During myocardial infarction, infiltrated macrophages have pivotal roles in cardiac remodeling and delayed M1 toward M2 macrophage phenotype transition is considered one of the major factors for ...adverse ventricular remodeling. We investigated whether dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, attenuates cardiac fibrosis via regulating macrophage phenotype by a reactive oxygen and nitrogen species (RONS)/STAT3-dependent pathway in postinfarcted rats. Normoglycemic male Wistar rats were subjected to coronary ligation and then randomized to either saline, dapagliflozin (a specific SGLT2 inhibitor), phlorizin (a nonspecific SGLT1/2 inhibitor), dapagliflozin + S3I-201 (a STAT3 inhibitor), or phlorizin + S3I-201 for 4 weeks. There were similar infarct sizes among the infarcted groups at the acute and chronic stages of infarction. At day 3 after infarction, post-infarction was associated with increased levels of superoxide and nitrotyrosine, which can be inhibited by administering either dapagliflozin or phlorizin. SGLT2 inhibitors significantly increased STAT3 activity, STAT3 nuclear translocation, myocardial IL-10 levels and the percentage of M2 macrophage infiltration. At day 28 after infarction, SGLT2 inhibitors were associated with attenuated myofibroblast infiltration and cardiac fibrosis. Although phlorizin decreased myofibroblast infiltration, the effect of dapagliflozin on attenuated myofibroblast infiltration was significantly higher than phlorizin. The effects of SGLT2 inhibitors on cardiac fibrosis were nullified by adding S3I-201. Furthermore, the effects of dapagliflozin on STAT3 activity and myocardial IL-10 levels can be reversed by 3-morpholinosydnonimine, a peroxynitrite generator. Taken together, these observations provide a novel mechanism of SGLT2 inhibitors-mediated M2 polarization through a RONS-dependent STAT3-mediated pathway and selective SGLT2 inhibitors are more effective in attenuating myofibroblast infiltration during postinfarction remodeling.
•Infiltrated macrophages play a role for adverse postinfarction remodeling.•It remained unclear whether dapagliflozin modulates M2 macrophage.•Post-infarction increased M1 macrophages, which were inhibited by dapagliflozin.•The effects of dapagliflozin on M2 polarization were nullified by S3I-201.•Thus, dapagliflozin mediated M2 polarization through a STAT3-related pathway.
This work studied polyphenylene oxide tetramethylammonium (PPO-TMA) anion exchange membrane by dissipative particle dynamics (DPD) simulations. The simulation method is validated by ...semiquantitatively reproducing the ion conductivity of a standard PPO-TMA and then applied to systematically explore the microstructure and ion diffusivity of modified PPO-TMA influenced by alkyl chain length, side-chain structure, and side-chain distribution. The nanosegregation of hydrophobic and hydrophilic domains is driven by alkyl side-chain modifiers, and the ionic pathways formed in lamellar structure are observed if the side chains are distributed normally as comblike structure. In these systems, ion conductivity has been elevated to 17 mS/cm compared to 11 mS/cm for nonmodified PPO-TMA. The solvation of cationic groups is also crucial for forming effective ion transport pathways. The percolated water domain breaks into smaller clusters if the charged TMA groups are moved toward PPO backbones, indicating that the alkyl spacer modification outperforms the alkyl extender design. By further altering the tethering style of side chains from comblike to block-copolymer-like, the lamellar water percolation transforms into interconnective water framework, which promotes the ion conductivity to 22 mS/cm.
Anion-exchange membranes (AEM) are polyelectrolytes functionalized with cationic groups. Studies of AEM in the past few decades suggest that AEM is a competitive alternative to conventional ...proton-exchange membranes in fuel cell (FC) application, mainly because of its alkaline environment that allows the use of non-noble metal for electrocatalysts. Understanding AEM morphology and anion transport is a key for improving the performance of AEMFC. The present work uses dissipative particle dynamics to simulate the mesoscale structure of hydrated poly(phenylene oxide) (PPO) functionalized with tetramethylamine (TMA) groups on different hydration levels (HL) and ion-exchange capacities (IEC). Additional spacers are tethered onto PPO–TMA to enhance the nanosegregation of hydrophilic and hydrophobic subdomains, and therefore expand the pathways for ion transportation. A variety of spacers studied include alkyl spacers in PPO–C4–TMA, PPO–C8–TMA, and alkoxy spacers in PPO–E2–TMA. Simulation results show that the diffusivities of anions and water increase with the elevation of HL and IEC, which is consistent with experimental observations. Adding hydrophobic alkyl spacers intensifies the phase segregation and the formation of larger water clusters. The size of the clusters further increases due to the agglomeration with the increase of HL or the length of the alkyl spacers. Nevertheless, hydrophobicity from the side chains results in overaggregated water phase, and therefore forms bottleneck within the transport pathways that retards the anion diffusivity. The same issue is observed if the alkyl fragment is tethered on TMA as an extender. A suggested design using less hydrophobic alkoxy spacers, PPO–E2–TMA, outperforms all of the other types of AEM in this work in anion transport by forming narrower channels but more connected network. The provided fundamental information may be useful for designing more versatile AEMFC.
The dissipative particle dynamics (DPD) mesoscopic method is used to investigate the self-assembly of rhamnolipid congeners and their aggregation behaviors with paraffins including nonane and ...pentadecane. The coarse-grained force field is parameterized by combining molecular dynamics (MD) simulations, COSMOtherm calculations, and available experimental data. This model reproduces the vesicular formation of α-l-rhamnopyranosyl-β-hydroxydecanoyl-β-hydroxydecanoate (Rha-C10-C10) reported by all-atom MD simulations. The vesicle composed of Rha-C10-C10 is found to be most stable at a surfactant concentration of 100–146 mM based on asphericity analysis. The architecture of rhamnolipid congeners affects the morphology of their aggregates. Di-rhamno-di-lipidic dRha-C16-C16 forms vesicles with a thicker unilamellar layer of 3.2 nm. Rha-C16-C16 forms vesicles at a lower concentration of 70 mM, but the enclosed water space collapses when the surfactant concentration increases. dRha-C10-C10 forms wormlike micelles, which agglomerate into a torus and interconnected network at higher concentrations. In the presence of alkane molecules, dRha-C10-C10 maintains its wormlike micellar morphology with alkane molecules wrapped inside the aggregates. For Rha-C10-C10, Rha-C16-C16, and dRha-C16-C16, nonane molecules are distributed in the hydrophobic subdomain formed by rhamnolipid molecules. Spherical vesicles are formed at a surfactant concentration of 50 mM and then develop into ellipsoidal vesicles when the concentration increases to 125 mM. When mixed with pentadecane, the alkane molecules are aggregated and surrounded by surfactants forming a core–shell structure at a low surfactant concentration of 20 mM. At higher alkane and surfactant concentrations, the morphologies develop into disk micelles, wormlike micelles, and vesicles, with pentadecane molecules being distributed and packed with rhamnolipids. The obtained simulation results suggest that these biosurfactants have potential as environmental remediation agents.
Hydroxide ion conductivity is a key aspect of anion exchange membranes and is mainly determined by the nanoscale membrane morphologies. Fundamental understanding of the structural and transport ...properties of membranes in terms of polymer architectures is crucial for future development of membrane-based applications. Using mesoscale simulations, this work predicts the mesostructure of the hydrated triblock copolymers; the designed polymers are composed of aromatic (polyphenylene oxide, PPO) or aliphatic (polystyrene-ethylene-butylene-styrene, SEBS) backbones, with cationic side chains being modified by hydrophobic or hydrophilic spacers. For PPO-based polymers, using octyl spacers creates a meshlike water network, yielding ion conductivity equal to 30.6 mS/cm at room temperature. For SEBS-based polymers, the nonmodified form is sufficient to produce ion-conducting pathways. Adding hydrophobic spacers further enhances the nanosegregation, and the membranes provide similar conductivity at a lower ion exchange capacity and water content. Adding hydrophilic spacers, however, has negative impacts on the ion transport. The side chains are in the stretched configurations, which sterically hinder the mobility of water and hydroxide ions. Such a resistance can be overcome by adapting multication side-chain designs, where large water channels are formed, yielding ion conductivity as high as 32.8 mS/cm.
Micellization of surfactant solutions is a ubiquitous phenomenon in natural systems and technological processes, and its theoretical description represents one of the cornerstone problems in the ...physical chemistry of colloidal systems. However, successful attempts of quantitative modeling confirmed by experimental data remains limited. We show, for the first time, that the dissipative particle dynamics with rigorously defined soft repulsion interaction and rigidity parameters is capable of predicting micellar self-assembly of nonionic surfactants. This is achieved due to a novel approach suggested for defining the interaction parameters by fitting to the infinite dilution activity coefficients of binary solutions formed by reference compounds that represent coarse-grained fragments of surfactant molecules. Using this new parametrization scheme, we obtained quantitative agreement with the experimental critical micelle concentration and aggregation number for several typical surfactants of different chemical structures. The proposed approach can be extended to various colloidal and polymeric systems beyond nonionic surfactant solutions.
The ω‐3 fatty acids exert as an antioxidant via the G protein‐coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. ...Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative‐nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle‐treated infarcted rats compared with sham. These changes of oxidative‐nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative‐nitrosative stress and connexin43 phosphorylation were abolished by administering AH‐7614, an inhibitor of GPR120. SIN‐1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up‐regulation of connexin43 phosphorylation through a GPR120‐dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
Using dissipative particle dynamics (DPD) simulations, we explore the specifics of micellization in the solutions of anionic and cationic surfactants and their mixtures. Anionic surfactant sodium ...dodecyl sulfate (SDS) and cationic surfactant cetyltrimethylammonium bromide (CTAB) are chosen as characteristic examples. Coarse-grained models of the surfactants are constructed and parameterized using a combination of atomistic molecular simulation and infinite dilution activity coefficient calibration. Electrostatic interactions of charged beads are treated using a smeared charge approximation: the surfactant heads and dissociated counterions are modeled as beads with charges distributed around the bead center in an implicit dielectric medium. The proposed models semiquantitatively describe self-assembly in solutions of SDS and CTAB at various surfactant concentrations and molarities of added electrolyte. In particular, the model predicts a decline in the free surfactant concentration with the increase of the total surfactant loading, as well as characteristic aggregation transitions in single-component surfactant solutions caused by the addition of salt. The calculated values of the critical micelle concentration reasonably agree with experimental observations. Modeling of catanionic SDS–CTAB mixtures show consecutive transitions to worm-like micelles and then to vesicles caused by the addition of CTAB to micellar solution of SDS.
Micelle formation in surfactant solutions is a self-assembly process governed by complex interplay of solvent-mediated interactions between hydrophilic and hydrophobic groups, which are commonly ...called heads and tails. However, the head–tail repulsion is not the only factor affecting the micelle formation. For the first time, we present a systematic study of the effect of chain rigidity on critical micelle concentration and micelle size, which is performed with the dissipative particle dynamics simulation method. Rigidity of the coarse-grained surfactant molecule was controlled by the harmonic bonds set between the second-neighbor beads. Compared to flexible molecules with the nearest-neighbor bonds being the only type of bonded interactions, rigid molecules exhibited a lower critical micelle concentration and formed larger and better-defined micelles. By varying the strength of head–tail repulsion and the chain rigidity, we constructed two-dimensional diagrams presenting how the critical micelle concentration and aggregation number depend on these parameters. We found that the solutions of flexible and rigid molecules that exhibited approximately the same critical micelle concentration could differ substantially in the micelle size and shape depending on the chain rigidity. With the increase of surfactant concentration, primary micelles of more rigid molecules were found less keen to agglomeration and formation of nonspherical aggregates characteristic of flexible molecules.
Oxidative damage in the brain may lead to cognitive impairments. There was considerable debate regarding the beneficial effects of physical exercise on cognitive functions because exercise protocols ...have varied widely across studies. We investigated whether different exercise intensities alter performance on cognitive tasks. The experiment was performed on spontaneously hypertensive rats (6 months at the established phase of hypertension) distributed into 3 groups: sedentary, low‐intensity exercise and high‐intensity exercise. Systolic blood pressure measurements confirmed hypertension in spontaneously hypertensive rats. In comparison to normotensive Wistar‐Kyoto rats, sedentary spontaneously hypertensive rats had similar escape latencies and a similar preference for the correct quadrant in the probe trial. Compared to the sedentary group, the low‐intensity exercise group had significantly better improvements in spatial memory assessed by Morris water maze. Low‐intensity exercise was associated with attenuated reactive oxygen species, as measured by dihydroethidine fluorescence and nitrotyrosine staining in the dentate gyrus of the hippocampus. This was coupled with increased numbers of neurons and dendritic spines as well as a significant upregulation of synaptic density. In contrast, the beneficial effects of low‐intensity exercise are abolished in high‐intensity exercise as shown by increased free radical levels and an impairment in spatial memory. We concluded that exercise is an effective strategy to improve spatial memory in spontaneously hypertensive rats even at an established phase of hypertension. Low‐intensity exercise exhibited better improvement on cognitive deficits than high‐intensity exercise by attenuating free radical levels and improving downstream synaptic plasticity.
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