- A Kidnapping Story: How Coxsackievirus B3 and Its Host Cell Interact. [Journal Article]
- CPCell Physiol Biochem 2019; 53(1):121-140
- Infections with Coxsackievirus B3 and other members of the enterovirus genus are a common reason for myocarditis and sudden cardiac death in modern society. Despite intensive scientific efforts to cu…
Infections with Coxsackievirus B3 and other members of the enterovirus genus are a common reason for myocarditis and sudden cardiac death in modern society. Despite intensive scientific efforts to cure enterovirus infections, there is still no standardized treatment option. The complexity of Coxsackievirus B3´s effects on the host cell make well defined studies on this topic very challenging. However, recent publications report newly found effects of CVB3´s structural and non-structural proteins on infected cells. For the first time, the viral capsid protein VP1 was shown to have direct influence on the viral life-cycle. By shortening the G0 and the G2 phase and simultaneously prolonging the G1 and G1-S phase, the translation of viral proteins is enhanced and the production of viable CVB3 particles is promoted. Coxsackievirus B3´s viroporin, protein 2B, was recently studied in more detail as well. Structural and physiological analyses identified two hydrophilic α-helices in the structure of 2B, enabling it to insert into cellular membranes of host cells. As main target of 2B the endoplasmatic reticulum was identified. The insertion of 2B into the ER membranes leads to an uncontrolled calcium outflow into the cytoplasm. Additional insertion of 2B into the cell membrane leads to host cell destabilization and in the end to release of viral progeny. The importance of the Coxsackievirus B3´s proteases 2A and 3C in pathogenicity is observed since years. Recently, DAP5 and eIf4G were identified as new cleavage targets for protease 2A. Cleavage of DAP-5 into DAP5-N and DAP5-C changes the gene expression of the host cell and promotes cell death. Additionally, protease 3C targets and cleaves procaspase 8 promoting the mitochondrial apoptosis pathway and cell death. Recent studies identified significant effects of CVB3 on mitochondria of infected cells. Mouse cardiomyocytes showed decreased activities of respiratory chain complexes I-III and changed transcription of important subunits of the complexes I-IV. A disrupted energy metabolism may be one of the main causes of cardiac insufficiency and death in CVB3 infected patients. In addition to a modified energy metabolism, CVB3 affects cardiac ion channels, KCNQ1 in particular. SGK1, which is an important mediator in KCNQ1 membrane insertions, is highly upregulated during CVB3 infections. This results in an increased insertion of KCNQ1 into the cell membrane of cardiac cells. Under stress conditions, this KCNQ1 overshoot may lead to a disturbed cardiac action potential and therefore to sudden cardiac death, as it is often observed in CVB3 infected persons.
- Potassium Channels in Vascular Smooth Muscle: A Pathophysiological and Pharmacological Perspective. [Editorial]
- FCFundam Clin Pharmacol 2019 Jun 23
- Potassium (K+) ion channels are the main determinant of vascular tone by regulating cell resting membrane potential (Em). Systemic arterial tone as well as pulmonary arterial tone is mainly controlle…
Potassium (K+) ion channels are the main determinant of vascular tone by regulating cell resting membrane potential (Em). Systemic arterial tone as well as pulmonary arterial tone is mainly controlled by the Em of systemic vascular smooth muscle cells (SVSMC) or pulmonary arterial smooth muscle cells (PASMC), and via endothelial cell (EC) functions. Resting membrane potential is dependent of membrane permeability to cations and anions. This article is protected by copyright. All rights reserved.
- A chemiluminescence resonance energy transfer strategy and its application for detection of platinum ions and cisplatin. [Journal Article]
- MAMikrochim Acta 2019 Jun 22; 186(7):463
- A novel chemiluminescence resonance energy transfer (CRET) system was developed and combined with a structure-switching aptamer for the highly sensitive detection of platinum. Platinum was chosen as …
A novel chemiluminescence resonance energy transfer (CRET) system was developed and combined with a structure-switching aptamer for the highly sensitive detection of platinum. Platinum was chosen as a model analyte to demonstrate the generality of the new CRET system. This aptameric platform consisted of a streptavidin labeled aptamer against platinum and a streptavidin-coated magnetic bead for the selective separation of platinum-bound aptamer. The platinum-aptamer probe contained several guanine (G) bases bound to the 3,4,5-trimethoxyphenyl-glyoxal (TMPG) donor group at the 5' end, a fluorescent acceptor (6-carboxy-2',4,7,7'-tetrachlorofluorescein, TET) at the 3' end, and a streptavidin aptamer sequence in which several base pairs were replaced by the G-G mismatch to induce the platinum-oligonucleotide coordination. The chemiluminescence (CL) generated by TMPG/G bases is transferred to the acceptor (TET). In the presence of platinum, the platinum-aptamer probe was folded such that the G bases at the 5' end and TET at the 3' were in close proximity. The complex was separated using streptavidin-coated magnetic beads by the addition of TMPG to form the TMPG/G bases complex. The ultraweak CL from the TMPG/G bases was strongly enhanced by TET. This novel CRET-based method can be easily performed with high limit of detection (50 ng·mL-1) and selectivity over other metal ions. This technique provides a novel method for simple, fast, and convenient point-of-care diagnostics for monitoring proteins and metal ions. Graphical abstract Schematic presentation of chemiluminescence resonance energy transfer (CRET) detection of platinum(II) by Pt-base pair coordination to the aptamer. TMPG: 3,4,5-trimethoxyphenyl-glyoxal, fluorophore TET: 6-carboxy-2',4,7,7'-tetrachlorofluorescein.
- The effect of thermal pre-incubation and exposure on sensitivity of zebrafish (Danio rerio) to copper and cadmium single and binary exposures. [Journal Article]
- ATAquat Toxicol 2019 Jun 13; 213:105226
- Zebrafish (Danio rerio) is a prominent model organism in a wide range of biological studies including toxicology. However, toxicological studies are often performed at species specific optimum temper…
Zebrafish (Danio rerio) is a prominent model organism in a wide range of biological studies including toxicology. However, toxicological studies are often performed at species specific optimum temperature, and knowledge on the effect of different temperature regimes on the toxicity of metal ions is rather limited. To address this knowledge gap, present study investigates the effect of various thermal scenarios (simultaneous and sequential; acute and chronic) on the toxicity of Cu and Cd in zebrafish. For this purpose we assessed mortality and whole body metal burdens as indicators of toxicity and bioavailability, respectively, and whole body electrolyte concentrations and body condition as the indicators of physiological condition. Thermal pre-incubations (for 12 or 96 h or 28 days) and subsequent metal ion exposures (for 10 days) were conducted at 17, 22, 25, 28, 32 and 34 °C. The metal exposures were performed at Cu concentrations of 1.2 μM and Cd concentrations of 0.2 μM, both singly and in binary mixtures. Irrespective of thermal treatments, Cu exposures resulted in greater mortality than Cd exposures at the given concentrations. Moreover, the Cu and Cd mixture indicated a synergistic effect. While acute pre-incubation for 12 or 96 h at elevated temperatures increased mortality in the subsequent metal exposure at the optimum temperature (28 °C), pre-incubation at cold temperatures in this scenario appeared to increase tolerance towards the subsequent metal exposure. Chronic thermal pre-incubation of zebrafish to a range of temperatures for 28 days moderated the effect of temperature fluctuations on subsequent metal toxicity at the optimum temperature. Chronic thermal pre-incubation at a range of temperatures followed by metal exposure at the same temperature showed that environmental temperature variations (higher or lower than optimal temperature) coupled with metal exposure, led to increased mortality, furthermore, the highest whole body metal burdens were measured in this scenario. Nevertheless, neither the whole body burden of metals, nor the metal accumulation rate, were predictors of mortality, i.e. these two values were not higher in dead fish in comparison to those that survived the exposures. Finally, we observed a significant decrease in the whole body Na+ level of dead fish in comparison to fish which survived the exposure conditions, suggesting that survival depends on maintaining Na+ homeostasis under the applied multi-stress conditions. Overall, our results show that thermal pre-history and ambient temperature play an important role in determining the tolerance of zebrafish towards metal ion stress.
- Impact of network heterogeneity on electrokinetic transport in porous media. [Journal Article]
- JCJ Colloid Interface Sci 2019 Jun 10; 553:451-464
- We present a numerical study of electrokinetic transport in porous media, focusing on the role of heterogeneity in a porous microstructure on ion concentration polarization and over-limiting current.…
We present a numerical study of electrokinetic transport in porous media, focusing on the role of heterogeneity in a porous microstructure on ion concentration polarization and over-limiting current. For simplicity, the porous medium is modeled as a network of long, thin charged cylindrical pores, each governed by one-dimensional effective transport equations. For weak surface conduction, when sufficiently large potential is applied, we demonstrate that electrokinetic transport in a porous network can be dominated by electro-convection via internally induced flow loops, which is not properly captured by existing homogenized models. We systematically vary the topology and "accessivity" of the pore network and compare with simulations of traditional homogenized parallel-pore (capillary-bundle) models, in order to reveal the effects of regular and hierarchical connectivity. Our computational framework sheds light on the complex physics of electrokinetic phenomena in microstructures and may be used to design porous media for applications, such as water desalination and purification by shock electrodialysis.
- Positive feedback nanoamplifier responded to tumor microenvironments for self-enhanced tumor imaging and therapy. [Journal Article]
- BBiomaterials 2019 Jun 06; 216:119255
- Targeted activation or enhancement is an attractive strategy in the design of nano-theranostics. However, the responsiveness of the nanoagents is restricted by the limited levels of intra-tumor stimu…
Targeted activation or enhancement is an attractive strategy in the design of nano-theranostics. However, the responsiveness of the nanoagents is restricted by the limited levels of intra-tumor stimuli. Herein, we constructed a positive feedback nanoamplifier by encapsulating glucose oxidase (GOx) in the ferric ions contained metal organic framework (MIL-100), and coating the nanoparticles with polydopamine modified hyaluronic acid (HA-PDA). The mechanism of action of the ensuing nanoamplifiers was three pronged: 1) the high intra-tumor acidity accelerated the release of GOx, which consumed endogenous glucose and "starved" the tumors, in addition to aggravating the local acidity and H2O2 levels; 2) the hydroxyl radicals (·OH) generated from the Fenton-like reaction between MIL-100 with H2O2 contributed to the chemodynamic tumor therapy and augmented the O2 microenvironment, which could be speeded up under acid condition; 3) the oxygen (O2) produced in the Fenton-like reaction relieved the intra-tumor hypoxia and ensured the enzymatic reaction of GOx, along with augmenting the photoacoustic signal of nanoamplifier. Preliminary experiments in tumor bearing mice showed that the nanoamplifier not only boosted the local acidity/H2O2/O2 levels in tumor site to successfully suppress the growth of tumors through the self-enhanced chemodynamic/starving therapy, but also achieved the photoacoustic imaging of tumors. Taken together, this novel nanoamplifier with the abilities of self-enhanced tumor imaging and therapy is a promising entrant in the field of anti-tumor theranostics.
- TLC-electrostatic field induced spray ionization-MS analysis of diverse structural skeletons and its coupling with TLC bioautography for characterization of lipase inhibitory components in American ginseng. [Journal Article]
- JPJ Pharm Biomed Anal 2019 Jun 15; 174:486-494
- Natural compounds with diverse structural skeletons have different ionization efficiencies and different mass spectrometry (MS) responses. Some key factors influencing the electrostatic field induced…
Natural compounds with diverse structural skeletons have different ionization efficiencies and different mass spectrometry (MS) responses. Some key factors influencing the electrostatic field induced spray ionization (EFISI)-MS for a variety of natural compounds have been optimized and improved. Fifteen reference substances representing ten well-known skeletons of natural products including alkaloids, flavonoids, phenolic acids, lignans, coumarins, anthraquinones, monoterpenoids, sesquiterpenoids, diterpenoids and triterpenoids, were selected and investigated for their EFISI-MSn responses on TLC plates using a dot-blot test. The optimized ionization conditions for these compounds in the positive ion mode were achieved, together with their limits of detection. In addition, to avoid the limitation of some compounds being difficultly ionized in the positive ion mode, the negative ion mode of the TLC-EFISI-MS method was developed and optimized for the first time. By coupling with a TLC bioautographic assay, nine lipase inhibitory components in American ginseng (Panax quinquefolium roots) have been successfully identified/ tentatively identified in situ by their EFISI-MSn data and further confirmed by comparisons of their Rf values and MSn data with those of reference substances. These lipase inhibitory compounds were 24(S)-pseudo-ginsenoside F11, ginsenosides Rg1, Re, XVII, Rc, Rb2/Rb3, Rb1, Ro and malonyl-ginsenoside Rb1. This is the first report that the TLC-EFISI-MSn method is adapted to a broad-spectrum analysis of structural skeletons present in herbal medicines.
- High-efficiency antioxidant system, chelating system and stress-responsive genes enhance tolerance to cesium ionotoxicity in Indian mustard (Brassica juncea L.). [Journal Article]
- EEEcotoxicol Environ Saf 2019 Jun 20; 181:491-498
- Indian mustard (Brassica juncea L.) was more tolerance to Cs than some sensitive plants, such as Arabidopsis thaliana and Vicia faba, and may have a special detoxification mechanism. In this study, t…
Indian mustard (Brassica juncea L.) was more tolerance to Cs than some sensitive plants, such as Arabidopsis thaliana and Vicia faba, and may have a special detoxification mechanism. In this study, the effects on reactive oxygen species (ROS) content, the antioxidant enzyme system and chelation system in Indian mustard were studied by observing different plant physiological responses. In addition, we focused on the analysis of gene regulatory networks related to ROS formation, ROS scavenging system, and other stress-response genes to Cs exposure using a transcriptome-sequencing database. The results showed that ROS and malonaldehyde content in seedlings increased significantly in Cs-treatment groups. The enzyme activities of superoxide dismutase, peroxidase, catalase, and ascorbate peroxidase were increased, and the synthesis of antioxidants glutathione, phytochelatin and metallothionein also increased under Cs treatment. Further analysis showed that ROS formation pathways were primarily the photosynthetic electron transport chain process and photorespiration process in the peroxisome. Antioxidant enzyme systems and the respiratory burst oxidase homolog protein-mediated signal transduction pathway played a key role in ROS scavenging. In summary, one of the mechanisms of tolerance and detoxification of Indian mustard to Cs was that it enhanced the scavenging ability of antioxidant enzymes to ROS, chelated free Cs ions in cells and regulated the expression of related disease-resistant genes.
- The solution thermodynamic stability of desferrioxamine B (DFO) with Zr(IV). [Journal Article]
- JIJ Inorg Biochem 2019 Jun 15; 198:110753
- Desferrioxamine B (DFO, [H4L]+, ligand) is currently the preferred chelator for 89Zr(IV), however the biological studies suggest that it releases the metal ion in vivo. Herein, we present the solutio…
Desferrioxamine B (DFO, [H4L]+, ligand) is currently the preferred chelator for 89Zr(IV), however the biological studies suggest that it releases the metal ion in vivo. Herein, we present the solution thermodynamics of complexes formed between Zr(IV) and this hexadentate chelating agent, the data surprisingly not yet available in the literature. Several techniques including electrospray ionization mass spectrometry (ESI-MS), potentiometry, UV-Vis spectroscopy and isothermal titration calorimetry (ITC) were used to determine the stoichiometry and thermodynamic stability of complexes formed in solution over pH range 1-11, overcoming all the difficulties with the characterisation of the aqueous solution chemistry of Zr(IV) complexes, like strong hydrolysis and lack of spectral information. A model containing only mononuclear complexes, i.e. [ZrHL]2+ [ZrL]+, [ZrLH-1] throughout the entire measured pH range is proposed. The stability constants and pM (Zr(IV)) value determined for Zr(IV)-DFO system, place DFO among good Zr(IV) chelators, however the formation of 6-coordinate unsaturated complexes (i.e. with coordination sphere of 8-coordinate Zr(IV) completed by water molecules), together with the susceptibility of coordinated water molecule to deprotonation, are suggested to be the reason of in vivo instability of 89Zr(IV)-DFO complexes.
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- Efficiency and mechanism of diclofenac degradation by sulfite/UV advanced reduction processes (ARPs). [Journal Article]
- STSci Total Environ 2019 Jun 15; 688:65-74
- Diclofenac (DCF) is a non-steroidal anti-inflammatory drug which is frequently detected in the aqueous environment. The synergistic treatment using sulfite and UV irradiation is proposed to be one of…
Diclofenac (DCF) is a non-steroidal anti-inflammatory drug which is frequently detected in the aqueous environment. The synergistic treatment using sulfite and UV irradiation is proposed to be one of the most effective advanced reduction processes (ARPs) to degrade refractory contaminants. This paper systematically investigated the performance and mechanism of DCF degradation by sulfite/UV ARP under various conditions. A significant enhancement in degradation efficiency of DCF was exhibited via sulfite/UV ARP compared with direct UV photolysis, which is primarily due to the generation of reductive radicals (eaq- and H). This process was well described by a pseudo first-order kinetic model with a rate constant of 0.154 min-1. The influence of solution pH, sulfite dosage, initial DCF concentration and UV intensity were evaluated. Results revealed that DCF more favorably reacted with H in an acidic environment than with eaq- under alkaline conditions. A positive impact on the DCF decomposition was observed with increasing sulfite dosage, but with an inhibiting trend at high sulfite concentrations. The degradation rate constant was accelerated by increasing the UV intensity, while decreased by promoting the initial DCF concentration. Degradation mechanisms at different pH levels revealed that the reduction reactions were induced by eaq- at pH 9.2, and dominated by H at pH 6.0. Complete dechlorination was readily achieved with all chlorine atoms in DCF released as chloride ions under sulfite/UV ARP, which may lead to a decreased toxicity of the degradation products. This observation emphasized the advantages of sulfite/UV ARP on DCF degradation, in comparison with that under direct UV photolysis.