ABSTRACT
Daptomycin is gaining prominence for the treatment of methicillin-resistant Staphylococcus aureus infections. However, the dosage selection for daptomycin in critically ill patients remains uncertain, especially in Chinese patients. This study aimed to establish the population pharmacokinetics of daptomycin in critically ill patients, optimize clinical administration plans, and recommend appropriate dosage for critically ill patients in China. The study included 64 critically ill patients. Blood samples were collected at the designated times. The blood daptomycin concentration was determined using validated liquid chromatography-tandem mass spectrometry. A nonlinear mixed-effects model was applied for the population pharmacokinetic analysis and Monte Carlo simulations of daptomycin. The results showed a two-compartment population pharmacokinetic model of daptomycin in critically ill adult Han Chinese patients. Monte Carlo simulations revealed that a daily dose of 400 mg of daptomycin was insufficient for the majority of critically ill adult patients to achieve the anti-infective target. For critically ill adult patients with normal renal function (creatinine clearance rate >90 mL/min), the probability of achieving the target only reached 90% when the daily dose was increased to 700 mg. For patients undergoing continuous renal replacement therapy (CRRT), 24 h administration of 500 mg met the pharmacodynamic goals and did not exceed the safety threshold in most patients. Therefore, considering its efficacy and safety, intravenous daptomycin doses are best scaled according to creatinine clearance, and an increased dose is recommended for critically ill patients with hyperrenalism. For patients receiving CRRT, medication is recommended at 24 h intervals.
ABSTRACT
After ischemic stroke, microRNAs (miRNAs) participate in various processes, including immune responses, inflammation, and angiogenesis. Diabetes is a key factor increasing the risk of ischemic stroke; however, the regulatory pattern of miRNAs at different stages of diabetic stroke remains unclear. This study comprehensively analyzed the miRNA expression profiles in diabetic mice at 1, 3, and 7 days post-reperfusion following the middle cerebral artery occlusion (MCAO). We identified differentially expressed (DE) miRNAs in diabetic stroke and found significant dysregulation of some novel miRNAs (novel_mir310, novel_mir89, and novel_mir396) post-stroke. These DEmiRNAs were involved in apoptosis and the formation of tight junctions. Finally, we identified three groups of time-dependent DE miRNAs (miR-6240, miR-135b-3p, and miR-672-5p). These have the potential to serve as biomarkers of diabetic stroke. These findings provide a new perspective for future research, emphasizing the dynamic changes in miRNA expression after diabetic stroke and offering potential candidates as biomarkers for future clinical applications.
Subject(s)
Diabetes Mellitus, Experimental , Ischemic Stroke , MicroRNAs , Stroke , Animals , Mice , Diabetes Mellitus, Experimental/genetics , Gene Expression Regulation, Plant , MicroRNAs/genetics , Plants, Genetically Modified , Stroke/genetics , BiomarkersABSTRACT
Atherosclerosis is initiated by vascular endothelial dysfunction, and low-shear stress (LSS) of blood flow is a key factor leading to endothelial dysfunction. Growing evidence suggests that endothelial cell pyroptosis plays an important role in the development of atherosclerosis. Studies have shown that low-shear stress can induce endothelial cell pyroptosis, but the exact mechanism remains unclear. Our experiments demonstrated that low-shear stress induced endothelial cell pyroptosis and the phosphorylation of IκB kinase ε (IKKε). IKKε knockdown not only significantly attenuated atherosclerosis lesions of aortic arch areas in ApoE-/- mice fed with high cholesterol diets, but also markedly reduced endothelial cell pyroptosis and NLRP3 expression triggered by low-shear stress. Further mechanism studies showed that IKKε promoted the expression of NLRP3 via activating signal transducer and activator of transcription 1 (STAT1) and the subsequent binding of STAT1 to NLRP3 promoter region. These results suggest that low-shear stress plays a pro-atherosclerotic role by promoting endothelial cell pyroptosis through the IKKε/STAT1/NLRP3 pathway, which provides new insights into the formation of atherosclerosis.
Subject(s)
Atherosclerosis , Endothelial Cells , I-kappa B Kinase , NLR Family, Pyrin Domain-Containing 3 Protein , Pyroptosis , STAT1 Transcription Factor , Stress, Mechanical , Pyroptosis/physiology , Atherosclerosis/metabolism , Atherosclerosis/pathology , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Animals , Mice , I-kappa B Kinase/metabolism , STAT1 Transcription Factor/metabolism , Endothelial Cells/metabolism , Humans , Signal Transduction/physiology , Mice, Inbred C57BL , Human Umbilical Vein Endothelial Cells/metabolismABSTRACT
Before menopause, females exhibit a lower incidence of cardiovascular disease than age-matched males, possibly owing to the protective effects of sex hormones. 17ß-estradiol (17ß-E2) protects against oxidative stress-induced injury by suppressing thrombospondin-1 (THBS1) expression in endothelial cells. Here, we examined the role of 17ß-E2-mediated THBS1 suppression in preventing cell senescence and apoptosis. Human umbilical vein endothelial cells (HUVECs) were cultivated and treated with siRNA or overexpression plasmids to regulate THBS1. H2O2, estrogen-activity modulating drugs, and LY2109761 (a TGF-ß kinase inhibitor) treatments were applied. THBS1 knockdown repressed, and its overexpression aggravated, H2O2-induced cell injury, affecting cell death, proliferation, senescence, and apoptosis. 17ß-E2 inhibited THBS1 mRNA and protein expression time- and dose-dependently, by targeting ERß. THBS1 overexpression blocked 17ß-E2 from preventing H2O2-induced injury, significantly activating the TGF-ß/Smad pathway. 17ß-E2 inhibited H2O2-induced oxidative stress by downregulating THBS1 expression and TGF-ß/Smad signaling in HUVECs. The THBS1/TGF-ß/Smad axis could thus be a therapeutic target.
Subject(s)
Hydrogen Peroxide , Transforming Growth Factor beta , Female , Humans , Human Umbilical Vein Endothelial Cells , Hydrogen Peroxide/toxicity , Hydrogen Peroxide/metabolism , Transforming Growth Factor beta/metabolism , Estradiol/pharmacology , Estradiol/metabolism , Estrogens/metabolism , ApoptosisABSTRACT
Most BTB-containing E3 ligases homodimerize to recognize a single substrate by engaging multiple degrons, represented by E3 ligase KEAP1 dimer and its substrate NRF2. Inactivating KEAP1 to hinder ubiquitination-dependent NRF2 degradation activates NRF2. While various KEAP1 inhibitors have been reported, all reported inhibitors bind to KEAP1 in a monovalent fashion and activate NRF2 in a lagging manner. Herein, we report a unique bivalent KEAP1 inhibitor, biKEAP1 (3), that engages cellular KEAP1 dimer to directly release sequestered NRF2 protein, leading to an instant NRF2 activation. 3 promotes the nuclear translocation of NRF2, directly suppressing proinflammatory cytokine transcription. Data from in vivo experiments showed that 3, with unprecedented potency, reduced acute inflammatory burden in several acute inflammation models in a timely manner. Our findings demonstrate that the bivalent KEAP1 inhibitor can directly enable sequestered substrate NRF2 to suppress inflammatory transcription response and dampen various acute inflammation injuries.
Subject(s)
Inflammation , Kelch-Like ECH-Associated Protein 1 , NF-E2-Related Factor 2 , NF-E2-Related Factor 2/metabolism , NF-E2-Related Factor 2/antagonists & inhibitors , Kelch-Like ECH-Associated Protein 1/metabolism , Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , Humans , Animals , Inflammation/drug therapy , Inflammation/metabolism , Mice , Mice, Inbred C57BL , Ubiquitin-Protein Ligases/metabolism , Ubiquitin-Protein Ligases/antagonists & inhibitors , MaleABSTRACT
Diabetes is a risk factor for stroke; however, its impact on stroke progression at the genomic level is not well understood. To address this gap, we used transcriptome sequencing to explore the relationship between lncRNA and mRNA expression patterns and the reperfusion duration in the cortex of diabetically induced stroke mice. First, focal ischemia was induced in adult male ob/ob mice, which were then subjected to reperfusion periods of one, three, or seven days. Total RNA was extracted from the ischemic cortical tissue for RNA sequencing, and the resulting reads were aligned to the GRCm38 murine reference genome. A total of 672 mRNAs and 301 lncRNAs were identified as differentially expressed one day post-stroke, 1195 mRNAs and 66 lncRNAs at three days post-stroke, and 1069 mRNAs and 75 lncRNAs at seven days post-stroke. Stage-specific differentially expressed mRNAs were bioinformatically analyzed and found significantly enriched in processes such as apoptosis, angiogenesis, and lipid metabolism at one, three, and seven days post-stroke, respectively. Stage-specific DElncRNA-mRNA cis-regulatory relationships were constructed using these biological processes as examples, revealing the potential roles of four pairs of lncRNA-mRNAs (Gm39787-Lcn2, Gm46111-Drd2, D3300500i16Rik-Fosl1, and Gm41689-Egr1) in apoptosis. Additionally, Gm40237-Tie1 and Gm52352-Pdgfrb are associated with angiogenesis and lipid metabolism, respectively. In conclusion, our study demonstrated that lncRNA and mRNA expression in the cortex of transient focal ischemia-induced diabetic mice undergo extensive alterations, providing insights into complex molecular interactions underlying diabetic stroke.
Subject(s)
Brain Ischemia , Diabetes Mellitus, Experimental , MicroRNAs , RNA, Long Noncoding , Stroke , Male , Mice , Animals , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism , Diabetes Mellitus, Experimental/genetics , Brain Ischemia/genetics , Stroke/genetics , Cerebral Infarction , Gene Expression , RNA, Messenger/metabolism , Gene Regulatory Networks , MicroRNAs/metabolismABSTRACT
According to the World Health Organization, cardiovascular diseases are the leading cause of deaths globally. Electrocardiogram (ECG) is a non-invasive approach for detecting heart diseases and reducing the risk of heart disease-related death. However, there are limited numbers of ECG samples and imbalance distribution for existing ECG databases. It is difficult to train practical and efficient neural networks. Based on the analysis and research of many existing ECG databases, this paper conduct an in-depth study on three fine-labeled ECG databases, to extract heartbeats, unify the sampling frequency, and propose a self-processing method of heartbeats, and finally form a unified ECG arrhythmia classification database, noted as Hercules-3. It is separated into training sets (80%) and testing sets (the remaining 20%). In order to verify its capabilities, we have trained a 16-classification fully connected neural network based on Hercules-3 and it achieves an accuracy rate of up to 98.67%. Compared with other data processing, our proposed method improves classification recall by at least 6%, classification accuracy by at least 4%, and F1-score by at least 7%.
Subject(s)
Cardiovascular Diseases , Heart Diseases , Humans , Arrhythmias, Cardiac/diagnosis , Databases, Factual , ElectrocardiographyABSTRACT
Meat safety and quality are the main concerns of consumers in the present food market. Chitosan-gelatin edible coatings containing nano-encapsulated clove ethanol extracts (CNPs), designated as CHI-GEL-CNPs, on the quality preservation of chilled pork were studied. Results showed that the mean particle diameters of CNPs were 346.15 ± 37.30 nm. Nano-modification improved the antibacterial activity of free clove ethanol extract. The increasing rate order of TVB-N and TBARS was CHI-GEL-CNPs < CHI-GEL-Clove < CHI-GEL < CHI < CON group. The CHI-GEL-CNPs coating inhibited the elevation of pH and total viable count (TVC) of chilled pork. The TVB-N and TVC values demonstrated that the CHI-GEL-CNPs coating effectively extended the shelf life of chilled pork up to 13 days. In addition, the sensory properties of CHI-GEL-CNPs chilled pork loins were superior to that of control samples. Therefore, the developed CHI-GEL-CNPs coatings have great promise as a nanocomposite for meat preservation.
Subject(s)
Chitosan , Edible Films , Pork Meat , Red Meat , Syzygium , Animals , Swine , Food Preservation/methods , Food Storage/methods , Chitosan/chemistry , Gelatin , EthanolABSTRACT
The loss of cardiomyocytes (CMs) after myocardial infarction (MI) is widely acknowledged to initiate the development of heart failure (HF). Herein, we found that circCDYL2 (583 nt) derived from chromodomain Y-like 2 (Cdyl2) is significantly upregulated in vitro (oxygen-glucose deprivation (OGD)-treated CMs) and in vivo (failing heart post-MI) and can be translated into a polypeptide termed Cdyl2-60aa (~7 kDa) in the presence of internal ribosomal entry sites (IRES). Downregulation of circCDYL2 significantly decreased the loss of OGD-treated CMs or the infarcted area of the heart post-MI. Additionally, elevated circCDYL2 significantly accelerated CM apoptosis via Cdyl2-60aa. We then discovered that Cdyl2-60aa could stabilize protein apoptotic protease activating factor-1 (APAF1) and promote CM apoptosis; heat shock protein 70 (HSP70) mediated APAF1 degradation in CMs by ubiquitinating APAF1, which Cdyl2-60aa could competitively block. In conclusion, our work substantiated the claim that circCDYL2 could promote CM apoptosis via Cdyl2-60aa, which enhanced APAF1 stability by blocking its ubiquitination by HSP70, suggesting that it is a therapeutic target for HF post-MI in rats.
Subject(s)
Myocardial Infarction , Myocytes, Cardiac , Rats , Animals , Myocytes, Cardiac/metabolism , Proteins/genetics , Apoptosis , Peptides/metabolism , Ubiquitination , Myocardial Infarction/metabolism , Apoptotic Protease-Activating Factor 1/genetics , Apoptotic Protease-Activating Factor 1/metabolismABSTRACT
M2-type polarization of tumor associated-macrophage (TAM) is involved in the malignancy of gastrointestinal stromal tumor (GIST) progression. ETS variant 1 (ETV1) has been previously validated to regulate GIST pathogenesis. Our study intended to explore the role and mechanism of ETV1 in mediating the M2-polarization of TAM in GIST progression. First, we analyzed the correlation between ETV1 expression and M2-polarization in GIST tissues. IL-4 was used to treat THP-1-derived TAM cells and IL-4-stimulated TAM were co-cultured with GIST-T1 cells to mimic the GIST microenvironment. A loss-of-function assay was performed to explore the role of ETV1. Results showed that ETV1 elevation was positively correlated with M2-polarization. IL-4-induced TAM promoted ETV1 expression, silencing ETV1 inhibited proliferation, invasion and KIT activation in IL-4-treated GIST cells, while cell apoptosis was enhanced. Besides, co-culture of ETV1-silenced GIST cells significantly depressed M2-polarization in TAM, presented as decreased levels of CD206, Agr-1 and cytokines, as well as the proportion of CD206-positive TAM. PDE3A was positively correlated with ETV1 and M2-polarization. Overexpressing PDE3A reversed the inhibitory effects of ETV1 silencing. Generally, ETV1 inhibition depressed M2-polarization of TAM in GIST and its promotion on pathological aggravation via down-regulating PDE3A. This evidence may provide a new target for GIST regulation.
ABSTRACT
BACKGROUND: Although TRIpartite Motif containing 8 (TRIM8) gene plays an important role in a number of biological processes, such as inflammation, its function and mechanism in ulcerative colitis (UC) remain unknown. METHODS: The UC model was established by feeding mice with 3.5% dextran sulfate sodium (DSS). The animals were divided into the following four groups: control group, DSS group, DSS+short hairpin (sh)-NC group, and DSS+sh-TRIM8 group. Changes in body weight and disease activity index (DAI) score of mice in all the groups were recorded for 7 days. The animals were executed at the end of the experiment, and the expression of TRIM8 in colon tissue was detected by polymerase chain reaction and Western blot assays. The length of colon was measured, and the histopathological changes in mice colon were examined by hematoxylin and eosin staining. The expression of pro-inflammatory factors in mice serum and colonic tissue homogenate was detected by enzyme-linked-immunosorbent serologic assay. The expression of nuclear factor kappa B (NF-κB) pathway-related proteins in colonic tissues was detected by Western-blot analysis. RESULTS: TRIM8 was highly expressed in the colonic tissues of UC mice. Knockdown of TRIM8 improved DSS-induced weight loss, increased DAI score, shortened colon length, and alleviated colonic injury and inflammation in mice. Western-blot experiments showed that knockdown of TRIM8 inhibited DSS-induced phosphorylation of p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein but increased IκBα expression. CONCLUSION: Knockdown of TRIM8 inhibits UC injury and inflammatory response caused by DSS. This could be related to the regulation of NF-κB signaling pathway by TRIM8 protein.
Subject(s)
Colitis, Ulcerative , Nerve Tissue Proteins , Ubiquitin-Protein Ligases , Animals , Mice , Colitis, Ulcerative/chemically induced , Colitis, Ulcerative/genetics , Colitis, Ulcerative/metabolism , Colon/pathology , Dextran Sulfate , Disease Models, Animal , Inflammation/metabolism , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , NF-kappa B/metabolism , NF-KappaB Inhibitor alpha/metabolism , Signal Transduction , Ubiquitin-Protein Ligases/genetics , Ubiquitin-Protein Ligases/metabolismABSTRACT
Background: Although TRIpartite Motif containing 8 (TRIM8) gene plays an important role in a number of biological processes, such as inflammation, its function and mechanism in ulcerative colitis (UC) remain unknown. Methods: The UC model was established by feeding mice with 3.5% dextran sulfate sodium (DSS). The animals were divided into the following four groups: control group, DSS group, DSS+short hairpin (sh)-NC group, and DSS+sh-TRIM8 group. Changes in body weight and disease activity index (DAI) score of mice in all the groups were recorded for 7 days. The animals were executed at the end of the experiment, and the expression of TRIM8 in colon tissue was detected by polymerase chain reaction and Western blot assays. The length of colon was measured, and the histopathological changes in mice colon were examined by hematoxylin and eosin staining. The expression of pro-inflammatory factors in mice serum and colonic tissue homogenate was detected by enzyme-linked-immunosorbent serologic assay. The expression of nuclear factor kappa B (NF-κB) pathway-related proteins in colonic tissues was detected by Western-blot analysis. Results: TRIM8 was highly expressed in the colonic tissues of UC mice. Knockdown of TRIM8 improved DSS-induced weight loss, increased DAI score, shortened colon length, and alleviated colonic injury and inflammation in mice. Western-blot experiments showed that knockdown of TRIM8 inhibited DSS-induced phosphorylation of p65 and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) protein but increased IκBα expression. Conclusion: Knockdown of TRIM8 inhibits UC injury and inflammatory response caused by DSS. This could be related to the regulation of NF-κB signaling pathway by TRIM8 protein (AU)
Subject(s)
Animals , Male , Mice , NF-kappa B/metabolism , Signal Transduction , Dextran Sulfate , Colitis/chemically induced , Colitis/prevention & control , Disease Models, Animal , Mice, Inbred C57BLABSTRACT
P300/CBP-Associated Factor (PCAF), one of the histone acetyltransferases (HATs), is known to be involved in cell growth and/or differentiation. PCAF is reported to be involved in atherosclerotic plaques and neointimal formation. However, its role in cellular senescence remains undefined. We investigated the potential mechanism for PCAF-mediated cellular senescence. Immunohistochemical (IHC) analysis showed PCAF was distinctly increased in the endothelia of aorta in aged mice. Palmitate acid (PA) or X radiation significantly induced the expression of senescence-associated markers and PCAF in human umbilical vein endothelial cells (HUVECs). PCAF silence in PA-treated HUVECs significantly rescued senescence-associated phenotypes, while PCAF overexpression accelerated it. Additionally, our results showed that Yes1 Associated Transcriptional Regulator (YAP) that acts as end effector of the Hippo signaling pathway is crucial in PCAF-mediated endothelial senescence. YAP activity declining was observed in aged vascular endothelia. Overexpression of YAP partially ameliorated PCAF-induced endothelial senescence. In vivo, endothelial-(EC-) specific PCAF downregulation in aged mice using adeno-associated virus revealed less vascular senescence-associated phenotypes. These results suggested that PCAF mediated endothelial senescence through the Hippo signaling pathway, implying that PCAF may become a potential target for the prevention and treatment of vascular aging.
Subject(s)
Endothelial Cells , Hippo Signaling Pathway , Aged , Animals , Humans , Mice , Cellular Senescence , Histone Acetyltransferases , PalmitatesABSTRACT
BACKGROUND: Low shear stress (LSS) is closely related to vascular endothelial inflammation and the development of atherosclerosis. Berberine (BBR), a natural compound isolated from Coptis chinensis, has been reported to exert anti-inflammatory and antiatherosclerotic effects. However, the role of berberine in low shear stress-induced endothelial inflammation remains unclear. METHODS: The role of berberine in low shear stress-induced vascular endothelial inflammation was investigated in human umbilical vein endothelial cells (HUVECs) using a plate flow chamber in vitro and in mice with an established LSS model by partial ligation of the carotid artery in vivo. RESULTS: First, in vitro experiments demonstrated that BBR significantly decreased the expression of vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) and the phosphorylation of Akt in HUVECs induced by low shear stress. Moreover, BBR significantly inhibited the low shear stress-mediated phosphorylation of IRF3 and its translocation to the nucleus. Notably, Akt overexpression markedly reversed the inhibitory effects of BBR on LSS-induced IRF3 activation and ICAM-1 expression. Moreover, in vivo experiments showed that BBR markedly decreased intimal ICAM-1 and IRF3 in the LSS areas of partially ligated carotid arteries in mice; however, EC-specific Akt overexpression mediated by adeno-associated viruses abolished the anti-inflammatory effect of BBR. CONCLUSION: Taken together, our findings suggest that BBR treatment attenuates LSS-induced vascular endothelial inflammation by decreasing the activation of the Akt/IRF3 signalling pathway.
Subject(s)
Berberine , Humans , Mice , Animals , Berberine/pharmacology , Phosphorylation , Intercellular Adhesion Molecule-1 , Proto-Oncogene Proteins c-akt/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , Inflammation/drug therapy , Inflammation/metabolism , Anti-Inflammatory Agents/pharmacology , Interferon Regulatory Factor-3/metabolism , Interferon Regulatory Factor-3/pharmacologyABSTRACT
Anxiety is a common disorder among college students, especially those with obesity. Obesity contributes to metabolic disorders and disturbs the neural functions, further leading to anxiety. In this cross-sectional study, we aimed to determine the association between obesity and anxiety among college students and identified the potential factors for obesity-associated anxiety. We evaluated the intervention effects of calorie restriction on anxiety. Self-reported questionnaires were distributed to 1381 college students from January to March in 2021. Anxiety was measured by the State-Trait Anxiety Inventory (STAI). Participants were classified into anxiety and non-anxiety groups according to their STAI scores. Chi-squared test and logistic regression were used to analyze the potential factors. We found that 383 college students exhibited anxiety, accounting for 30.1% among all included college students, which was higher than the global average. The association between anxiety and obesity was observed among college students (p = 0.009), especially in males (p = 0.007). We identified that pre-obesity (p = 0.012), unhealthy calorie intake (p = 0.001), dieting (p = 0.003) and high academic year (p = 0.006) as the risk factors for anxiety and found that the long sleep duration was a protective factor for anxiety (p < 0.001). We found that more obese students showed an improvement of anxiety than the underweight students after calorie restriction (p < 0.001). Collectively, our findings suggest that obesity-associated anxiety is prevalent among the college students and could be alleviated by moderate calorie restriction. It is necessary for students to receive anxiety management in their college life. Additionally, the proper calorie restriction should be promoted to help students protect against obesity and obesity-associated anxiety.
Subject(s)
Caloric Restriction , Students , Anxiety/epidemiology , Cross-Sectional Studies , Humans , Male , Obesity/complications , Obesity/epidemiologyABSTRACT
Lysine acetyltransferase 7 (KAT7) was upregulated in gastric cancer (GC) patient tissues, and associated with poor prognosis and metastasis. However, its specific role in GC remains unclear. This study aimed to annotate the role of KAT7 in GC cells. The results showed that the overexpression of KAT7 promoted cell growth, migration, and invasion, while KAT7 inhibition has the opposite effect. Besides, KAT7 participated in cell cycle phase distribution and epithelial-mesenchymal transition (EMT) process of GC cells. In addition, KAT7 promoted the transcription and nuclear translocation of Yes-associated protein 1 (YAP1) in MKN45 cells. Silence of YAP1 partly reversed the promoting effect of KAT7 on GC cells progression. In summary, this study indicates that KAT7 promoted GC cells progression through promoting YAP1 activation, contributes to understand the specific role of KAT7 in GC.
Subject(s)
Lysine Acetyltransferases , Stomach Neoplasms , Humans , Stomach Neoplasms/pathology , YAP-Signaling Proteins , Cell Movement , Gene Expression Regulation, Neoplastic/genetics , Cell Line, Tumor , Epithelial-Mesenchymal Transition , Cell Proliferation , Lysine Acetyltransferases/metabolism , Histone AcetyltransferasesABSTRACT
HgTe colloidal quantum dots (CQDs) are promising absorber systems for infrared detection due to their widely tunable photoresponse in all infrared regions. Up to now, the best-performing HgTe CQD photodetectors have relied on using aggregated CQDs, limiting the device design, uniformity and performance. Herein, we report a ligand-engineered approach that produces well-separated HgTe CQDs. The present strategy first employs strong-binding alkyl thioalcohol ligands to enable the synthesis of well-dispersed HgTe cores, followed by a second growth process and a final postligand modification step enhancing their colloidal stability. We demonstrate highly monodisperse HgTe CQDs in a wide size range, from 4.2 to 15.0 nm with sharp excitonic absorption fully covering short- and midwave infrared regions, together with a record electron mobility of up to 18.4 cm2 V-1 s-1. The photodetectors show a room-temperature detectivity of 3.9 × 1011 jones at a 1.7 µm cutoff absorption edge.
ABSTRACT
Myeloid cell leukemia 1 (Mcl-1) protein is a key negative regulator of apoptosis, and developing Mcl-1 inhibitors has been an attractive strategy for cancer therapy. Herein, we describe the rational design, synthesis, and structure-activity relationship study of 3,5-dimethyl-4-sulfonyl-1H-pyrrole-based compounds as Mcl-1 inhibitors. Stepwise optimizations of hit compound 11 with primary Mcl-1 inhibition (52%@30 µM) led to the discovery of the most potent compound 40 with high affinity (Kd = 0.23 nM) and superior selectivity over other Bcl-2 family proteins (>40,000 folds). Mechanistic studies revealed that 40 could activate the apoptosis signal pathway in an Mcl-1-dependent manner. 40 exhibited favorable physicochemical properties and pharmacokinetic profiles (F% = 41.3%). Furthermore, oral administration of 40 was well tolerated to effectively inhibit tumor growth (T/C = 37.3%) in MV4-11 xenograft models. Collectively, these findings implicate that compound 40 is a promising antitumor agent that deserves further preclinical evaluations.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Discovery , Myeloid Cell Leukemia Sequence 1 Protein/antagonists & inhibitors , Pyrroles/pharmacology , Administration, Oral , Animals , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Biological Availability , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Mice , Molecular Structure , Myeloid Cell Leukemia Sequence 1 Protein/metabolism , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , Pyrroles/administration & dosage , Pyrroles/chemistry , Structure-Activity RelationshipABSTRACT
As a powerful signal amplification tool, the DNA walker has been widely applied to detect rare microRNA (miRNA) in vivo. Despite the significant advances, a near-infrared (NIR) light controllable DNA walker for signal amplification powered by an endogenous initiator has not been realized, which is crucial for spatiotemporal imaging of miRNA in living cells with high sensitivity. Herein, we constructed a NIR-photoactivatable DNA walker system, which was powered by endogenous adenosine triphosphate (ATP) for in situ miRNA imaging with spatial and temporal resolution. The system was very stable with an extremely low fluorescent background for the bioimaging in living cells. We employed upconversion nanoparticles (UCNPs) as the carriers of the DNA probe and transducers of converting NIR to UV light. Coupled with the DNA walker fueled by intracellular ATP, a smart system based on the NIR light initiated DNA walker was successfully developed for precise spatiotemporal control in living cells. Triggered by NIR light, the DNA walker could autonomously and progressively travel along the track with the assistance of intracellular ATP. The system has been successfully applied for in situ miRNA imaging in different cell lines with highly spatial and temporal resolution. This strategy can expand NIR photocontrol the DNA walker for precise imaging in a biological system.
Subject(s)
Adenosine Triphosphate , MicroRNAs , DNA/genetics , MicroRNAs/geneticsABSTRACT
OBJECTIVE: . To compare the metabolic profile of women with spontaneous premature ovarian insufficiency (POI) with that of age-matched healthy controls. STUDY DESIGN: . A cross-sectional case-control study was conducted using 1:1 matching by age. Women below the age of 40 with spontaneous POI who did not receive any medication (n = 303) and age-matched healthy women (n = 303) were included in this study. MAIN OUTCOME MEASURES: . Metabolic profiles, including serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), glucose, uric acid, urea and creatinine, were compared between women with POI and controls. For women with POI, factors associated with the metabolic profile were analyzed. RESULTS: . Women with POI were more likely to exhibit increased serum levels of TG (ß, 0.155; 95% CI, 0.086, 0.223) and glucose (0.067; 0.052, 0.083), decreased levels of HDL-C (-0.087; -0.123, -0.051), LDL-C (-0.047; -0.091, -0.003) and uric acid (-0.053; -0.090, -0.015), and impaired kidney function (urea [0.070; 0.033, 0.107]; creatinine [0.277; 0.256, 0.299]; eGFR [-0.234; -0.252, -0.216]) compared with controls after adjusting for age and BMI. BMI, parity, gravidity, FSH and E2 levels were independent factors associated with the metabolic profile of women with POI. CONCLUSION: . Women with POI exhibited abnormalities in lipid metabolism, glucose metabolism, and a decrease in kidney function. In women with POI, early detection and lifelong management of metabolic abnormalities are needed.