Dickkopf-1 promotes vascular smooth muscle cell foam cell formation and atherosclerosis development through CYP4A11/SREBP2/ABCA1.

Vascular smooth muscle cells (VSMCs) are considered to be a crucial source of foam cells in atherosclerosis due to their low expression level of cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) intrinsically. While the definite regulatory mechanisms are complicated and have not yet been fully elucidated, we previously reported that Dickkopf-1 (DKK1) mediates endothelial cell (EC) dysfunction, thereby aggravating atherosclerosis. However, the role of smooth muscle cell (SMC) DKK1 in atherosclerosis and foam cell formation remains unknown. In this study, we established SMC-specific DKK1-knockout (DKK1SMKO ) mice by crossbreeding DKK1flox/flox mice with TAGLN-Cre mice. Then, DKK1SMKO mice were crossed with APOE-/- mice to generate DKK1SMKO /APOE-/- mice, which exhibited milder atherosclerotic burden and fewer SMC foam cells. In vitro loss- and gain-of-function studies of DKK1 in primary human aortic smooth muscle cells (HASMCs) have proven that DKK1 prevented oxidized lipid-induced ABCA1 upregulation and cholesterol efflux and promoted SMC foam cell formation. Mechanistically, RNA-sequencing (RNA-seq) analysis of HASMCs as well as chromatin immunoprecipitation (ChIP) experiments showed that DKK1 mediates the binding of transcription factor CCAAT/enhancer-binding protein delta (C/EBPδ) to the promoter of cytochrome P450 epoxygenase 4A11 (CYP4A11) to regulate its expression. In addition, CYP4A11 as well as its metabolite 20-HETE-promoted activation of transcription factor sterol regulatory element-binding protein 2 (SREBP2) mediated the DKK1 regulation of ABCA1 in SMC. Furthermore, HET0016, the antagonist of CYP4A11, has also shown an alleviating effect on atherosclerosis. In conclusion, our results demonstrate that DKK1 promotes SMC foam cell formation during atherosclerosis via a reduction in CYP4A11-20-HETE/SREBP2-mediated ABCA1 expression.

Highly pH-Responsive Sensor Based on a EuIII Metal-Organic Framework with Efficient Recognition of Arginine and Lysine in Living Cells.

A lanthanide-based three-dimensional metal-organic framework with excellent water, acid/base, and solvent stability, namely {[(CH3)2NH2]0.7[Eu2(BTDBA)1.5(lac)0.7(H2O)2]·2H2O·2DMF·2CH3CN}n (JXUST-29, H4BTDBA = 4',4‴-(benzo[c][1,2,5]thiadiazole-4,7-diyl)bis([1,1'-biphenyl]-3,5-dicarboxylic acid), Hlac = lactic acid), has been synthesized and characterized. Since the N atoms of the thiadiazole group will not coordinate with lanthanide ions, JXUST-29 has a free basic N-site accessible to small H+ ions, which allows it to be used as a promising pH fluorescence sensor. Interestingly, the luminescence signal was significantly enhanced, with an approximately 54-fold enhancement in the emission intensity when the pH value was increased from 2 to 5, which is the typical behavior of pH probes. In addition, JXUST-29 can also be used as a luminescence sensor to detect l-arginine (Arg) and l-lysine (Lys) in an aqueous solution through fluorescence enhancement and the blue-shift effect. The detection limits were 0.023 and 0.077 µM, respectively. In addition, JXUST-29-based devices were designed and developed to facilitate detection. Importantly, JXUST-29 is also capable of detecting and sensing Arg and Lys in living cells.

Highly Stable Rare Earth Metal-Organic Frameworks for Fluorescence Recognition of Folic Acid, Proton Conduction, and Magnetic Refrigeration.

Four new isostructural rare earth metal-organic frameworks (RE-MOFs) were synthesized and full characterized, namely, {[(CH)2NH2]3[RE2(BTDBA)2(HCOO)]·5H2O·2DMF}n (H4BTDBA = (4',4'''-(benzo[c][1,2,5]thiadiazole-4,7-diyl)bis([1,1'-biphenyl]-3,5-dicarboxylic acid); RE = Eu (JXUST-34), Gd (JXUST-35), Tb (JXUST-36), and Dy (JXUST-37)). The single-crystal structures analysis shows that JXUST-34-37 are chain-based three-dimensional structures. Importantly, JXUST-34 exhibits excellent water, organic solvents, and acid-base stability, which can be used as a fluorescence sensor for folic acid and Al3+ with detection limits of 0.02 mM and 0.05 µM, respectively. The presence of free [(CH)2NH2]+ cations in the channels can engage the proton carrier during proton conduction. JXUST-34-37 display good proton conductivity, and the conductivities vary with relative humidity and temperatures, among which JXUST-37 has the highest conductivity of 9.66 × 10-3 S·cm-1 at 60 °C and 98% RH. The magnetic studies show that the -ΔSm of JXUST-35 reaches 16.13 J kg-1 K-1 at 2 K and ΔH = 7 T. JXUST-34-37 show multifunctional properties of fluorescence sensing, high proton conductivity, and magnetic refrigeration, which provides a new clue for the development of fluorescent-responsive, magnetic-refrigerant, and proton-conductive RE-MOF materials.

Enhanced Heterogeneous Catalytic Activity of Peroxymonosulfate for Rhodamine B Degradation via a CoII-Based Metal-Organic Framework.

A stable metal-organic framework with the formula {[Co(BBZB)(IPA)]·H2O}n (JXUST-23, BBZB = 4,7-bis(1H-benzimidazole-1-yl)-2,1,3-benzothiadiazole and H2IPA = isophthalic acid) was constructed by incorporating Co2+ ions and two conjugated ligands under solvothermal conditions. JXUST-23 takes a dinuclear cluster-based layer structure with a porosity of 2.7%. In this work, JXUST-23 was used to activate peroxymonosulfate (PMS) to degrade rhodamine B (RhB), a difficult-to-degrade pollutant in water. Compared with pure PMS or JXUST-23, the JXUST-23/PMS system displays the best degradation ability of RhB in neutral solution. When the mass ratio of JXUST-23 to PMS was 2:3, 99.72% of RhB (50 ppm) was removed within 60 min, and the reaction rate was 0.1 min-1. Furthermore, free radical quenching experiments show that SO4•- was the main free radical during the process of RhB degradation. In addition, JXUST-23 exhibits good reusability for the degradation of the organic dye RhB, making it a potential candidate for environmental remediation.

Controllable Synthesis of TbIII Metal-Organic Frameworks with Reversible Luminescence Sensing for Benzaldehyde Vapor.

Two novel lanthanide metal-organic frameworks (MOFs) with the formulas [Tb(bidc)(Hbidc)(H2O)]n (JXUST-20) and {[Tb3(bidc)4(HCOO)(DMF)]·solvents}n (JXUST-21) were synthesized based on 2,1,3-benzothiadiazole-4,7-dicarboxylic acid (H2BTDC) under solvothermal conditions. Interestingly, benzimidazole-4,7-dicarboxylic acid (H2bidc) was formed in situ using H2BTDC as the starting material. The self-assembly process of the targeted MOFs with different topological structures can be controlled by the solvents and concentration of the reactants. Luminescence experiments show that JXUST-20 and JXUST-21 exhibit strong yellow-green emission. JXUST-20 and JXUST-21 can selectively sense benzaldehyde (BzH) via a luminescence quenching effect with detection limits of 15.3 and 1.44 ppm, respectively. In order to expand the practical application of MOF materials, mixed-matrix membranes (MMMs) have been constructed by mixing targeted MOFs and poly(methyl methacrylate) in a N,N-dimethylformamide (DMF) solution, which can also be used for BzH vapor sensing. Therefore, the first case of MMMs derived from TbIII MOFs has been developed for the reversible detection of BzH vapor, providing a simple and efficient platform for the future detection of volatile organic compounds.

Triglyceride-glucose index in the prediction of adverse cardiovascular events in patients with premature coronary artery disease: a retrospective cohort study.

BACKGROUND: Premature coronary artery disease (PCAD) has become more common in recent years and is often associated with poor outcomes. Triglyceride-glucose (TyG) index is a simple and reliable surrogate for insulin resistance (IR) and is an independent predictor of cardiovascular prognosis. However, the prognostic value of the TyG index in patients with PCAD remains uncertain. Thus, this study aimed to investigate the prognostic value and predictive performance of the TyG index in patients with PCAD. METHODS: A total of 526 young subjects (male < 45 years, female < 55 years) with angiographically proven CAD from January 2013 to December 2018 were included consecutively in this study. Their clinical and laboratory parameters were collected, and the TyG index was calculated as [Formula: see text]. The follow-up time after discharge was 40-112 months (median, 68 months; interquartile range, 49‒83 months). The primary endpoint was the occurrence of the major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction (MI), coronary artery revascularization, and non-fatal stroke. RESULTS: The TyG index was significantly associated with traditional cardiovascular risk factors and the Gensini score (GS). Kaplan-Meier survival (MACE-free) curves by tertiles of the TyG index showed statistically significant differences (log-rank test, p = 0.001). In the fully adjusted Cox regression model, the Hazard ratio (95% CI) of MACE was 2.17 (1.15-4.06) in tertile 3 and 1.45 (1.11-1.91) for per SD increase in the TyG index. Time-dependent ROC analyses of the TyG for prediction of MACE showed the area under the curves (AUC) reached 0.631 at 3 years, 0.643 at 6 years, and 0.710 at 9 years. Furthermore, adding TyG index to existing risk prediction model could improve outcome prediction [C-statistic increased from 0.715 to 0.719, p = 0.007; continuous net reclassification improvement (NRI) = 0.101, p = 0.362; integrated discrimination improvement (IDI) = 0.011, p = 0.017]. CONCLUSION: The TyG index is an independent predictor of MACE in patients with PCAD, suggesting that the TyG index has important clinical implications for risk stratification and early intervention of PCAD.

A pH-Stable TbIII-Based Metal-Organic Framework as a Turn-On and Blue-Shift Fluorescence Sensor toward Benzaldehyde and Salicylaldehyde in Aqueous Solution.

A new polydentate tetracarboxylic acid with a benzothiadiazole unit (4',4'''-(benzo[c][1,2,5]thiadiazole-4,7-diyl)bis([1,1'-biphenyl]-3,5-dicarboxylic acid), H4BTDBA) has been used to prepare a pH-stable three-dimensional TbIII-based metal-organic framework (MOF) with the formula {[(CH3)2NH2]0.7[Tb2(BTDBA)1.5(lac)0.7(H2O)2]·solvents}n (Hlac = lactic acid, JXUST-19). JXUST-19 exhibits a new (4,4,12)-connected topology based on tetranuclear [Tb4] clusters. JXUST-19 can remain stable when soaked in water for at least 1 week and in aqueous solutions with various pH values (2-12) for 24 h. Fluorescence study indicates JXUST-19 can be employed as a rare turn-on and blue-shift MOF sensor toward benzaldehyde (BZ) and salicylaldehyde (SA). To date, JXUST-19 represents the first TbIII-based turn-on MOF sensor toward salicylaldehyde in aqueous solution, and the fluorescence enhancement and naked-eye detection of BZ have been rarely reported. In addition, JXUST-19 based fluorescent test papers, light-emitting diode lamp beads, and portable composite films were developed to realize naked-eye detection of BZ and SA, which has great potential in practical applications.

A Benzothiadiazole-Based Eu3+ Metal-Organic Framework as the Turn-On Luminescent Sensor toward Al3+ and Ga3+ with Potential Bioimaging Application.

The design and preparation of novel multifunctional lanthanide metal-organic frameworks (Ln-MOFs) have been arisen widespread attention. In particular, Ln-MOFs have shown great luminescence potential in chemical sensing. Herein, a new benzothiadiazole-based Eu-MOF {[(CH3)2NH2][Eu(BTDB)2]·2H2O}n (JXUST-11) was obtained based on 4,4'-(benzo[c][1,2,5]thiadiazole-4,7-diyl)dibenzoic acid (H2BTDB), which exhibits a chain-based three-dimensional framework. Moreover, JXUST-11 is considered as a photoluminescent sensor to identify Al3+ and Ga3+ ions by fluorescence enhancement with the detection limits of 2.9 and 10.2 ppm, severally. Importantly, Al3+ and Ga3+ can be discerned with the naked eye by color change under a natural lamp. In addition, a portable MOF film based on JXUST-11 was developed for Al3+ and Ga3+ detection. This is the first Ln-MOF that can be employed as a naked-eye fluorescent probe to identify Ga3+. Interestingly, JXUST-11 is also capable of detecting Al3+ and Ga3+ in living cells.

Fabrication and DFT Calculation of Amine-Functionalized Metal-Organic Framework as a Turn-On Fluorescence Sensor for Fe3+ and Al3+ Ions.

Due to their important role in biological systems, it is urgent to develop a material that can rapidly and sensitively detect the concentration of Fe3+ and Al3+ ions. In this work, a brand-new CdII-based metal-organic framework [Cd(BTBD)2(AIC)]n (JXUST-18, BTBD = 4,7-bis(1H-1,2,4-triazol-1-yl)-2,1,3-benzothiadiazole and H2AIC = 5-aminoisophthalic acid) with a 4-connected sql topology was designed and synthesized. The symmetrical CdII centers are linked by AIC2- ligands with µ3-η1:η1:η1:η1 coordination mode to form a [Cd2(COO)2] secondary building unit (SBU). The contiguous SBUs are further connected by BTBD ligands to form a two-dimensional (2D) layer structure. JXUST-18 can remain stable in aqueous solutions with pH values of 3-12 or in boiling water. Luminescent experiments suggest that JXUST-18 displays more than eightfold fluorescence enhancement in the presence of Fe3+ and Al3+ ions, and the detection limits for Fe3+ and Al3+ ions are 0.196 and 0.184 µM, respectively. Furthermore, the change in luminescence color is uncomplicatedly distinguishable with the naked eye under ultraviolet light at 365 nm. In addition, a series of devices based on JXUST-18 including fluorescence test strips, lamp beads, and composite films were developed to detect metal ions via visual changes in luminescence color. Significantly, JXUST-18 is a rare MOF-based turn-on fluorescence sensor for the detection of Fe3+ ions. The theoretical calculation suggests that the complexation of Fe3+/Al3+ ions and the -NH2 group contributes to fluorescence enhancement.

Tritoroidal particle rings formation in open microfluidics induced by standing surface acoustic waves.

In this paper, the particle movements in a sessile droplet induced by standing surface acoustic waves (SSAWs) are studied. Tritoroidal particle rings are formed under the interaction of acoustic field and electric field. The experimental results demonstrate that the electric field plays an important role in patterning nanoparticles. The electric field can define the droplet shape due to electrowetting. When the droplet approximates a hemisphere, the acoustic radiation force induced by SSAWs drives the particles to form tritoroidal particle rings. When the droplet approximates a convex plate, the drag force induced by acoustic steaming drives the particle to move. The results will be useful for better understanding the nanoparticle movements in a sessile droplet, which is important to explain the mechanism that SSAWs enhance reaction and crystallization in droplet.

Focusing surface acoustic waves assisted electrochemical detector in microfluidics.

This article demonstrates a novel electrochemical detection device. The device is composed by two focusing interdigital transducers for exciting focused surface acoustic waves by applying an AC signal, a three-electrode system for electrochemical measurement, and a liquid pool for holding liquid on a LiNbO3 wafer. The amperometry current of ferrocenecarboxylic acid and potassium phosphate buffer solution is used to characterize the detection sensitivity. Two experiments are carried out to optimize the device design. The result shows that the two focusing interdigital transducers with arc degree 30° and distance 5 mm can remarkably enhance the liquid mixing rate. Under this condition, the oxidation current is about 27 times larger than that without surface acoustic wave stirring.

Turn-On Luminescent Sensor toward Fe3+, Cr3+, and Al3+ Based on a Co(II) Metal-Organic Framework with Open Functional Sites.

A novel Co-based metal-organic framework (MOF) with the formula of {[Co3(BIBT)3(BTC)2(H2O)2]·solvents}n (JXUST-2, where JXUST denotes Jiangxi University of Science and Technology, BIBT = 4,7-bi(1H-imidazol-1-yl)benzo-[2,1,3]thiadiazole, and H3BTC = 1,3,5-benzenetricarboxylic acid) has been solvothermally prepared, which takes 3D structure with a rare 3,4,6-c topology and contains intramolecular hydrogen bonds. Interestingly, the sensing investigations suggest that JXUST-2 could be considered as a multifunctional fluorescence sensor toward Fe3+, Cr3+, and Al3+ via a turn-on effect with good reusability and detection limits of 0.13, 0.10, and 0.10 µM, respectively. The turn-on effect of JXUST-2 could be ascribed to an absorbance caused enhancement (ACE) mechanism. Notably, JXUST-2 is the first turn-on MOF fluorescent sensor for Fe3+, Cr3+, and Al3+ simultaneously.

A ZnII-Based Metal-Organic Framework with a Rare tcj Topology as a Turn-On Fluorescent Sensor for Acetylacetone.

A ZnII-based metal-organic framework (MOF) with a rare tcj topology has been solvothermally synthesized and displays relatively good thermal and chemical stabilities. Interestingly, the MOF can sensitively and selectively sense acetylacetone (acac) via a fluorescence enhancement effect with a detection limit of 0.10 ppm and good reusability, which demonstrates the first example of a MOF-based turn-on fluorescent sensor for acac.

Siderophore-based immunization strategy to inhibit growth of enteric pathogens.

Infections with Gram-negative pathogens pose a serious threat to public health. This scenario is exacerbated by increases in antibiotic resistance and the limited availability of vaccines and therapeutic tools to combat these infections. Here, we report an immunization approach that targets siderophores, which are small molecules exported by enteric Gram-negative pathogens to acquire iron, an essential nutrient, in the host. Because siderophores are nonimmunogenic, we designed and synthesized conjugates of a native siderophore and the immunogenic carrier protein cholera toxin subunit B (CTB). Mice immunized with the CTB-siderophore conjugate developed anti-siderophore antibodies in the gut mucosa, and when mice were infected with the enteric pathogen Salmonella, they exhibited reduced intestinal colonization and reduced systemic dissemination of the pathogen. Moreover, analysis of the gut microbiota revealed that reduction of Salmonella colonization in the inflamed gut was accompanied by expansion of Lactobacillus spp., which are beneficial commensal organisms that thrive in similar locales as Enterobacteriaceae. Collectively, our results demonstrate that anti-siderophore antibodies inhibit Salmonella colonization. Because siderophore-mediated iron acquisition is a virulence trait shared by many bacterial and fungal pathogens, blocking microbial iron acquisition by siderophore-based immunization or other siderophore-targeted approaches may represent a novel strategy to prevent and ameliorate a broad range of infections.

Evaluation of (acyloxy)alkyl ester linkers for antibiotic release from siderophore-antibiotic conjugates.

The syntheses of five ciprofloxacin-modified (acyloxyl)alkyl esters and two siderophore-ciprofloxacin conjugates based on enterobactin that harbor such hydrolyzable linkages are reported. The hydrolytic stabilities of ciprofloxacin-modified (acyloxy)alkyl esters, evaluated at pH 7.5 and 30°C, vary by >370-fold depending on the substituents in the vicinity of the ester linkage.

Enterobactin-mediated delivery of ß-lactam antibiotics enhances antibacterial activity against pathogenic Escherichia coli.

The design, synthesis, and characterization of enterobactin-antibiotic conjugates, hereafter Ent-Amp/Amx, where the ß-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent ß-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.

Fluorescence sensing and device fabrication with luminescent metal-organic frameworks.

Metal-organic frameworks (MOFs) are a novel class of hybrid porous multi-functional materials consisting of metal ions/clusters and organic ligands. MOFs have exclusive benefits due to their tunable structure and diverse properties. Luminescent MOFs (LMOFs) exhibit both porosity and light emission. They display abundant host and guest responses, making them conducive to sensing. Currently, LMOF sensing research is gaining more depth, with attention given to their device and practical applications. This work reviews recent advancements and device applications of LMOFs as chemical sensors toward ions, volatile organic compounds, biomolecules, and environmental toxins. Furthermore, the detection mechanism and the correlation between material properties and structure are elaborated. This analysis serves as a valuable reference for the preparation and efficient application of targeted LMOFs.

In vivo tracing of cyromazine and three neonicotinoids in cowpea under field conditions by solid-phase microextraction combined with ultra-performance liquid chromatography-tandem mass spectrometry.

BACKGROUND: Excessive pesticide residues in agricultural products could accumulate in organisms through the food chain, causing potential harm to human health. The investigation of dissipation kinetics and residues of pesticides in crops is crucial for the scientific application of pesticides and the mitigation of their adverse effects on human health. In vivo solid-phase microextraction (in vivo SPME) has unique advantages, but the research on field plants is still lacking and the quantitative correction methods need to be further developed. RESULTS: A method combining in vivo solid-phase microextraction with ultra-performance liquid chromatography-tandem mass spectrometry (in vivo SPME-UPLC-MS/MS) was developed to monitor the presence of acetamiprid, cyromazine, thiamethoxam and imidacloprid in cowpea fruits grown in the field. The sampling rates (Rs) were determined using both in vitro SPME in homogenized cowpea samples and in vivo SPME in intact cowpea fruit samples. The in vivo-Rs values were significantly higher than the in vitro-Rs for the same analyte, which were used for in vivo SPME correction. The accuracy of this method was confirmed by comparison with a QuEChERS-based approach and subsequently applied to trace pesticide residues in field-grown cowpea fruits. The residual concentrations of each pesticide positively correlated with application doses. After 7 days of application at two different doses, all of the pesticides had residual concentrations below China's maximum residue limits. Both experimental data and predictions indicated that a safe preharvest interval for these pesticides is 7 days; however, if the European Union standards are to be met, a safe preharvest interval for cyromazine should be at least 13 days. SIGNIFICANCE: This study highlights the advantages of in vivo SPME for simultaneous analysis and tracking of multiple pesticides in crops under field conditions. This technique is environmentally friendly, minimally invasive, highly sensitive, accurate, rapid, user-friendly, cost-effective, and capable of providing precise and timely data for long-term pesticide surveillance. Consequently, it furnishes valuable insights to guide the safe utilization of pesticides in agricultural production.