Polypills can contain multiple pharmaceutical agents targeting the cardiovascular system. The use of polypills in the secondary prevention of cardiovascular disease (CVD) has received broad support; ...however, the use of polypills in the primary prevention of CVD is more controversial. This controversy stems from an inherent resistance to the medicalization of primary prevention, and the lower CVD event rate in this population means that smaller absolute benefits are derived. Indeed, drug-related adverse effects, such as from aspirin, might even outweigh the benefits. The role of fixed-dose combination (FDC) therapy for blood pressure (BP) lowering in combatting the widespread undertreatment of high BP - the leading modifiable risk factor contributing to the global burden of CVD - has gained momentum. Increasing evidence suggests that FDC pills containing multiple low doses of BP-lowering drugs produce more effective BP lowering than the use of fewer separate BP-lowering drugs at higher doses, without an increase in adverse effects. Trials of FDC pills comprising three half-dose or four quarter-dose BP-lowering drugs have shown substantial efficacy. In this Review, we summarize the current evidence on low-dose BP-lowering FDC pills and the justification for this approach in the context of polypills in the primary prevention of CVD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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We designed and synthesized a magnetic metal organic frameworks (MOFs) composite, Cu-MOFs/Fe3O4 as the adsorbent for removal of lead (Pb(II)) and malachite green (MG) in wastewater. ...This Cu-MOFs/Fe3O4 can be easily prepared by in-situ growth of Cu-MOFs with doping Fe3O4 nanoparticles. The prepared Cu-MOFs/Fe3O4 composite was well characterized by SEM, XRD, and FTIR spectra. The adsorption experiments found that Cu-MOFs/Fe3O4 can serve as adsorbent for removal of Pb(II) and MG simultaneously. The adsorption capacities were found to be 113.67 mg/g for MG and 219.00 mg/g for Pb2+, respectively, which are significantly higher than reported materials. Adsorption isotherm, kinetics and recyclability of Cu-MOFs/Fe3O4 for removal of Pb(II) and MG were then studied. Adsorption of Pb(II) and MG exhibited Freundlich adsorption isotherm model, with the adsorption kinetics of available second-order kinetic. Physical adsorption for MG and chemical adsorption for Pb(II) were confirmed by Dubinin-Radushkevich (D-R) isothermal adsorption model. The adsorption of Pb(II) and MG in real water samples were then studied. The Fe3O4/Cu-MOFs was found to be recyclable for removal of Pb(II) and MG, can be explored as the potential adsorbent for waste water treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
The effective synthesis of chiral compounds in a highly enantioselective manner is obviously attractive. Inspired by the enzymatic reactions that occur in pocket‐like cavities with high efficiency ...and specificity, chemists are seeking to construct catalysts that mimic this key feature of enzymes. Recent progress in supramolecular coordination chemistry has shown that metal–organic cages (MOCs) and metal–organic frameworks (MOFs) with chiral confined cavities/pores may offer a novel platform for achieving asymmetric catalysis with high enantioselectivity. The inherent chiral confined microenvironment is considered to be analogous to the binding pocket of enzymes, and this pocket promotes enantioselective transformations. This work focuses on the recent advances in MOCs and MOFs with chiral confined spaces for asymmetric catalysis, and each section is separated into two parts based on how the chirality is achieved in these metal–organic architectures. A special emphasis is placed on discussing the relationship between the enantioselectivity and the confined spaces of the chiral functional MOCs and MOFs rather than catalytic chemistry. Finally, current challenges and perspectives are discussed. This work is anticipated to offer researchers insights into the design of sophisticated chiral confined space‐based metal–organic architectures for asymmetric catalysis with high enantioselectivity.
Supramolecular metal–organic architectures (metal–organic cages and metal–organic frameworks) feature with chiral confined space analogous to the binding pocket of enzymes exhibiting an ideal working yard to accelerate the series of novel asymmetric catalysis. The relationship between the enantioselectivity and chiral confined environment rather than catalytic chemistry is emphasized here.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
As a novel class of noncoding RNAs, circRNAs have been recently identified to regulate tumorigenesis and aggressiveness. However, the function of circRNAs in colorectal cancer (CRC) metastasis ...remains unclear. We aimed to identify circRNAs that are upregulated in CRC tissues from patients and study their function in CRC metastasis.
We compared six pairs of CRC tissues and their matched adjacent non-tumor tissues by using circRNA microarray. We first evaluated the expression of circPTK2 (hsa_circ_0005273) in fresh tissues from CRC tumors and corresponding adjacent tissues by qPCR analysis. CircPTK2 expression levels in the tissue microarray with 5 years of survival information were determined by RNA-ISH analysis. Meanwhile, the expression levels of circulating circPTK2 were further analyzed according to the patients' clinical features. We analyzed cell apoptosis, colony formation, migration, and invasion in CRC cells. To further elucidate the effect of circPTK2 in CRC metastasis, we also conducted a colon cancer hepatic and pulmonary metastasis experiment. We used RNA biotin-labeled pull down and mass spectrometry to identify the target of circPTK2. We established a PDTX model to evaluate the effect of shRNA specifically targeting circPTK2 on tumor metastasis.
We identified a novel circRNA, circPTK2, which is back-spliced of three exons (exons 27, 28 and 29) of PTK2 by using circRNA microarray, bioinformatics and functional studies. CircPTK2 was elevated in CRC tissues and positively associated with tumor growth and metastasis. CRC patients with increased circPTK2 expression were positively correlated with poorer survival rates. Furthermore, our studies showed that circPTK2 could promote EMT of CRC cells in vitro and in vivo by binding to vimentin protein on sites Ser38, Ser55 and Ser82. We further demonstrated the interaction of circPTK2 and vimentin mediated the regulation of CRC by knockdown or overexpression of vimentin. In addition, we revealed that tail vein injection of shRNA specifically targeting circPTK2 blunt tumor metastasis in a patient-derived CRC xenograft model.
Collectively, these results demonstrate that circPTK2 exerts critical roles in CRC growth and metastasis and may serve as a potential therapeutic target for CRC metastasis, and also a promising biomarker for early diagnosis of metastasis.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chimeric antigen receptor (CAR) - T cell therapy is a new class of cellular immunotherapies, which has made great achievements in the treatment of malignant tumors. Despite improvements in colorectal ...cancer (CRC) therapy, treatment of many patients fails because of metastasis and recurrence. The human epidermal growth factor receptor 2 (HER2) is a substantiated target for CAR-T therapy, and has been reported recently to be over-expressed in CRC, which may provide a potential therapeutic target for CRC treatment. Herein, HER2 was a promising target of metastatic colorectal cancer (mCRC) in CAR-T therapy as assessed by flow cytometry and tissue microarray (TMA) with 9-year survival follow-up data. Furthermore, HER2-specific CAR-T cells exhibited strong cytotoxicity and cytokine-secreting ability against CRC cells in vitro. Moreover, through the tumor-bearing model of the NOD-Prkdc
Il2rg
/Nju (NCG) mice, HER2 CAR-T cells showed signs of effectively preventing CRC progression in three different xenograft models. Notably, HER2 CAR-T cells displayed greater aggressiveness in HER2
CRC in the patient-derived tumor xenograft (PDX) models and had potent immunotherapeutic capacity for mCRC in the metastatic xenograft mouse models. In conclusion, our studies provide scientific evidence that HER2 CAR-T cells represent an emerging immunotherapy for the treatment of mCRC.
A new complex between coumarin-based ligand (CL) and copper ion has been prepared and applied to be an ON–OFF–ON reversible fluorescence chemosensor for the detection of Cys with high sensitivity and ...specificity. In HEPES buffer, CL displayed high affinity towards Cu2+ ion over other physiological and environmental metal ions, accompanied with a 98.4% of fluorescence quenching. In the presence of Cys, the detachment of Cu2+ ion of CL–Cu2+ ensemble led to the liberation of the fluorophore, CL, and thus fluorescence was recovered. The results of absorption and emission spectroscopy analyses confirmed that the fluorescence turn ON response of CL–Cu2+ ensemble was selective towards Cys only with high sensitivity (detection of limit, 7.2×10−7M). Confocal microscopy studies indicated that the lipophilic CL targets the endoplasmic reticulum (ER) of live cells, where it could be functioned as a fluorescent chemosensor for visualization of Cys in this organelle. Quantitative fluorescence detection of Cys in ER was successfully realized by flow cytometry analysis. The developed chemosensor was further applied to detect Cys in real urine samples with great recoveries ranges from 95.41% to 107.40%.
•New chemosensor was designed and synthesized for the reversible detection of Cys.•The fluorescence chemosensor exhibited effective discrimination of cysteine from other biological thiols.•New chemsensor exhibited low cytotoxicity, good cell-membrane permeability, and endoplasmic reticulum specificity.•The application in visualization of Cys in endoplasmic reticulum and detection of Cys in real samples were demonstrated.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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•The response of ecosystem WUE to soil moisture drought was quantitatively examined.•WUE increased significantly in most vegetated areas of the world during 1982–2018.•Drought had ...approximately 4-month lagged effect on WUE.•Drought-resilient ecosystems were concentrated in the Northern Hemisphere.
Water use efficiency (WUE) is an ecological indicator reflecting the link between carbon and water cycles in terrestrial ecosystems, which is often affected by drought disturbance. However, knowledge about the influences of soil moisture drought on WUE is still lacking. Therefore, this paper aims to quantify the lagged effect and impact of soil moisture drought on terrestrial ecosystem WUE from 1982 to 2018 using ERA5 and Global Land Surface Satellite (GLASS) datasets. Drought conditions are described by the soil moisture anomaly percentage index (SMAPI). The lagged effect of drought on WUE is measured by the month with the maximum significant correlation between SMAPI and WUE. The impact of drought on WUE is estimated through the relative change of WUE during drought and non-drought periods. The results showed that: (1) Drought had an approximately 4-month lagged effect on WUE, which was observed in 70.87% of the global vegetated areas. The lagged effect of drought on WUE was a short period (1–4 months) for shrubland and sparse vegetation, middle and long periods (5–12 months) for forest. (2) When drought occurred, WUE decreased by 36.95% in the Tibetan Plateau and 24.93% in West Africa, while WUE in North Europe, Alaska/N.W. Canada, and West Asia increased by 14.64%, 8.83%, and 8.53%, respectively. The negative and positive impacts of drought on WUE in each vegetation type were commensurate. Our results provide useful information for understanding the response of ecosystem carbon and water cycles to drought..
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background and Aims
Sam50, a key component of the sorting and assembly machinery (SAM) complex, is also involved in bridging mitochondrial outer‐membrane and inner‐membrane contacts. However, the ...physiological and pathological functions of Sam50 remain largely unknown.
Approach and Results
Here we show that Sam50 interacts with MICOS (mitochondrial contact site and cristae organizing system) and ATAD3 (ATPase family AAA domain‐containing protein 3) to form the Sam50‐MICOS‐ATAD3‐mtDNA axis, which maintains mtDNA stability. Loss of Sam50 causes mitochondrial DNA (mtDNA) aggregation. Furthermore, Sam50 cooperates with Mic60 to bind to cardiolipin, maintaining the integrity of mitochondrial membranes. Sam50 depletion leads to cardiolipin externalization, which causes mitochondrial outer‐membrane and inner‐membrane (including crista membrane) remodeling, triggering Bax mitochondrial recruitment, mtDNA aggregation, and release. Physiologically, acetaminophen (an effective antipyretic and analgesic)–caused Sam50 reduction or Sam50 liver‐specific knockout induces mtDNA release, leading to activation of the cGAS‐STING pathway and liver inflammation in mice. Moreover, exogenous expression of Sam50 remarkably attenuates APAP‐induced liver hepatoxicity.
Conclusions
Our findings uncover the critical role of Sam50 in maintaining mitochondrial membrane integrity and mtDNA stability in hepatocytes and reveal that Sam50 depletion–induced cardiolipin externalization is a signal of mtDNA release and controls mtDNA‐dependent innate immunity.
Chen et al. reveal that hepatocyte Sam50 reduction‐induced cardiolipin externalization augments Bax/Bak oligomerlation and then facilates mtDNA release to aggrevate liver injury.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Diagnosis and early assessment of the treatment response of rheumatoid arthritis (RA) necessitates a reliable bioanalytical method for rapid, sensitive, and specific detection of the hypochlorous ...acid (HOCl) biomarker in inflammatory diseases. Herein, two fluorescence probes, Probe‐1 and Probe‐2 are developed for quantitative monitoring and visualization of inflammatory response–related HOCl levels in vitro and in vivo. In the presence of HOCl, fluorescence “OFF–ON” response is obtained for both the probes as a result of specific HOCl‐triggered CN bond cleavage reaction. Probe‐1 and Probe‐2 feature rapid response (<4 s), a high degree of sensitivity and selectivity toward HOCl, which allow them to be used for quantification of HOCl in a simulated physiological condition. Using Probe‐2 as the probe, fluorescence imaging and flow cytometry analysis of HOCl levels in lysosome of inflammatory mimic cells, visualization of HOCl generation in endotoxin‐induced inflammation of adult zebrafish and RA of mice are possible. Probe‐2 exhibits high effectiveness for early assessment of the treatment response of HOCl‐mediated RA in mice with an antiarthritic drug, methotrexate (MTX). The results demonstrate that Probe‐2 is a powerful tool for future studies on diagnosis and monitoring treatment efficiency in a broad range of inflammatory diseases, including RA.
Unique fluorescence probes, Probe‐1 and Probe‐2, are reported for rapid and sensitive detection of hypochlorous acid (HOCl) biomarker in inflammatory diseases. Probe‐2 exhibits superb performance in monitoring and visualizing of HOCl generation in lysosomes of inflammatory mimic macrophage cells and zebrafish. Inflammatory response of rheumatoid arthritis in living mice and HOCl‐mediated treatment response are possible using Probe‐2 as a probe.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The reactive oxygen species- (ROS-) induced nod-like receptor protein-3 (NLRP3) inflammasome triggers sterile inflammatory responses and pyroptosis, which is a proinflammatory form of programmed cell ...death initiated by the activation of inflammatory caspases. NLRP3 inflammasome activation plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Our present study investigated whether diabetes aggravated MI/R injury through NLRP3 inflammasome-mediated pyroptosis. Type 1 diabetic rat model was established by intraperitoneal injection of streptozotocin (60 mg/kg). MI/R was induced by ligating the left anterior descending artery (LAD) for 30 minutes followed by 2 h reperfusion. H9C2 cardiomyocytes were exposed to high glucose (HG, 30 mM) conditions and hypoxia/reoxygenation (H/R) stimulation. The myocardial infarct size, CK-MB, and LDH release in the diabetic rats subjected to MI/R were significantly higher than those in the nondiabetic rats, accompanied with increased NLRP3 inflammasome activation and increased pyroptosis. Inhibition of inflammasome activation with BAY11-7082 significantly decreased the MI/R injury. In vitro studies showed similar effects, as BAY11-7082 or the ROS scavenger N-acetylcysteine, attenuated HG and H/R-induced H9C2 cell injury. In conclusion, hyperglycaemia-induced NLRP3 inflammasome activation may be a ROS-dependent process in pyroptotic cell death, and NLRP3 inflammasome-induced pyroptosis aggravates MI/R injury in diabetic rats.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
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