Dapagliflozin reduces pulmonary vascular damage and susceptibility to atrial fibrillation in right heart disease.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have made considerable progress in the field of heart failure, but their application in arrhythmia remains to be in-depth. Right heart disease (RHD) often leads to right heart dysfunction and is associated with atrial fibrillation (AF). Here, we explored the possible electrophysiologic effect of dapagliflozin (a type of SGLT2is) in the development of AF in rats with RHD. METHODS AND RESULTS: Rats in the experimental group were intraperitoneally injected with a single dose of 60 mg/kg monocrotaline (MCT group, n = 32) on the first day of the experiment, whereas rats in the control group were injected with vehicle (CTL group, n = 32). Rats in the treatment subgroup were treated with dapagliflozin solution orally (MCT + DAPA and CTL + DAPA groups) for a total of 4 weeks, whereas rats in the rest of subgroups were given sterile drinking water. After 4 weeks, echocardiography demonstrated that MCT group rats developed obvious pulmonary arterial hypertension and right heart dysfunction. In addition, there were also obvious inflammatory infiltration, fibrosis, and muscularization in right atrial and pulmonary arteries. The P-wave duration (17.00 ± 0.53 ms, vs. 14.43 ± 0.57 ms in CTL; 14.00 ± 0.65 ms in CTL + DAPA; 14.57 ± 0.65 ms in MCT + DAPA; P < 0.05), RR interval (171.60 ± 1.48 ms, vs. 163.10 ± 1.10 ms in CTL; 163.30 ± 1.19 ms in CTL + DAPA; 163.10 ± 1.50 ms in MCT + DAPA; P < 0.05), Tpeak-Tend interval (65.93 ± 2.55 ms, vs. 49.55 ± 1.71 ms in CTL; 48.27 ± 3.08 ms in CTL + DAPA; P < 0.05), and corrected QT interval (200.90 ± 2.40 ms, vs. 160.00 ± 0.82 ms in CTL; 160.40 ± 1.36 ms in CTL + DAPA; 176.6 ± 1.57 ms in MCT + DAPA; P < 0.01) were significantly prolonged in the MCT group after 4 weeks, whereas P-wave amplitude (0.07 ± 0.0011 mV, vs. 0.14 ± 0.0009 mV in CTL; 0.14 ± 0.0011 mV in CTL + DAPA; 0.08 ± 0.0047 mV in MCT + DAPA; P < 0.05) and T-wave amplitude (0.04 ± 0.002 mV, vs. 0.13 ± 0.003 mV in CTL; 0.13 ± 0.003 mV in CTL + DAPA; P < 0.01) were decreased, and atrial 90% action potential duration (47.50 ± 0.93 ms, vs. 59.13 ± 2.1 ms in CTL; 59.75 ± 1.13 ms in CTL + DAPA; 60.63 ± 1.07 ms in MCT + DAPA; P < 0.01) and effective refractory periods (41.14 ± 0.88 ms, vs. 62.86 ± 0.99 ms in CTL; 63.14 ± 0.67 ms in CTL + DAPA; 54.86 ± 0.70 ms in MCT + DAPA; P < 0.01) were shortened. Importantly, the inducibility rate (80%, vs. 0% in CTL; 10% in CTL + DAPA; 40% in MCT + DAPA; P < 0.05) and duration of AF (30.85 ± 22.90 s, vs. 0 ± 0 s in CTL; 0.24 ± 0.76 s in CTL + DAPA; 5.08 ± 7.92 s in MCT + DAPA; P < 0.05) were significantly increased, whereas the expression levels of cardiac ion channels and calcium-handling proteins such as potassium/calcium channels and calmodulin were decreased. Mechanistically, 'NACHT, LRR, and PYD domain-containing protein 3' inflammasome-related pathway was significantly activated in the MCT group. Nevertheless, in the MCT + DAPA group, the above abnormalities were significantly improved. CONCLUSIONS: Dapagliflozin reduces pulmonary vascular damage and right heart dysfunction, as well as the susceptibility to AF in RHD rats.

Protective effects of Dapagliflozin on the vulnerability of ventricular arrhythmia in rats with pulmonary artery hypertension induced by monocrotaline.

Monocrotaline (MCT)-induced pulmonary artery hypertension (PAH) has been reported to cause right heart failure (RHF). Moreover, Right heart diseases have been determined to cause ventricular arrhythmia (VA). So we can conclude that MCT-induced PAH increases the incidence of VA. In addition, Previous studies have determined the benefits of Dapagliflozin (DA) on the cardiac system, but the responses of MCT-induced RHF to DA are not fully reported. So the present study sought to evaluate the effects of DA on the MCT-induced PAH. A dose intraperitoneal injection of MCT (60 mg/kg) was carried out to induce a rat model with PAH. DA (60 mg/l) was administered for 4 weeks following MCT injection. Echocardiography, body weight, blood pressure, blood glucose, electrophysiological study, and Western blot were performed. Four weeks after the MCT injection, MCT-treated rats decreased body weight, blood glucose and blood pressure. In addition, MCT caused the formation of PAH and RHF. Moreover, MCT-induced PAH rats increased the incidence of VA, prolonged action potential duration (APD), and shortened effective refractory period (ERP). Additionally, PAH rats significantly prevented the activated expressions of Ion channel proteins such as potassium channel (Kv1.5, Kv2.1, Kv4.2, Kv4.3) and L-type Ca channel (Cav1.2). As we expected, these changes above in PAH rats were reversed when DA was administered. Mechanistically, DA significantly reduced the levels of toll-like receptor (TLR4), the nuclear factor kappa B (NF-κB) in MCT-treated rats. In conclusion, these findings determine that DA reduces the vulnerability of VA in PAH rats through the TLR4/NF-κB signaling pathway.

Inhibition of ferroptosis reduces susceptibility to frequent excessive alcohol consumption-induced atrial fibrillation.

Both long-term and short-term alcohol consumption can cause internal homeostasis imbalance, and they have been proved to be related to the initiation and development of atrial fibrillation (AF). Ferroptosis is an iron-dependent form of non-apoptotic oxidative death which also regulate the cell death homeostasis, but whether it involves in AF induced by alcohol consumption remains unclear. Here, we report a study on the effect of ferroptosis on susceptibility to AF at different alcohol consumption frequencies. We divided the mice into single or frequent excessive alcohol consumption group which given sterile drinking water or alcohol by gavage at different frequencies. Meanwhile, the experimental group was given an intraperitoneal injection of ferroptosis inhibitor (Fer-1) before alcohol drinking. It was found that once exposure to 5 g/kg/d frequent excessive alcohol consumption, compared with the single excessive alcohol consumption group, the mice serum non-heme iron concentration, accumulation of iron and oxidative stress reaction in atrial tissues were increased, while the body weight, heart weight and heart weight to tibia length (HW/TL) ratio were decreased. In addition, the inducibility rate of AF increased, while RR interval, effective refractory periods (ERPs) and 90 % action potential duration (APD90) shortened, as well as QTc interval prolonged. Furthermore, the protein and mRNA expression levels of GPx4, FTL, FTH1, Kv1.5, Kv2.1, Kv4.3, Cav1.2, Serca2α, p-PLB were down-regulated, while PTGS2 was up-regulated. Most of the changes can be partially or completely reversed by Fer-1. These results suggest that frequent excessive alcohol consumption activates ferroptosis and increases the inducibility rate of AF. Nevertheless, inhibition of ferroptosis can balance iron overload disorders and reduce the generation of reactive oxygen species (ROS), eventually decrease the susceptibility to AF. Our results highlight the importance of guidance and warnings for unhealthy alcohol-abuse lifestyle.

Multi-Component Collaborative Step-by-Step Coloring Strategy to Achieve High-Performance Light-Responsive Color-Switching.

Light-responsive color-switching materials (LCMs) are long-lasting hot fields. However, non-ideal comprehensive performance (such as color contrast and retention time cannot be combined, unsatisfactory repeatability, and non-automated coloring mode) significantly hinder their development toward high-end products. Herein, the development of LCMs that exhibit long retention time, good color contrast, repeatability, and the property of automatic coloring is reported. The realization of this goal stems from the adoption of a bio-inspired multi-component collaborative step-by-step coloring strategy. Under this strategy, a conventional one-step photochromic process is divided into a "light+heat" controlled multi-step process for the fabrication of the desired LCMs. The obtained LCMs can effectively resist the long-troubled ambient-light interference and avoid its inherent yellow background, thereby achieving the longest retention time and good repeatability. Multiple colors are generated and ultra-fast imaging compatible with the laser-printing technology is also realized. The application potential of the materials in short-term reusable identity cards, absorptive readers, billboards, and shelf labels is demonstrated. The results reported herein can potentially help in developing and designing various high-performance, switchable materials that can be used for the production of high-end products.

Ferroportin-mediated ferroptosis involved in new-onset atrial fibrillation with LPS-induced endotoxemia.

Sepsis is a known risk factor for new-onset atrial fibrillation (AF), and previous studies have demonstrated that ferroptosis participates in sepsis-induced organ injury development. Nevertheless, the role of ferroptosis in new-onset AF with sepsis remains largely unknown. This study aims to investigate the underlying mechanisms linking ferroptosis and AF caused by sepsis. LPS-induced endotoxemia is often used to model the acute inflammatory response associated with sepsis. Herein, we reported that ferroptosis was significantly activated in LPS-induced endotoxemia rat model. We also observed that ferroportin (Fpn), the only identified mammalian non-heme iron exporter, was downregulated in the atrium of endotoxemia model. Vulnerability to AF was also significantly increased in a endotoxemia rat model. Additionally, Fpn knockdown by shFpn further increased intracellular iron concentration and oxidative stress and exaggerated the AF vulnerability, which was alleviated by ferroptosis inhibition. Mechanistically, silencing Fpn worsened the alterations in calcium handling proteins expression in a endotoxemia rat model. These findings suggest that Fpn-mediated ferroptosis is involved in the new-onset AF with LPS-induced endotoxemia via worsening the calcium handling proteins dysregulation and provides a novel and promising strategy for preventing AF development in sepsis.

Ferrostatin-1 alleviates lipopolysaccharide-induced cardiac dysfunction.

Cardiac dysfunction is a common complication of sepsis, and is attributed to severe inflammatory responses. Ferroptosis is reported to be involved in sepsis-induced cardiac inflammation. Therefore, we speculated that ferrostatin-1 (Fer-1), a ferroptosis inhibitor, improves cardiac dysfunction caused by sepsis. An intraperitoneal injection of lipopolysaccharide (LPS) was performed to induce a rat cardiac dysfunction model. Echocardiography, cardiac histopathology, biochemical and western blot results were analyzed. Twelve hours after the LPS injection, LPS-treated rats exhibited deteriorating cardiac systolic function, increased levels of cardiac injury markers and levels of ferroptosis markers prostaglandin endoperoxide synthase 2 (PTGS2). Additionally, LPS increased iron deposition in the myocardium, with downregulating ferroportin (FPN, SLC40A1) and transferrin receptor (TfR)expression, and upregulating ferritin light chain (FTL) and ferritin heavy chain (FTH1) expression. Meanwhile, LPS also increased lipid peroxidation in the rat heart by decreasing the expression of glutathione peroxidase 4 (GPX4). Moreover, the expression of inflammatory cytokines, such as tumor necrosis-alpha (TNF-α), interleukin-1 (IL-1ß), and interleukin-6 (IL-6), and inflammatory cell infiltration were also increased following LPS challenge. Finally, the abovementioned adverse effects of LPS were relieved by Fer-1 except for TfR expression. Mechanistically, Fer-1 significantly reduced the levels of toll-like receptor 4 (TLR4), phospho-nuclear factor kappa B (NF-κB), and phospho-inhibitor of kappa Bα (IκBα) in LPS-treated rats. In summary, these findings imply that Fer-1 improved sepsis-induced cardiac dysfunction at least partially via the TLR4/NF-κB signaling pathway.

Incidence, risk factors, and clinical impact of peridevice leak following left atrial appendage closure with the LAmbre device-Data from a prospective multicenter clinical study.

BACKGROUND: In the present study, we sought to explore the incidence, risk factors, and clinical impact of peridevice leaks (PDLs), following LAmbre-assisted left atrial appendage closure (LAAC). METHODS: We performed transesophageal echocardiography (TEE) on patients participating in the LAmbre multicenter study, at Day 1 postimplantation, then at 3 and 12 months to assess PDL, device-related thrombus, left atrial appendage (LAA) thrombus, and left atrial thrombus. Clinical events were recorded during follow-up. RESULT: A total of 152 patients with atrial fibrillation successfully completed LAAC. At 3 months follow-up, 123 patients underwent TEE, with 21 (17%) of them presenting PDL. Among the 121 patients who underwent TEE at 12 months follow-up, 19 (15.7%) presented PDL. Patients with PDL exhibited larger LAA orifice diameters and larger device sizes compared to those in the no leak group. In addition, we found no significant differences in thromboembolic events between patients in the PDL and no leak groups. CONCLUSION: LAmbre-assisted LAA closure resulted in a relatively low PDL occurrence, and its rate decreased over time. In addition, PDL was more prominent in patients with larger LAA orifice diameter and larger device size. However, the condition was not associated with an increased risk for thromboembolic events.

Key Player in Cardiac Hypertrophy, Emphasizing the Role of Toll-Like Receptor 4.

Toll-like receptor 4 (TLR4), a key pattern recognition receptor, initiates the innate immune response and leads to chronic and acute inflammation. In the past decades, accumulating evidence has implicated TLR4-mediated inflammatory response in regulation of myocardium hypertrophic remodeling, indicating that regulation of the TLR4 signaling pathway may be an effective strategy for managing cardiac hypertrophy's pathophysiology. Given TLR4's significance, it is imperative to review the molecular mechanisms and roles underlying TLR4 signaling in cardiac hypertrophy. Here, we comprehensively review the current knowledge of TLR4-mediated inflammatory response and its interaction ligands and co-receptors, as well as activation of various intracellular signaling. We also describe the associated roles in promoting immune cell infiltration and inflammatory mediator secretion, that ultimately cause cardiac hypertrophy. Finally, we provide examples of some of the most promising drugs and new technologies that have the potential to attenuate TLR4-mediated inflammatory response and prevent or reverse the ominous cardiac hypertrophy outcomes.

Highly Tunable Multicolor Water-Jet Rewritable Paper Based on Simple New-Type Dual-Addressable Oxazolidines.

Rewritable paper based on switchable molecules has attracted great attention in both academic research and marketplace. However, most available switchable dyes have single switchable color state only, which cannot meet the long-awaited multicolor reversible displays. Herein, through simple introduction of phenolic hydroxyl group, we develop a series of new oxazolidines with one switch unit, which could reversibly display two different as well as their mix-gradient colors by treating with water and mild acid, respectively, both in solution and solid substrate. The structures and mechanism for the formation of two colors had been studied in detail via UV-vis/NMR spectroscopy, skillfully designing contrast molecules, and kinetics experiments. This multiple switchable colors of the dyes have been further applied to construct a rewritable paper for ink-free printing with multi/gradient-color display.

A Multiaddressable Dyad with Switchable Cyan/Magenta/Yellow Colors for Full-Color Rewritable Paper.

Reversible multicolor displays on solid media created from single-molecule pigments are a long-awaited goal. Herein, a new and simple molecular dyad, which can undergo switchable cyan (C), magenta (M), and yellow (Y) color changes in both solution and the solid state upon exposure to light, water/acid, and nucleophiles, has been designed and synthesized. The stimuli used herein can be applied independent of each other, which is beneficial for color changes without mutual interference. For comparison, mixtures of the two molecular switching motifs that form the basis of the dyad were also studied. The dyad greatly outperforms the corresponding mixed system with respect to reversible color switching on the paper substrate. Its potential for full-color rewritable paper with excellent reversibility has been demonstrated. Legible multicolor prints, that is, high color contrast and resolution, good dispersion, and excellent reversibility, were achieved by using common water-jet and light-based printers. This work provides a very promising approach for the further development of full-color switchable molecules, materials, and displays.

Oxazolidine Transient Bases as Molecular Platforms for Testing Dynamic CO2 Capture in Biochemical Systems.

Understanding the dynamic processes of CO2 capture in biosystems is important because of the great effect CO2 has on the carbon cycle, human health, the global climate, and living environments. After years of multidisciplinary studies, researchers have gained only basic mechanistic knowledge about how enzymes or protein-aggregates capture and deliver CO2, a process involving reversible bonding of CO2 with basic amino acid residues. However, vital mechanistic details of how the activated basic residues within these enzymes or protein-aggregates are initially formed, a crucial step for CO2 capture, are still lacking. Herein, we designed specific molecules, i.e., oxazolidines, which are able to reversibly change their alkalinity via ultrafast isomerizations. Serving as so-called transient bases, these oxazolidines mimic the activated/deactivated states of enzymes or protein-aggregates responsible for dynamic CO2 capture/release. A detailed mechanism for CO2 capture, which involves dynamic covalent bonding and multimolecular cooperative interactions among functional groups that occur with the help of a polyhydroxyl environment, is demonstrated by UV-vis and multiple NMR spectroscopies as well as theoretical calculations. Using suitable oxazolidine transient bases, applications for visual CO2 detection under different detection limit requirements were also developed. Insights for further understanding the process of dynamic CO2 capture in biosystems are also discussed. This oxazolidine-inspired biomimetic CO2 capture serves as a platform for the future development of additional biomimicking systems, as well as offers unique perspectives for other complicated life processes.

Water-soluble and adjustable fluorescence copolymers containing a hydrochromic dye: synthesis, characterization and properties.

Water solubility and adjustable fluorescence properties have been successfully implemented in the hydrochromic amino rhodamine via copolymerization. Four copolymers have been synthesized and clearly characterized by UV-Vis spectroscopy, proving greater detail than the commonly used NMR and IR technologies. The four copolymers have good solubility in pure water and in many common organic solvents, while preserving the hydrochromism of the dye monomer. Based on aggregation and dispersion of the copolymers as adjusted by solvent media and temperature, reversible fluorescence properties were successfully realized. Furthermore, their luminescence in solid state was observed. These studies are of great significance for expanding the application of hydrochromic dyes in biological fields and promoting green industrialization.

Stereoselective synthesis of organosulfur compounds incorporating N-aromatic heterocyclic motifs and quaternary carbon centers via a sulfa-Michael triggered tandem reaction.

A novel sulfa-Michael addition (SMA)-triggered tandem reaction was developed by combining a SMA reaction with a simultaneous rearomatization process utilizing a less reactive carbonyl group as an intramolecular electrophile partner, which provided a unique synthetic route to access various organosulfur compounds incorporating an N-aromatic heterocyclic motif and quaternary carbon centers.

Asymmetric organocatalytic allylic alkylation of Reissert compounds: a facile access to chiral 1,1-disubstituted 1,2-dihydroisoquinolines.

The first asymmetric organocatalytic allylic alkylation of 1,2-dihydro-Reissert compounds and Morita-Baylis-Hillman (MBH) carbonates has been developed, which provided a novel protocol to construct enantioenriched functionalized 1,2-dihydroisoquinolines bearing vicinal quaternary and tertiary chiral centers at C-1 position (up to 94% ee, dr > 20 : 1).