a new field to improve noninvasive diagnostic tool for HFpEF.
Subject(s)
Heart Failure , Humans , Heart Failure/diagnosis , Cross-Sectional Studies , Stroke Volume , Inflammation , LiverABSTRACT
We investigate phylogenetic relationships of the jumping spider subfamily Euophryinae, diverse in species and genera in both the Old World and New World. DNA sequence data of four gene regions (nuclear: 28S, Actin 5C; mitochondrial: 16S-ND1, COI) were collected from 263 jumping spider species. The molecular phylogeny obtained by Bayesian, likelihood and parsimony methods strongly supports the monophyly of a Euophryinae re-delimited to include 85 genera. Diolenius and its relatives are shown to be euophryines. Euophryines from different continental regions generally form separate clades on the phylogeny, with few cases of mixture. Known fossils of jumping spiders were used to calibrate a divergence time analysis, which suggests most divergences of euophryines were after the Eocene. Given the divergence times, several intercontinental dispersal events are required to explain the distribution of euophryines. Early transitions of continental distribution between the Old and New World may have been facilitated by the Antarctic land bridge, which euophryines may have been uniquely able to exploit because of their apparent cold tolerance. Two hot-spots of diversity of euophryines are discovered: New Guinea and the Caribbean Islands. Implications of the molecular phylogeny on the taxonomy of euophryines, and on the evolution of unusual genitalic forms and myrmecophagy, are also briefly discussed.
Subject(s)
Genetic Speciation , NADH Dehydrogenase/classification , Phylogeny , RNA, Ribosomal, 28S/classification , Spiders/classification , Actins/classification , Actins/genetics , Animals , Bayes Theorem , Biodiversity , Cytochromes b/classification , Cytochromes b/genetics , Fossils , NADH Dehydrogenase/genetics , Phylogeography , RNA, Ribosomal, 28S/genetics , Spiders/geneticsABSTRACT
BACKGROUND: Influenza is an acute respiratory infectious disease caused by the influenza virus, which poses a certain threat to humans due to its short incubation period, fast transmission and strong infectivity. OBJECTIVES: To evaluate the awareness and prevention behavior against influenza among healthcare workers on the eve of the coronavirus disease 2019 (COVID-19) epidemic in Beijing, China. MATERIAL AND METHODS: Using the cross-sectional research design based on the principle of convenience sampling, an online questionnaire survey on the knowledge of flu, vaccination, medical protection behavior, and flu medication was conducted between January and February 2020. Healthcare workers from different healthcare facilities and different job positions in Beijing participated in this survey. RESULTS: A total of 1910 healthcare workers from different medical institutions and jobs were included in the study. The mean age of the participants was 32.69 ±8.72 years (range: 18-64 years). There were significant differences in knowledge about clinical signs about flu and prevention approaches among different age groups, individuals with different work experience and job titles (χ2 = 8.903-32.839; p < 0.05). Personnel with different job positions and education levels differed only in the knowledge about clinical signs of flu and identification of high-risk populations. A multivariate logistic regression analysis revealed that age (odds ratio (OR) = 0.979, 95% confidence interval (95% CI): 0.966-0.992) and education level (OR = 0.736, 95% CI: 0.588-0.921) were risk factors for hand hygiene practices, whereas job position (OR = 1.757, 95% CI: 1.146-2.695) and awareness of high-risk populations (OR = 1.405, 95% CI: 1.096-1.800) were protective factors influencing hand hygiene practices (p < 0.05). The only factor influencing mask wearing was the education level (OR = 0.610, 95% CI: 0.450-0.828). CONCLUSION: The knowledge level and preventive behavior of healthcare workers before the outbreak of COVID-19 has been insufficient.
Subject(s)
COVID-19 , Influenza, Human , Humans , Adolescent , Young Adult , Adult , Middle Aged , Influenza, Human/epidemiology , Beijing , Cross-Sectional Studies , Seasons , Surveys and Questionnaires , Health PersonnelABSTRACT
Aims: We aim to examine the association of estimated pulse wave velocity (ePWV) with all-cause and cardiovascular mortality in patients with diabetes. Methods: All of adult participants with diabetes from the National Health and Nutrition Examination Survey (NHANES) (1999-2018) were enrolled. ePWV was calculated according to the previously published equation based on age and mean blood pressure. The mortality information was obtained from the National Death Index database. Weighted Kaplan-Meier (KM) plot and weighted multivariable Cox regression was used to investigate the association of ePWV with all-cause and cardiovascular mortality risks. Restricted cubic spline was adopted to visualize the relationship between ePWV and mortality risks. Results: 8,916 participants with diabetes were included in this study and the median follow-up duration was ten years. The mean age of study population was 59.0 ± 11.6 years, 51.3% of the participants were male, representing 27.4 million patients with diabetes in weighted analysis. The increment of ePWV was closely associated with increased risks of all-cause mortality (HR: 1.46, 95% CI: 1.42-1.51) and cardiovascular mortality (HR: 1.59, 95% CI: 1.50-1.68). After adjusting for cofounding factors, for every 1â m/s increase in ePWV, there was a 43% increased risk of all-cause mortality (HR: 1.43, 95% CI: 1.38-1.47) and 58% increased of cardiovascular mortality (HR: 1.58, 95% CI: 1.50-1.68). ePWV had positive linear associations with all-cause and cardiovascular mortality. KM plots also showed that the risks of all-cause and cardiovascular mortality were significantly elevated in patients with higher ePWV. Conclusions: ePWV had a close association with all-cause and cardiovascular mortality risks in patients with diabetes.
ABSTRACT
Gossypin is a flavone that was originally isolated from Hibiscus vitifolius and has traditionally been used for the treatment of diabetes, jaundice, and inflammation. Recently, gossypin was found to have potent anticancer properties; however, its effect on human gliomas still remain unknown. To investigate the potential anticancer effects of gossypin on malignant gliomas and analyze the associated molecular mechanisms, we treated human glioma U251 cells with gossypin. Our study showed that the treatment of U251 cells with gossypin inhibited cell proliferation in a dose- and time-dependent manner and was observed to be minimally toxic to normal human astrocytes. Gossypin's effect on cell cycle distribution was observed, and we found that it induced G2/M-phase arrest in U251 cells. An analysis of cell-cycle regulatory proteins indicated that the arresting effect of gossypin on the cell cycle at G2/M phase was involved in the phosphorylation of cell division cycle 25C (Cdc25C) tyrosine phosphatase via the activation of checkpoint kinase 1 (Chk1). These findings indicate that gossypin is a potential treatment of gliomas because of gossypin's potential to regulate the proliferation of U251 cells via the cell-cycle regulatory proteins Chk1 and Cdc25C.