Dexmedetomidine inhibited arrhythmia susceptibility to adrenergic stress in RyR2R2474S mice through regulating the coupling of membrane potential and intracellular calcium.

BACKGROUND: Dexmedetomidine (DEX), a highly selective α2-adrenoceptor agonist, can decrease the incidence of arrhythmias, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). However, the underlying mechanisms by which DEX affects cardiac electrophysiological function remain unclear. METHODS: Ryanodine receptor (RyR2) heterozygous R2474S mice were used as a model for CPVT. WT and RyR2R2474S/+ mice were treated with isoproterenol (ISO) and DEX, and electrocardiograms were continuously monitored during both in vivo and ex vivo experiments. Dual-dye optical mapping was used to explore the anti-arrhythmic mechanism of DEX. RESULTS: DEX significantly reduced the occurrence and duration of ISO-induced of VT/VF in RyR2R2474S/+ mice in vivo and ex vivo. DEX remarkably prolonged action potential duration (APD80) and calcium transient duration (CaTD80) in both RyR2R2474S/+ and WT hearts, whereas it reduced APD heterogeneity and CaT alternans in RyR2R2474S/+ hearts. DEX inhibited ectopy and reentry formation, and stabilized voltage-calcium latency. CONCLUSION: DEX exhibited an antiarrhythmic effect through stabilizing membrane voltage and intracellular Ca2+. DEX can be used as a beneficial perioperative anesthetic for patients with CPVT or other tachy-arrhythmias.

The Potential Mechanisms of Arrhythmia in Coronavirus disease-2019.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) leads to coronavirus disease-2019 (COVID-19) which can cause severe cardiovascular complications including myocardial injury, arrhythmias, acute coronary syndrome and others. Among these complications, arrhythmias are considered serious and life-threatening. Although arrhythmias have been associated with factors such as direct virus invasion leading to myocardial injury, myocarditis, immune response disorder, cytokine storms, myocardial ischemia/hypoxia, electrolyte abnormalities, intravascular volume imbalances, drug interactions, side effects of COVID-19 vaccines and autonomic nervous system dysfunction, the exact mechanisms of arrhythmic complications in patients with COVID-19 are complex and not well understood. In the present review, the literature was extensively searched to investigate the potential mechanisms of arrhythmias in patients with COVID-19. The aim of the current review is to provide clinicians with a comprehensive foundation for the prevention and treatment of arrhythmias associated with long COVID-19.

Ventricular SK2 upregulation following angiotensin II challenge: Modulation by p21-activated kinase-1.

Effects of hypertrophic challenge on small-conductance, Ca2+-activated K+(SK2) channel expression were explored in intact murine hearts, isolated ventricular myocytes and neonatal rat cardiomyocytes (NRCMs). An established experimental platform applied angiotensin II (Ang II) challenge in the presence and absence of reduced p21-activated kinase (PAK1) (PAK1cko vs. PAK1f/f, or shRNA-PAK1 interference) expression. SK2 current contributions were detected through their sensitivity to apamin block. Ang II treatment increased such SK2 contributions to optically mapped action potential durations (APD80) and their heterogeneity, and to patch-clamp currents. Such changes were accentuated in PAK1cko compared to PAK1f/f, intact hearts and isolated cardiomyocytes. They paralleled increased histological and echocardiographic hypertrophic indices, reduced cardiac contractility, and increased SK2 protein expression, changes similarly greater with PAK1cko than PAK1f/f. In NRCMs, Ang II challenge replicated such increases in apamin-sensitive SK patch clamp currents as well as in real-time PCR and western blot measures of SK2 mRNA and protein expression and cell hypertrophy. Furthermore, the latter were enhanced by shRNA-PAK1 interference and mitigated by the PAK1 agonist FTY720. Increased CaMKII and CREB phosphorylation accompanied these effects. These were rescued by both FTY720 as well as the CaMKII inhibitor KN93, but not its inactive analogue KN92. Such CREB then specifically bound to the KCNN2 promoter sequence in luciferase assays. These findings associate Ang II induced hypertrophy with increased SK2 expression brought about by a CaMKII/CREB signaling convergent with the PAK1 pathway thence upregulating the KCNN2 promoter activity. SK2 may then influence cardiac electrophysiology under conditions of cardiac hypertrophy and failure.

Downregulation of AT2R decreases the responsiveness of BKCa channels to angiotensin II in patients with hypertension.

Angiotensin II (Ang II) modulates blood pressure via Ang II type 1 receptor (AT1R) and type 2 receptor (AT2R). The activation of AT2R relaxes vascular tone through opening large-conductance Ca2+-activated potassium (BKCa) channels in vascular smooth muscle cells (SMCs). In the present study, we studied the role of the AT2R-BKCa pathway in patients with hypertension. The mesenteric arterial SMCs (MSMCs) were obtained from normotensive patients (NP) and hypertensive patients (HP). BKCa currents were recorded with patch clamp and the expressions of mRNAs and proteins of AT1R/AT2R were analyzed by RT-PCR and Western blotting, respectively. Ang II significantly increased the macroscopic BKCa currents at the whole cell level, while increased the open probability and decreased the mean close time of BKCa channels at the single channel level with AT1R blockade by valsartan in NP. However, Ang II had no effect on the BKCa currents at the same condition in HP. Furthermore, the expressions of mRNA and protein of AT2R but not AT1R were markedly decreased in the MSMCs of HP compared to that of NP. The data suggest that AT2R is well functioned in the MSMCs in NP but not in HP and deficiency in the AT2R-BKCa pathway may contribute to the development of hypertension.

Mechanisms Underlying Spontaneous Action Potential Generation Induced by Catecholamine in Pulmonary Vein Cardiomyocytes: A Simulation Study.

Cardiomyocytes and myocardial sleeves dissociated from pulmonary veins (PVs) potentially generate ectopic automaticity in response to noradrenaline (NA), and thereby trigger atrial fibrillation. We developed a mathematical model of rat PV cardiomyocytes (PVC) based on experimental data that incorporates the microscopic framework of the local control theory of Ca2+ release from the sarcoplasmic reticulum (SR), which can generate rhythmic Ca2+ release (limit cycle revealed by the bifurcation analysis) when total Ca2+ within the cell increased. Ca2+ overload in SR increased resting Ca2+ efflux through the type II inositol 1,4,5-trisphosphate (IP3) receptors (InsP3R) as well as ryanodine receptors (RyRs), which finally triggered massive Ca2+ release through activation of RyRs via local Ca2+ accumulation in the vicinity of RyRs. The new PVC model exhibited a resting potential of -68 mV. Under NA effects, repetitive Ca2+ release from SR triggered spontaneous action potentials (APs) by evoking transient depolarizations (TDs) through Na+/Ca2+ exchanger (APTDs). Marked and variable latencies initiating APTDs could be explained by the time courses of the α1- and ß1-adrenergic influence on the regulation of intracellular Ca2+ content and random occurrences of spontaneous TD activating the first APTD. Positive and negative feedback relations were clarified under APTD generation.

Propofol attenuates H2O2-induced oxidative stress and apoptosis via the mitochondria- and ER-medicated pathways in neonatal rat cardiomyocytes.

Previous studies have shown that propofol, an intravenous anesthetic commonly used in clinical practice, protects the myocardium from injury. Mitochondria- and endoplasmic reticulum (ER)-mediated oxidative stress and apoptosis are two important signaling pathways involved in myocardial injury and protection. The present study aimed to test the hypothesis that propofol could exert a cardio-protective effect via the above two pathways. Cultured neonatal rat cardiomyocytes were treated with culture medium (control group), H2O2 at 500 µM (H2O2 group), propofol at 50 µM (propofol group), and H2O2 plus propofol (H2O2 + propofol group), respectively. The oxidative stress, mitochondrial membrane potential (ΔΨm) and apoptosis of the cardiomyocytes were evaluated by a series of assays including ELISA, flow cytometry, immunofluorescence microscopy and Western blotting. Propofol significantly suppressed the H2O2-induced elevations in the activities of caspases 3, 8, 9 and 12, the ratio of Bax/Bcl-2, and cell apoptosis. Propofol also inhibited the H2O2-induced reactive oxygen species (ROS) generation, lactic dehydrogenase (LDH) release and mitochondrial transmembrane potential (ΔΨm) depolarization, and restored the H2O2-induced reductions of glutathione (GSH) and superoxide dismutase (SOD). In addition, propofol decreased the expressions of glucose-regulated protein 78 kDa (Grp78) and inositol-requiring enzyme 1α (IRE1α), two important signaling molecules in the ER-mediated apoptosis pathway. Propofol protects cardiomyocytes from H2O2-induced injury by inhibiting the mitochondria- and ER-mediated apoptosis signaling pathways.

Bidirectional Regulatory Effects of Dexmedetomidine on Porcine Coronary Tone In Vitro.

BACKGROUND Studies in vivo have shown that dexmedetomidine (DEX) could protect the myocardium and modulate the coronary blood flow. This study aimed to investigate the direct and concentration-dependent effects of DEX on the tone of porcine coronary artery in vitro and the underlying mechanisms. MATERIAL AND METHODS Distal branches of the porcine anterior descending coronary arteries were dissected and cut into 3-5 mm rings. The tones of coronary rings in response to cumulative DEX were measured using the PowerLab system. Coronary rings were divided into three groups: 1) endothelium-intact coronary rings without drug pretreatment (control); 2) endothelium-intact coronary rings pretreated with either yohimbine, tetraethylamine (TEA) or NG-nitro-L-arginine methyl ester (L-NAME); and 3) endothelium-denuded coronary rings pretreated with either yohimbine or TEA. RESULTS DEX induced coronary ring relaxation at lower concentrations (10^-9 to 10^-7 M) followed by constriction at higher concentrations (10^-6 to 10^-5 M). The coronary constrictive effect of higher DEX (10^-5 M) was greater in the endothelium-denuded rings than in the endothelium-intact rings. Yohimbine reduced the coronary constrictive effect of DEX at higher concentrations (10^-6 to 10^-5 M). TEA and L-NAME significantly reduced the coronary relaxing effect of DEX at lower concentrations (10^-9 to 10^-7 M) in endothelium-intact rings. TEA attenuated the coronary relaxation induced by DEX in endothelium-denuded rings. CONCLUSIONS DEX exerts bidirectional effects on porcine coronary tone. The coronary relaxing effect of DEX at lower concentrations is likely associated with endothelium integrity, NO synthesis and BKCa channel activation, while the coronary constrictive effect of DEX at higher concentrations is mediated by a2 adrenoceptors in the coronary smooth muscle cells.

Plasma Growth Differentiation Factor-15 is a Potential Biomarker for Pediatric Pulmonary Arterial Hypertension Associated with Congenital Heart Disease.

We aimed to investigate plasma growth differentiation factor-15 (GDF-15) levels in pediatric pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD), and assess the association with hemodynamic parameters. Plasma GDF-15 levels were measured in children with PAH-CHD (n = 46) and compared to children with CHD without PAH (n = 39). Normal individuals (n = 30) served as health control group. Plasma GDF-15 levels were significantly elevated in patients with PAH-CHD compared with those with CHD without PAH (median 1415 ng/L, interquartile range [IQR] 926.7-2111.7 ng/L vs. 890.6 ng/L, IQR 394.7-1094.3 ng/L, p < 0.01). Elevated plasma GDF-15 levels were positively related to Functional Class, uric acid, N-terminal pro-B-type natriuretic peptide (NT-proBNP), pulmonary artery systolic pressure, mean pulmonary artery pressure, pulmonary blood flow/systemic blood flow and pulmonary vascular resistance, and a lower mixed venous oxygen saturation (Svo2). The area under the curve (AUC) for adding GDF-15 to NT-proBNP was not superior to the AUC of NT-pro BNP alone (AUC difference 0.0295, p = 0.324) (NT-proBNP, AUC 0.823, 95% CI 0.725-0.897; GDF-15 plus NT-proBNP, AUC 0.852, 95% CI 0.759-0.92), whereas it revealed a slightly greater specificity and positive predictive value. The diagnostic power of NT-pro BNP was not inferior to GDF-15 (AUC difference 0.0443, p = 0.43). Plasma GDF-15 levels might be a surrogate marker for pediatric PAH-CHD.

[Reconstitution of large conductance calcium-activated potassium channels into artificial planar lipid bilayers].

This study was aimed to establish a method to create a stable planar lipid bilayer membranes (PLBMs), in which large conductance calcium-activated potassium channels (BKCa) were reconstituted. Using spreading method, PLBMs were prepared by decane lipid fluid consisting of N2-weathered mixture of phosphatidylcholine and cholesterol at 3:1 ratio. After successful incorporation of BKCa channel into PLBMs, single channel characteristics of BKCa were studied by patch clamp method. The results showed that i) the single channel conductance of BKCa was (206.8 ± 16.9) pS; ii) the activities of BKCa channel were voltage dependent; iii) in the bath solution without Ca2+, there was almost no BKCa channel activities regardless of under hyperpolarization or repolarization conditions; iv) under the condition of +40 mV membrane potential, BKCa channels were activated in a Ca2+ concentration dependent manner; v) when [Ca2+] was increased from 1 µmol/L to 100 µmol/L, both the channel open probability and the average open time were increased, and the average close time was decreased from (32.2 ± 2.8) ms to (2.1 ± 1.8) ms; vi) the reverse potential of the reconstituted BKCa was -30 mV when [K+] was at 40/140 mmol/L (Cis/Trans). These results suggest that the spreading method could serve as a new method for preparing PLBMs and the reconstituted BKCa into PLBMs showed similar electrophysiological characteristics to natural BKCa channels, so the PLBMs with incorporated BKCa can be used in the studies of pharmacology and dynamics of BKCa channel.

Activation of AMPA receptor promotes TNF-α release via the ROS-cSrc-NFκB signaling cascade in RAW264.7 macrophages.

The relationship between glutamate signaling and inflammation has not been well defined. This study aimed to investigate the role of AMPA receptor (AMPAR) in the expression and release of tumor necrosis factor-alpha (TNF-α) from macrophages and the underlying mechanisms. A series of approaches, including confocal microscopy, immunofluorescency, flow cytometry, ELISA and Western blotting, were used to estimate the expression of AMPAR and downstream signaling molecules, TNF-α release and reactive oxygen species (ROS) generation in the macrophage-like RAW264.7 cells. The results demonstrated that AMPAR was expressed in RAW264.7 cells. AMPA significantly enhanced TNF-α release from RAW264.7 cells, and this effect was abolished by CNQX (AMPAR antagonist). AMPA also induced elevation of ROS production, phosphorylation of c-Src and activation of nuclear factor (NF)-κB in RAW264.7 cells. Blocking c-Src by PP2, scavenging ROS by glutathione (GSH) or inhibiting NF-κB activation by pyrrolidine dithiocarbamate (PDTC) decreased TNF-α production from RAW264.7 cells. We concluded that AMPA promotes TNF-α release in RAW264.7 macrophages likely through the following signaling cascade: AMPAR activation â†’ ROS generation â†’ c-Src phosphorylation â†’ NF-κB activation â†’ TNF-α elevation. The study suggests that AMPAR may participate in macrophage activation and inflammation.

Fe2O3 nanoparticles suppress Kv1.3 channels via affecting the redox activity of Kvß2 subunit in Jurkat T cells.

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising nanomaterials in medical practice due to their special magnetic characteristics and nanoscale size. However, their potential impacts on immune cells are not well documented. This study aims to investigate the effects of Fe2O3 nanoparticles (Fe2O3-NPs) on the electrophysiology of Kv1.3 channels in Jurkat T cells. Using the whole-cell patch-clamp technique, we demonstrate that incubation of Jurkat cells with Fe2O3-NPs dose- and time-dependently decreased the current density and shifted the steady-state inactivation curve and the recovery curve of Kv1.3 channels to a rightward direction. Fe2O3-NPs increased the NADP level but decreased the NADPH level of Jurkat cells. Direct induction of NADPH into the cytosole of Jurkat cells via the pipette abolished the rightward shift of the inactivation curve. In addition, transmission electron microscopy showed that Fe2O3-NPs could be endocytosed by Jurkat cells with relatively low speed and capacity. Fe2O3-NPs did not significantly affect the viability of Jurkat cells, but suppressed the expressions of certain cytokines (TNFα, IFNγ and IL-2) and interferon responsive genes (IRF-1 and PIM-1), and the time courses of Fe2O3-NPs endocytosis and effects on the expressions of cytokines and interferon responsive genes were compatible. We conclude that Fe2O3-NPs can be endocytosed by Jurkat cells and act intracellularly. Fe2O3-NPs decrease the current density and delay the inactivation and recovery kinetics of Kv1.3 channels in Jurkat cells by oxidizing NADPH and therefore disrupting the redox activity of the Kvß2 auxiliary subunit, and as a result, lead to changes of the Kv1.3 channel function. These results suggest that iron oxide nanoparticles may affect T cell function by disturbing the activity of Kv1.3 channels. Further, the suppressing effects of Fe2O3-NPs on the expressions of certain inflammatory cytokines and interferon responsive genes suggest that iron oxide nanoparticles may exert modulatory effects on T cell immune activities and anti-inflammation effects.

Tanshinone II-A sodium sulfonate (DS-201) enhances human BKCa channel activity by selectively targeting the pore-forming α subunit.

AIM: Tanshinone II-A sodium sulfonate (DS-201), a water-soluble derivative of Tanshinone II-A, has been found to induce vascular relaxation and activate BKCa channels. The aim of this study was to explore the mechanisms underlying the action of DS-201 on BKCa channels. METHODS: Human BKCa channels containing α subunit alone or α plus ß1 subunits were expressed in HEK293 cells. BKCa currents were recorded from the cells using patch-clamp technique. The expression and trafficking of BKCa subunits in HEK293 cells or vascular smooth muscle cells (VSMCs) were detected by Western blotting, flow cytometry and confocal microscopy. RESULTS: DS-201 (40-160 µmol/L) concentration-dependently increased the total open probability of BKCa channels in HEK293 cells, associated with enhancements of Ca(2+) and voltage dependence as well as a delay in deactivation. Coexpression of ß1 subunit did not affect the action of DS-201: the values of EC50 for BKCa channels containing α subunit alone and α plus ß1 subunit were 66.6±1.5 and 62.0±1.1 µmol/L, respectively. In both HEK293 cells and VSMCs, DS-201 (80 µmol/L) markedly increased the expression of α subunit without affecting ß1 subunit. In HEK293 cells, DS-201 enriched the membranous level of α subunit, likely by accelerating the trafficking and suppressing the internalization of α subunit. In both HEK293 cells and VSMCs, DS-201 (≥320 µmol/L) induced significant cytotoxicity. CONCLUSION: DS-201 selectively targets the pore-forming α subunit of human BKCa channels, thus enhancing the channel activities and increasing the subunit expression and trafficking, whereas the ß1 subunit does not contribute to the action of DS-201.

The effect of macrophages and their exosomes in ischemic heart disease.

Ischemic heart disease (IHD) is a leading cause of disability and death worldwide, with immune regulation playing a crucial role in its pathogenesis. Various immune cells are involved, and as one of the key immune cells residing in the heart, macrophages play an indispensable role in the inflammatory and reparative processes during cardiac ischemia. Exosomes, extracellular vesicles containing lipids, nucleic acids, proteins, and other bioactive molecules, have emerged as important mediators in the regulatory functions of macrophages and hold promise as a novel therapeutic target for IHD. This review summarizes the regulatory mechanisms of different subsets of macrophages and their secreted exosomes during cardiac ischemia over the past five years. It also discusses the current status of clinical research utilizing macrophages and their exosomes, as well as strategies to enhance their therapeutic efficacy through biotechnology. The aim is to provide valuable insights for the treatment of IHD.

The molecular mechanisms of peptidyl-prolyl cis/trans isomerase Pin1 and its relevance to kidney disease.

Pin1 is a member of the peptidyl-prolyl cis/trans isomerase subfamily and is widely expressed in various cell types and tissues. Alterations in Pin1 expression levels play pivotal roles in both physiological processes and multiple pathological conditions, especially in the onset and progression of kidney diseases. Herein, we present an overview of the role of Pin1 in the regulation of fibrosis, oxidative stress, and autophagy. It plays a significant role in various kidney diseases including Renal I/R injury, chronic kidney disease with secondary hyperparathyroidism, diabetic nephropathy, renal fibrosis, and renal cell carcinoma. The representative therapeutic agent Juglone has emerged as a potential treatment for inhibiting Pin1 activity and mitigating kidney disease. Understanding the role of Pin1 in kidney diseases is expected to provide new insights into innovative therapeutic interventions and strategies. Consequently, this review delves into the molecular mechanisms of Pin1 and its relevance in kidney disease, paving the way for novel therapeutic approaches.

Cope with copper: From molecular mechanisms of cuproptosis to copper-related kidney diseases.

Cuproptosis has recently been identified as a novel regulatory mechanism of cell death. It is characterized by the accumulation of copper in mitochondria and its binding to acylated proteins. These characteristics lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, ultimately resulting in cell death. Cuproptosis is distinct from other types of cell death, including necrosis, apoptosis, ferroptosis, and pyroptosis. Cu induces oxidative stress damage, protein acylation, and the oligomerization of acylated TCA cycle proteins. These processes lead to the downregulation of iron-sulfur cluster proteins and protein toxicity stress, disrupting cellular Cu homeostasis, and causing cell death. Cuproptosis plays a significant role in the development and progression of various kidney diseases such as acute kidney injury, chronic kidney disease, diabetic nephropathy, kidney transplantation, and kidney stones. On the one hand, inducers of cuproptosis, such as disulfiram (DSF), chloroquinolone, and elesclomol facilitate cuproptosis by promoting cell oxidative stress. In contrast, inhibitors of Cu chelators, such as tetraethylenepentamine and tetrathiomolybdate, relieve these diseases by inhibiting apoptosis. To summarize, cuproptosis plays a significant role in the pathogenesis of kidney disease. This review comprehensively discusses the molecular mechanisms underlying cuproptosis and its significance in kidney diseases.

Empagliflozin rescues pro-arrhythmic and Ca2+ homeostatic effects of transverse aortic constriction in intact murine hearts.

We explored physiological effects of the sodium-glucose co-transporter-2 inhibitor empagliflozin on intact experimentally hypertrophic murine hearts following transverse aortic constriction (TAC). Postoperative drug (2-6 weeks) challenge resulted in reduced late Na+ currents, and increased phosphorylated (p-)CaMK-II and Nav1.5 but not total (t)-CaMK-II, and Na+/Ca2+ exchanger expression, confirming previous cardiomyocyte-level reports. It rescued TAC-induced reductions in echocardiographic ejection fraction and fractional shortening, and diastolic anterior and posterior wall thickening. Dual voltage- and Ca2+-optical mapping of Langendorff-perfused hearts demonstrated that empagliflozin rescued TAC-induced increases in action potential durations at 80% recovery (APD80), Ca2+ transient peak signals and durations at 80% recovery (CaTD80), times to peak Ca2+ (TTP100) and Ca2+ decay constants (Decay30-90) during regular 10-Hz stimulation, and Ca2+ transient alternans with shortening cycle length. Isoproterenol shortened APD80 in sham-operated and TAC-only hearts, shortening CaTD80 and Decay30-90 but sparing TTP100 and Ca2+ transient alternans in all groups. All groups showed similar APD80, and TAC-only hearts showed greater CaTD80, heterogeneities following isoproterenol challenge. Empagliflozin abolished or reduced ventricular tachycardia and premature ventricular contractions and associated re-entrant conduction patterns, in isoproterenol-challenged TAC-operated hearts following successive burst pacing episodes. Empagliflozin thus rescues TAC-induced ventricular hypertrophy and systolic functional, Ca2+ homeostatic, and pro-arrhythmogenic changes in intact hearts.

IP3 decreases coronary artery tone via activating the BKCa channel of coronary artery smooth muscle cells in pigs.

Large conductance Ca(2+)-activated K(+) channel (BKCa) is a potential target for coronary artery-relaxing medication, but its functional regulation is largely unknown. Here, we report that inositol trisphosphate (IP3) activated BKCa channels in isolated porcine coronary artery smooth muscle cells and by which decreased the coronary artery tone. Both endogenous and exogenous IP3 increased the spontaneous transient outward K(+) currents (STOC, a component pattern of BKCa currents) in perforated and regular whole-cell recordings, which was dependent on the activity of IP3 receptors. IP3 also increased the macroscopic currents (MC, another component pattern of BKCa currents) via an IP3 receptor- and sarcoplasmic Ca(2+) mobilization-independent pathway. In inside-out patch recordings, direct application of IP3 to the cytosolic side increased the open probability of single BKCa channel in an IP3 receptor-independent manner. We conclude that IP3 is an activator of BKCa channels in porcine coronary smooth muscle cells and exerts a coronary artery-relaxing effect. The activation of BKCa channels by IP3 involves the enhancement of STOCs via IP3 receptors and stimulation of MC by increasing the Ca(2+) sensitivity of the channels.

Messenger Nanozyme for Reprogramming the Microenvironment of Rheumatoid Arthritis.

Dysregulation of superoxide anion (O2-) and hydrogen peroxide (H2O2) metabolism in the microenvironment of rheumatoid arthritis (RA) drives the feedback loops of TNF-α and IL-1ß thereby inducing an inflammatory storm between immune cells and joint tissue cells. Here, we combine nanoscale manganese dioxide (MnO2) with microvesicles derived from macrophage (MMV). The former possesses superoxide dismutase (SOD) and catalase (CAT)-like activities that can modulate this imbalance, and we amplify the enzyme-like activities by using the amorphous hollow mesoporous structure and surface modification. The latter is a natural endogenous component with the parent cell-like inflammatory homing ability and a unique function of transmitting information to surrounding and distant cells (″messenger function″), which helps amorphous hollow MnO2 (H-MnO2) nanozymes to cloak in the blood and reach the site of inflammation, where they can not only accumulate in activated macrophages but also pretend to be ″messengers″ that are utilized by fibroblast-like synoviocytes (FLS) and chondrocytes. In addition, we also load dexamethasone sodium phosphate (DSP) for helping the nanozymes work. Messenger nanozyme (MMV-MnO2@DSP) inherits the natural properties of MMV and mimics the enzymatic activity of SOD and CAT. It accumulates in activated macrophages to restore the metabolism of O2- and H2O2 while promoting repolarization and inhibits the feedback loops of TNF-α and IL-1ß among macrophages, fibroblast-like synoviocytes, and chondrocytes, leading to anti-rheumatoid arthritis effects in vitro and in vivo.

The characteristics and molecular targets of antiarrhythmic natural products.

Arrhythmia is one of the most common cardiovascular diseases. The search for new drugs to suppress various types of cardiac arrhythmias has always been the focus of attention. In the past decade, the screening of antiarrhythmic active substances from plants has received extensive attention. These natural compounds have obvious antiarrhythmic effects, and chemical modifications based on natural compounds have greatly increased their pharmacological properties. The chemical modification of botanical antiarrhythmic drugs is closely related to the development of new and promising drugs. Therefore, the structural characteristics and action targets of natural compounds with antiarrhythmic effects are reviewed in this paper, so that pharmacologists can select antiarrhythmic lead compounds from natural compounds based on the disease target - chemical structural characteristics.

Oxidative stress signaling in the pathogenesis of diabetic cardiomyopathy and the potential therapeutic role of antioxidant naringenin.

Diabetes mellitus (DM) is one of the most prevalent metabolic disorders that poses a global threat to human health. It can lead to complications in multiple organs and tissues, owing to its wide-ranging impact on the human body. Diabetic cardiomyopathy (DCM) is a specific cardiac manifestation of DM, which is characterized by heart failure in the absence of coronary heart disease, hypertension and valvular heart disease. Given that oxidative stress is a key factor in the pathogenesis of DCM, intervening to mitigate oxidative stress may serve as a therapeutic strategy for managing DCM. Naringenin is a natural product with anti-oxidative stress properties that can suppress oxidative damage by regulating various oxidative stress signaling pathways. In this review, we address the relationship between oxidative stress and its primary signaling pathways implicated in DCM, and explores the therapeutic potential of naringenin in DCM.