Mitochondrial Dysfunction in Atrial Fibrillation—Mechanisms and Pharmacological Interventions

Despite the enormous progress in the treatment of atrial fibrillation, mainly with the use of invasive techniques, many questions remain unanswered regarding the pathomechanism of the arrhythmia and its prevention methods. The development of atrial fibrillation requires functional changes in the myocardium that result from disturbed ionic fluxes and altered electrophysiology of the cardiomyocyte. Electrical instability and electrical remodeling underlying the arrhythmia may result from a cellular energy deficit and oxidative stress, which are caused by mitochondrial dysfunction. The significance of mitochondrial dysfunction in the pathogenesis of atrial fibrillation remains not fully elucidated; however, it is emphasized by the reduction of atrial fibrillation burden after therapeutic interventions improving the mitochondrial welfare. This review summarizes the mechanisms of mitochondrial dysfunction related to atrial fibrillation and current pharmacological treatment options targeting mitochondria to prevent or improve the outcome of atrial fibrillation.

Lidocaine Hydrochloride Nanoparticles Preparation using Multiple Emulsions and its Physicochemical Evaluation

Lidocaine is a primary local anesthesia that blocks the ionic fluxes required for the beginning and operation of impulses in the neuronal membrane. The benefits of local anesthetics, such as enhancing patient acceptance, prohibiting systemic toxicity and delivering continuous drug delivery, make them the attracting field for pharmaceutical researchers. The nanoparticles were prepared by solvent evaporation W1/O/W2 emulsion method and in the ratios of 1 to 1, 1 to 2 and 1 to 3 drug to polymer. The production yield, loading efficiency, particle size, poly dispersity index and zeta potential of selected formulation were 84.30%, 80.60%, 192[Formula: see text]nm, 0.18[Formula: see text]mV and [Formula: see text][Formula: see text]mV, respectively. DSC and FTIR studies showed that no chemical interactions between drug and polymer Formulations showed an initial burst release, which is a reason for the good capacity of the polymer to maintain the drug in it and lead to a primary slow release.

Dynamic entropy of human blood

Temperature control is a process that is used by biological systems to maintain a stable internal state for survival. People have an individually variable physiological temperature of about 36.6 °C, which can be modified by many undesirable factors. Based on an analysis of a time series of extracellular ionic fluxes that were obtained using the non-invasive solute-semiconductor interface technique, I show that this extremely specific (critical) temperature is encoded by a local minimum in the dynamic entropy of an isolated drop of human blood. Moreover, a dynamic zeroth-order normal fluid/“superfluid” nonequilibrium phase transition, which was reflected by a spontaneous symmetry breaking that occurred in the phase space, was revealed. The critical scaling of the dynamic measures for the covariates such as the spectral signature and Lyapunov exponent was also determined.

PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

NINJ1 mediates plasma membrane rupture during lytic cell death

Plasma membrane rupture (PMR) is the final cataclysmic event in lytic cell death. PMR releases intracellular molecules termed damage-associated molecular patterns (DAMPs) that propagate the inflammatory response. The underlying mechanism for PMR, however, is unknown. Here we show that the ill-characterized nerve injury-induced protein 1 (NINJ1) — a cell surface protein with two transmembrane regions — plays an essential role in the induction of PMR. A forward-genetic screen of randomly mutagenized mice linked NINJ1 to PMR. Ninj1–/– macrophages exhibited impaired PMR in response to diverse inducers of pyroptotic, necrotic and apoptotic cell death, and failed to release numerous intracellular proteins including High Mobility Group Box 1 (HMGB1, a known DAMP) and Lactate Dehydrogenase (LDH, a standard measure of PMR). Ninj1–/– macrophages died, but with a distinctive and persistent ballooned morphology, attributable to defective disintegration of bubble-like herniations. Ninj1–/– mice were more susceptible than wild-type mice to Citrobacter rodentium, suggesting a role for PMR in anti-bacterial host defense. Mechanistically, NINJ1 utilized an evolutionarily conserved extracellular α-helical domain for oligomerization and subsequent PMR. The discovery of NINJ1 as a mediator of PMR overturns the long-held dogma that cell death-related PMR is a passive event. Pyroptosis is a potent inflammatory mode of lytic cell death triggered by diverse infectious and sterile insults1-3. It is driven by the pore-forming fragment of gasdermin D (GSDMD)4-7 and releases two exemplar proteins: interleukin-1β (IL-1β), a pro-inflammatory cytokine, and LDH, a standard marker of PMR and lytic cell death. An early landmark study8 predicted two sequential steps for pyroptosis: (1) initial formation of a small plasma membrane pore causing IL-1β release and non-selective ionic fluxes, and (2) subsequent PMR attributable to oncotic cell swelling. PMR releases LDH (140 kDa) and large DAMPs. While the predicted size of gasdermin pores (~18 nm inner diameter9) is large enough to release IL-1β (17 kDa, ~4.5 nm diameter), the underlying mechanism for subsequent PMR has been considered a passive osmotic lysis event.

Mature and immature β-cells both contribute to islet function and insulin release

Transcriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that differences in β-cell maturity, defined using PDX1 and MAFA expression, are required for proper islet operation. Functional mapping of rodent and human islets containing proportionally more mature β-cells revealed defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of mature β-cells led to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, the islet signalling network was found to contribute to differences in maturity across β-cells. During metabolic stress, islet function could be restored by redressing the balance between immature and mature β-cells. Thus, preserving a balance between immature and mature β-cells might be important for islet engineering efforts and more broadly the treatment of type 1 and type 2 diabetes.

Nitric oxide modulates cardiomyocyte pH control through a biphasic effect on sodium/hydrogen exchanger-1

Aims When activated, Na+/H+ exchanger-1 (NHE1) produces some of the largest ionic fluxes in the heart. NHE1-dependent H+ extrusion and Na+ entry strongly modulate cardiac physiology through the direct effects of pH on proteins and by influencing intracellular Ca2+ handling. To attain an appropriate level of activation, cardiac NHE1 must respond to myocyte-derived cues. Among physiologically important cues is nitric oxide (NO), which regulates a myriad of cardiac functions, but its actions on NHE1 are unclear. Methods and results NHE1 activity was measured using pH-sensitive cSNARF1 fluorescence after acid-loading adult ventricular myocytes by an ammonium prepulse solution manoeuvre. NO signalling was manipulated by knockout of its major constitutive synthase nNOS, adenoviral nNOS gene delivery, nNOS inhibition, and application of NO-donors. NHE1 flux was found to be activated by low [NO], but inhibited at high [NO]. These responses involved cGMP-dependent signalling, rather than S-nitros(yl)ation. Stronger cGMP signals, that can inhibit phosphodiesterase enzymes, allowed [cAMP] to rise, as demonstrated by a FRET-based sensor. Inferring from the actions of membrane-permeant analogues, cGMP was determined to activate NHE1, whereas cAMP was inhibitory, which explains the biphasic regulation by NO. Activation of NHE1-dependent Na+ influx by low [NO] also increased the frequency of spontaneous Ca2+ waves, whereas high [NO] suppressed these aberrant forms of Ca2+ signalling. Conclusions Physiological levels of NO stimulation increase NHE1 activity, which boosts pH control during acid-disturbances and results in Na+-driven cellular Ca2+ loading. These responses are positively inotropic but also increase the likelihood of aberrant Ca2+ signals, and hence arrhythmia. Stronger NO signals inhibit NHE1, leading to a reversal of the aforementioned effects, ostensibly as a potential cardioprotective intervention to curtail NHE1 overdrive.