Triggered Activity Research Articles

Astaxanthin Prevents Glucocorticoid-Induced Femoral Head Osteonecrosis by Targeting Ferroptosis through the JAK2/STAT3 Signaling Pathway.

Glucocorticoid (GC) is extensively used in clinical practice, and the osteonecrosis of the femoral head caused by them is a common issue in orthopedic surgery, yet the underlying mechanisms remain unclear. Astaxanthin (AST), a potent natural antioxidant, has an unexplored impact on GC-induced osteonecrosis of the femoral head (GIONFH). This study explores the effects and mechanisms of AST in counteracting dexamethasone (Dex)-induced ferroptosis and GIONFH. We developed a rat model of GIONFH using intraperitoneal Dex injections and conducted in vitro analysis by culturing osteoblasts (OBs) with Dex treatment. We assessed the impact of AST on Dex-treated OBs using C11-BODIPY and FerroOrange staining, mitochondrial functionality tests, and protein expression analyses through Western blot and immunofluorescence. The influence of AST on bone microarchitecture of femoral head in rat was assessed using micro-CT, hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry at imaging and histological levels. Our findings suggest that AST exerts an inhibitory effect on Dex-induced ferroptosis and GIONFH. In vitro, AST treatment increased glutathione and decreased malondialdehyde, lipid peroxidation, and mitochondrial-reactive oxygen species. Additionally, AST treatment also enhances the phosphorylation of STAT3, upregulates glutathione peroxidase 4 and osteogenic-related proteins, and stimulates bone formation. To delve deeper into the mechanism, the findings revealed that AST triggered activation of JAK2/STAT3 signaling. Moreover, the use of siRNA-STAT3 blocked the beneficial effect of AST in OBs cultivated with Dex. In brief, AST combats GIONFH by activating the JAK2/STAT3 pathway to inhibit ferroptosis.

Chained occurrences of early afterdepolarizations may create a directional triggered activity to initiate reentrant ventricular tachyarrhythmias.

It has been believed that polymorphic ventricular tachycardia (VT) such as torsades de pointes (TdP) seen in patients with long QT syndromes is triggered by creating early afterdepolarization (EAD)-mediated triggered activity (TA). Although the mechanisms creating the TA have been studied intensively, characteristics of the arrhythmogenic (torsadogenic) substrates that link EAD developments to TA formation are still not well understood. Computer simulations of excitation propagation in a homogenous two-dimensional ventricular tissue with an anisotropic conduction property were performed to characterize torsadogenic substrates that potentially form TA. We examined how the configuration of islands (clusters) of myocytes with synchronously chained occurrence of EADs within the tissue, each EAD cluster size and stimulation from different directions impact the TA creation. The presence of EAD clusters within the tissue created local regions of cardiomyocytes maintained at a depolarized membrane potential above 0 mV due to the chained occurrence of EADs. When the local area contained a concave surface border, the TA was created depending on its curvature. We found that the distance of EAD clusters was a critical factor for the development of EAD-mediated TA and polymorphic VT in long QT syndromes, that there existed a region of the distance favorable for the development of TA and VT, and that the TA was always created along the myocardial fiber orientation regardless of stimulating directions. The chained occurrences of EADs may create a directional TA. Our findings provide deeper understandings of the cardiac arrhythmogenic substrates for preventing and treating arrhythmias.

Papillary Muscles of the Left Ventricle: Integrating Electrical and Mechanical Dynamics.

Papillary muscles are structures integrated into the mitral valve apparatus, having both electrical and mechanical roles. The importance of the papillary muscles (PM) is mainly related to cardiac arrhythmias and mitral regurgitation. The aim of this review is to offer an overview of the anatomy and physiology of the papillary muscles, along with their involvement in cardiovascular pathologies, including arrhythmia development in various conditions and their contribution to secondary mitral regurgitation. A literature search was performed on PubMed using the following relevant keywords: papillary muscles, mitral valve, arrhythmia, anatomy, and physiology. During the cardiac cycle, papillary muscles have continuous dimensional and pressure changes. On one hand, their synchrony or dyssynchrony impacts the process of mitral valve opening and closure, and on the other hand, the pressure changes can trigger electrical instability. There is increased awareness of papillary muscles as an arrhythmic source. Arrhythmias arising from PM were found in patients with or without structural heart disease, via Purkinje fibres, due to increased automaticity or triggered activity. Despite the interest in mitral valve physiology, there are still many unknowns in relation to the papillary muscles, especially with regard to their role in arrhythmogenesis and the pathogenesis of mitral regurgitation.

Curzerenone inactivates the nuclear factor-kappa B signaling to suppress malignancy and immune evasion in cervical cancer by targeting CSNK2B.

Curzerenone is a major component of the traditional herbal medicine Curcumae Rhizoma with potential cancer-suppressing effects. This study aims to investigate the treatment effect of Curzerenone on cervical cancer cells and the underpinning mechanism. HeLa and SiHa cells were treated with Curzerenone. The 100μM Curzerenone treatment repressed proliferation, migration, and invasion of the cells. The Curzerenone treatment also reduced cellular expression of programmed death ligand 1, which increased the proliferation and activity of CD8+ T cells in a co-culture system with cancer cells. Casein kinase 2 beta (CSNK2B), a predicted physiological target of Curzerenone, was found to be suppressed by Curzerenone. Further overexpression of CSNK2B blocked the treatment effects of Curzerenone. Curzerenone inhibited while CSNK2B triggered activation of the nuclear factor-kappa B (NF-κB) pathway. The oncogenic and immunosuppressive effects of CSNK2B were blocked by an NF-κB-specific inhibitor. In vivo, Curzerenone treatment inhibited the tumorigenic activity of cancer cells, and it increased the proportion of CD8+ T cells in the xenograft tumor tissues. However, these anti-tumor effects were diminished by the CSNK2B overexpression as well. In conclusion, this research suggests that Curzerenone targets CSNK2B and inactivates the NF-κB signaling to suppress malignancy and immune evasion in cervical cancer.

Inositol 1,4,5-Trisphosphate Receptor 1 Gain-of-Function Increases the Risk for Cardiac Arrhythmias in Mice and Humans.

Ca2+ mishandling in cardiac Purkinje cells is a well-known cause of cardiac arrhythmias. The Purkinje cell resident inositol 1,4,5-trisphosphate receptor 1 (ITPR1) is believed to play an important role in Ca2+ handling, and ITPR1 gain-of-function (GOF) has been implicated in cardiac arrhythmias. However, nearly all known disease-associated ITPR1 variants are loss-of-function and are primarily linked to neurological disorders. Whether ITPR1 GOF has pathological consequences, such as cardiac arrhythmias, is unclear. This study aimed to identify human ITPR1 GOF variants and determine the impact of ITPR1 GOF on Ca2+ handling and arrhythmia susceptibility. There are a large number of rare ITPR1 missense variants reported in open data repositories. Based on their locations in the ITPR1 channel structure, we selected and characterized 33 human ITPR1 missense variants from open databases and identified 21 human ITPR1 GOF variants. We generated a mouse model carrying a human ITPR1 GOF variant, ITPR1-W1457G (W1447G in mice). We showed that the ITPR1-W1447G± and recently reported ITPR1-D2594K± GOF mutant mice were susceptible to stress-induced ventricular arrhythmias. Confocal Ca2+ and voltage imaging in situ in heart slices and Ca2+ imaging and patch-clamp recordings of isolated Purkinje cells showed that ITPR1-W1447G± and ITPR1-D2594K± variants increased the occurrence of stress-induced spontaneous Ca2+ release, delayed afterdepolarization, and triggered activity in Purkinje cells. To assess the potential role of ITPR1 variants in arrhythmia susceptibility in humans, we looked up a gene-based association study in the UK Biobank data set and identified 7 rare ITPR1 missense variants showing potential association with cardiac arrhythmias. Remarkably, in vitro functional characterization revealed that all these 7 ITPR1 variants resulted in GOF. Our studies in mice and humans reveal that enhanced function of ITPR1, a well-known movement disorder gene, increases the risk for cardiac arrhythmias.

The effectiveness of community-led total sanitation cadre intervention in improving stunting knowledge and behavior

The prevalence of stunting remains high in Central Sulawesi Province, Indonesia. Poor sanitation is a significant risk factor for stunting, and community-based interventions such as Community-Led Total Sanitation (CLTS) show promise in addressing this issue. Despite the government’s multi-sectoral and integrated approach, encompassing both specific and sensitive nutrition interventions, the problem of stunting persists. This study aimed to assess the effectiveness of cadre-led interventions in improving community knowledge and behavior related to CLTS as a means of stunting prevention. A quasi-experimental, non-randomized design was used, with proportional stratified random sampling applied to a population of 332, resulting in a sample size of 182 individuals. Data collection was conducted from July to September 2023. The intervention involved CLTS cadres delivering counseling and triggering activities to mothers of stunted children. Knowledge and behavior regarding the five pillars of CLTS were measured as the dependent variables using a CLTS questionnaire with a scoring system. Data analysis was performed using SPSS version 22.0, specifically employing the independent-sample t-test with a significance threshold of p<0.05. Results indicated a significant increase in knowledge across the five pillars of CLTS (p=0.000), as well as a significant improvement in behavior concerning handwashing with soap, drinking water, food management, and household wastewater management (p=0.000). The findings suggest that cadres play an effective role in enhancing community knowledge and behavior regarding CLTS, contributing to stunting prevention efforts.

Assessment of electrophysiological mechanisms of ventricular ectopia in arrhythmogenic right ventricular dysplasia

Relevance of the problem. Arrhythmogenic right ventricular dysplasia (ARVD) is one of the significant causes of sudden cardiac death (SCD) among young people. ARVD is characterized by premature ventricular ectopic contractions (PVCs) from the right ventricular outflow tract (RVOT), which may occur before morphological changes appear and, in these cases, it is necessary to assess the risk of developing SCD based on an analysis of the electrophysiological mechanism of the development of PVCs. Purpose of the study. To evaluate the electrophysiological mechanisms of PVCs in patients with ARVD according to stress tests. Material and methods. We examined 13 patients with confirmed ARVD on MRI, including 9 men and 4 women, aged from 26 to 63 years (42.9±11.0). All patients underwent the following studies: standard electrocardiography (ECG), 24-hour ECG monitoring, echocardiography, cardiac MRI, treadmill stress test. During the stress test, at each load level, ventricular ectopy was analyzed (morphology, number of ventricular ectopic complexes), and the dependence of corrected QTc on heart rate was assessed. Results. According to the data obtained, the patients were divided into two groups depending on the response of PVCs to physical activity. The first group – patients in whom the number of PVCs increased during physical activity – stress-induced ventricular ectopy – 10 people (77%). The second group – patients in whom the number of PVCs decreased, or they disappeared at the peak of the load – stress-inhibited ventricular ectopy – 3 people (23%). All patients had a normal reaction of the QT interval to physical activity – its shortening in response to an increase in heart rate. Conclusions. ARVD is characterized by ventricular ectopia from the right ventricle outflow tract or bifocal ectopia from the right ventricle outflow tract and the right ventricle apex. The electrophysiological mechanisms of ventricular ectopia in ARVD are different: the mechanism of trigger activity and increased automaticity.

Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer’s disease via cGAS‐STING

AbstractBackgroundAlzheimer’s disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear.MethodAPP/PS1 AD mice were treated with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) at 40 mg/kg/day and 80 mg/kg/day respectively for 5 consecutive months, and then the Morris water maze test (MWM) and the novel object recognition test were performed to assess the effect of TSG on the cognitive and memory ability of AD mice. Moreover, central microglia activation, peripheral inflammation as well as the correlated cGAS‐STING signal pathway were analysed by Immunostaining and ELISA, which was further verified in BV2 cell experiments.ResultTreating with TSG, learning‐memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN‐γ induced microglia activation showed that TSG reversed the polarization status of M1‐type microglia to restore the quiescence, and cGAS‐STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL‐1β, IL‐6, TNF‐ α, IFN‐ αand IFN‐β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN‐γ‐stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS‐STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS‐STING inhibitors.ConclusionOur findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS‐STING signaling pathway in AD.

Suppression of colorectal cancer growth: Interplay between curcumin and metformin through DMT1 downregulation and ROS-mediated pathways.

The rising incidence of colorectal cancer (CRC) poses significant healthcare challenges. This study explored the therapeutic potential of combined curcumin (CUR) and metformin (MET) treatment in CRC models. Our findings indicate that the combination treatment (COMB) effectively downregulates the expression of divalent metal transporter-1 (DMT-1), leading to a reduction in cell proliferation aligned with suppression of the pAKT/mTOR/Cyclin D1 signaling pathway. The COMB increased reactive oxygen species (ROS) production, triggering activation of the NRF2/KEAP1 pathway. This pathway elicits an antioxidant response to manage oxidative stress in CRC cell lines. Interestingly, the response of NRF2 varied between CT26 and HCT116 cells. Moreover, our study highlights the induction of apoptosis and autophagy, as evidenced by upregulations in Bax/Bcl-2 ratios and autophagy-related protein expressions. Notably, the COMB promoted lipid peroxidation and downregulated xCT levels, suggesting the induction of ferroptosis. Ferroptosis has been shown to activate autophagy, which helps eliminate cells potentially damaged by the increased oxidative stress. Furthermore, the COMB effectively diminished the migratory ability of CRC cells. In vivo experiments using CRC-bearing mouse models, the results confirmed the anti-tumor efficacy of the COMB, leading to substantial inhibition of tumor growth without inducing general toxicity. In conclusion, our study suggests that combining CUR with MET holds promise as a potential option for CRC treatment, with critical mechanisms likely involving ROS elevation, autophagy, and ferroptosis.

Role of ryanodine receptor cooperativity in Ca2+-wave-mediated triggered activity in cardiomyocytes.

Ca2+ waves are known to trigger delayed after-depolarizations that can cause malignant cardiac arrhythmias. However, modelling Ca2+ waves using physiologically realistic models has remained a major challenge. Existing models with low Ca2+ sensitivity of ryanodine receptors (RyRs) necessitate large release currents, leading to an unrealistically large Ca2+ transient amplitude incompatible with the experimental observations. Consequently, current physiologically detailed models of delayed after-depolarizations resort to unrealistic cell architectures to produce Ca2+ waves with a normal Ca2+ transient amplitude. Here, we address these challenges by incorporating RyR cooperativity into a physiologically detailed model with a realistic cell architecture. We represent RyR cooperativity phenomenologically through a Hill coefficient within the sigmoid function of RyR open probability. Simulations in permeabilized myocytes with high Ca2+ sensitivity reveal that a sufficiently large Hill coefficient is required for Ca2+ wave propagation via the fire-diffuse-fire mechanism. In intact myocytes, propagating Ca2+ waves can occur only within an intermediate Hill coefficient range. Within this range, the spark rate is neither too low, enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during diastole of the action potential. Moreover, this model successfully replicates other experimentally observed manifestations of Ca2+-wave-mediated triggered activity, including phase 2 and phase 3 early after-depolarizations and high-frequency voltage-Ca2+ oscillations. These oscillations feature an elevated take-off potential with depolarization mediated by the L-type Ca2+ current. The model also sheds light on the roles of luminal gating of RyRs and the mobile buffer ATP in the genesis of these arrhythmogenic phenomena. KEY POINTS: Existing mathematical models of Ca2+ waves use an excessively large Ca2+-release current or unrealistic diffusive coupling between release units. Our physiologically realistic model, using a Hill coefficient in the ryanodine receptor (RyR) gating function to represent RyR cooperativity, addresses these limitations and generates organized Ca2+ waves at Hill coefficients ranging from ∼5 to 10, as opposed to the traditional value of 2. This range of Hill coefficients gives a spark rate neither too low, thereby enabling Ca2+ wave propagation, nor too high, allowing for the maintenance of a high sarcoplasmic reticulum load during the plateau phase of the action potential. Additionally, the model generates Ca2+-wave-mediated phase 2 and phase 3 early after-depolarizations, and coupled membrane voltage with Ca2+ oscillations mediated by the L-type Ca2+ current. This study suggests that pharmacologically targeting RyR cooperativity could be a promising strategy for treating cardiac arrhythmias linked to Ca2+-wave-mediated triggered activity.

Abstract 4145899: The Danger of Moderator Band Ectopy: A Case of Premature Ventricular Contraction induced Recurrent Ventricular Fibrillation

Introduction: Premature Ventricular Contractions (PVCs) are often a benign arrhythmia. However, those originating from the Purkinje system can result in fatal arrhythmias. One example is PVCs originating from the moderator band (MB) within the right ventricle (RV) of the heart. We present a case of PVCs originating from the MB triggering idiopathic ventricular fibrillation (VF) and electrical storm. Case: A previously healthy 49-year-old woman was admitted following a witnessed VF cardiac arrest. She had recurrent episodes of VF, initially treated with Amiodarone and Procainamide which failed to suppress the recurrent VF. She received 54 external defibrillations before a transvenous pacer (TVP) was placed to override the PVCs at a pacing rate of 110 bpm. Post-resuscitation ECGs revealed frequent PVCs originating from the RV free wall, potentially from the lateral part of MB (Figure 1). Quinidine was added to suppress the PVCs ultimately allowing removal of the TVP. Transthoracic Echocardiogram revealed normal cardiac function and a prominent MB. A cardiac MRI was performed showing no infiltrative disease or any other abnormalities. The patient underwent sympathectomy and defibrillator placement. Despite recurrent cardiac arrest, she had excellent neurologic recovery and was subsequently discharged on Quinidine. Discussion: MB extends from the septal wall to the base of the anterior papillary muscle in the RV, carrying Purkinje fibers(PF) from the right bundle branch as it exits the septum. Purkinje fibers have been shown to initiate arrhythmias by several mechanisms including enhanced automaticity, triggered activity and re-entry. In the genesis of PVCs, triggered activity is the likely mechanism. This can degenerate into VF in a structurally normal heart, hence the term “idiopathic VF”. Familiarity with this entity and ECG features of MB ectopy leads to timely management and may potentially prevent lethal arrhythmias in symptomatic patients with such PVCs. Further studies are required to fully understand the arrhythmogenic mechanisms and the optimal management approach for MB ectopy.

Abstract 4132820: S-nitrosylation of cardiac Cx43 hemichannels at Cys271 promotes arrhythmogenicity and myocardial injury upon cardiac stress in Duchenne Muscular Dystrophy

Connexin-43 (Cx43) plays a critical role in the propagation of action potentials among cardiomyocytes and proper cardiac contractility. In healthy cardiomyocytes, Cx43 is located at the intercalated disk; however, Cx43 remodeling is observed in cardiac pathologies and is linked with arrhythmogenesis and sudden cardiac death. Utilizing a mouse model of Duchenne muscular dystrophy (DMD mdx ), we have previously demonstrated that cardiac Cx43 is laterally localized, forming undocked hemichannels that activate via S-nitrosylation in response to isoproterenol-evoked cardiac stress. This activation leads to the disruption of cardiac membrane permeability, triggered activity, and deadly arrhythmogenic behaviors. To establish the direct role of S-nitrosylated Cx43 in DMD cardiomyopathy, we developed a specific knock-in mouse line in which the single Cx43 site for S-nitrosylation, cysteine 271 (Cys271), was substituted with a serine (C271S +/- ). Here, we developed a DMD mdx :C271S +/- line (4–6 months old), exhibiting reduced levels of S-nitrosylated Cx43 after crossing DMDmdx mice and C271S +/- mouse lines to assess the effect of β-adrenergic stimulation-induced cardiac stress and heart dysfunction. We show that cardiac Cx43 remodeling was not prevented in DMD mdx :C271S +/- , similar to what was shown in DMD mdx mice via immunofluorescence analysis. In addition, DMD mdx mice displayed an increased number of deadly arrhythmogenic events, increased Ca 2+ signaling, and prolonged action potentials in Langendorff-perfused whole hearts via optical mapping, compared to wild-type and DMD mdx :C271S +/- mice. Similarly, isoproterenol treatment evoked severe myocardial injury, increased levels of plasmatic cardiac troponin I (cTnI), and 40% mortality in DMD mdx mice. Notably, DMD mdx :C271S +/- mice, similar to DMD mdx mice treated with the Cx43 hemichannel blocker Gap19, exhibited cardioprotection compared to the cardiac dysfunction observed in DMD mdx mice. Therefore, these findings strongly suggest that S-nitrosylation of Cx43 proteins at site Cys271 represents a fundamental NO-mediated mechanism involved in the induction of arrhythmias and myocardial injury in DMD mdx after β-adrenergic stress.

BALB/c mice challenged with SARS-CoV-2 B.1.351 β variant cause pathophysiological and neurological changes within the lungs and brains.

Up to one-third of individuals suffering from acute SARS-CoV-2 infection with the onset of severe-to-mild diseases could develop several symptoms of neurological disorders, which could last long after resolving the infection, known as neuro-COVID. Effective therapeutic treatments for neuro-COVID remain unavailable, in part, due to the absence of animal models for studying its underlying mechanisms and developing medical countermeasures against it. Here, we explored the impact of SARS-CoV-2 infection on the well-being of respiratory and neurological functions of BALB/c mice by using a clinical isolate of β-variant, i.e. B.1.351. We found that this β-variant of SARS-CoV-2 primarily infected the lungs, causing tissue damage, profound inflammatory responses, altered respiratory functions and transient but significant hypoxia. Although live progeny viruses could not be isolated, viral RNAs were detected across many anatomical regions of the brains in most challenged mice and triggered activation of genes encoding for NF-kB, IL-6, IP-10 and RANTES and microglial cells. We noted that the significantly activated IL-6-encoded gene persisted at 4 weeks after infection. Together, these results suggest that this B.1.351/BALB/c model of SARS-CoV-2 infection warrants further studies to establish it as a desirable model for studies of neuropathogenesis and the development of effective therapeutics of neuro-COVID.

Alda-1 attenuation of binge alcohol-caused atrial arrhythmias through a novel mechanism of suppressed c-Jun N-terminal Kinase-2 activity

Holiday Heart Syndrome (HHS) is caused by excessive binge alcohol consumption, and atrial fibrillation (AF) is the most common arrhythmia among HHS patients. AF is associated with substantial morbidity and mortality, making its prevention and treatment of high clinical interest. This study defines the anti-AF action of Alda-1 (an established cardioprotective agent) and the underlying mechanisms of the action in our well-characterized HHS and cellular models. We found that Alda-1 effectively eliminated binge alcohol-evoked Ca2+ triggered activities (Ca2+ waves, prolonged Ca2+ transient diastolic decay) and arrhythmia inducibility in intact mouse atria. We then demonstrated that alcohol impaired human RyR2 channels (isolated from organ donors' hearts). The functional role of alcohol-caused RyR2 channel dysfunction in Ca2+ triggered arrhythmic activities was evidenced in a unique transgenic mouse model with a loss-of-function mutation (RyR2E4872Q+/-). Alda-1 is known to activate aldehyde dehydrogenase 2 (ALDH2), a key enzyme in alcohol detoxification. However, we found an increased level of ALDH2 and a preserved normal balance of pro- vs anti-apoptotic signaling in binge alcohol exposed hearts and H9c2 differentiated myocytes, which suggests that the link of alcohol-ALDH2-apoptosis is unlikely to be a key factor leading to binge alcohol-evoked arrhythmogenicity. We have previously reported that binge alcohol-activated stress response kinase JNK2 causatively drives Ca2+-triggered atrial arrhythmogenicity. Here, we found that JNK2-specific inhibition in either isolated human RyR2 channels or intact mouse atria abolished alcohol-evoked RyR2 channel dysfunction and Ca2+ triggered arrhythmic activities, suggesting a strong alcohol-JNK2-RyR2 interaction in atrial arrhythmogenicity. Furthermore, we revealed, for the first time, that Alda-1 suppresses JNK2 (but not JNK1) enzyme activity independently of ALDH2, which in turn alleviates binge alcohol-evoked Ca2+ triggered atrial arrhythmogenesis. Our findings provide novel mechanistic insights into the anti-arrhythmic action of Alda-1 and suggest that Alda-1 represents a potential preventative agent for AF management for HHS patients.

Activated single nucleotide mismatch determination through toehold-embedded hairpin-mediated strand displacement reaction alongside CRISPR-Cas12a for detection of TP53 point mutation

Activated single nucleotide mismatch determination through toehold-embedded hairpin-mediated strand displacement reaction alongside CRISPR-Cas12a for detection of TP53 point mutation

The role of metabolic disorders in the development of atherosclerosis.

Atherosclerosis is a major risk factor for cardiovascular disease (CVD), which is the leading cause of death worldwide. Atherosclerosis is initiated by endothelial activation, followed by a cascade of events (accumulation of lipids, fibrous elements, and calcification) triggering vasoconstriction and activation of inflammatory pathways. This review focuses on the various stages in the development of atherosclerosis, ranging from endothelial dysfunction to plaque rupture. In addition, disorders of lipid, glucose and amino acid metabolism in atherosclerosis are considered here. The key pathological stages of metabolism disruption and their role in atherosclerosis are considered in detail which may be helpful for the more better understanding of atherosclerosis pathogenesis. Finally, some therapeutic approaches aimed at modulating lipid metabolism will also be presented which show the therapeutic targets (enzymes and transport proteins) which modulation can prevent further deterioration of patients symptoms.

PPP3CB overexpression mediates EGFR TKI resistance in lung tumors via calcineurin/MEK/ERK signaling.

Despite initial high response rates to first-line EGFR TKI, all non-small-cell lung cancer (NSCLC) with EGFR-activating mutation will ultimately develop resistance to treatment. Identification of resistance mechanisms is critical to adapt treatment and improve patient outcomes. Here, we show that a PPP3CB transcript that encodes full-length catalytic subunit 2B of calcineurin accumulates in EGFR-mutant NSCLC cells with acquired resistance against different EGFR TKIs and in post-progression biopsies of NSCLC patients treated with EGFR TKIs. Neutralization of PPP3CB by siRNA or inactivation of calcineurin by cyclosporin A induces apoptosis in resistant cells treated with EGFR TKIs. Mechanistically, EGFR TKIs increase the cytosolic level of calcium and trigger activation of a calcineurin/MEK/ERK pathway that prevents apoptosis. Combining EGFR, calcineurin, and MEK inhibitors overcomes resistance to EGFR TKI in both in vitro and in vivo models. Our results identify PPP3CB overexpression as a new mechanism of acquired resistance to EGFR TKIs, and provide a promising therapeutic approach for NSCLC patients that progress under TKI treatment.

An unemployment re-insurance scheme for the eurozone? Stabilizing and redistributive effects

An unemployment re-insurance scheme for the eurozone? Stabilizing and redistributive effects

Nanomedicine Advancements in Cancer Therapy: A Scientific Review

Cancer nanomedicines, characterized by submicrometer-sized formulations, aim to optimize the biodistribution of anticancer drugs by minimizing off-target effects, reducing toxicity, enhancing target site accumulation, and improving overall efficacy. Numerous nanomedicines have been developed to improve the effectiveness and safety of traditional anticancer treatments. These include formulations with carbon nanotubes, nanodiamonds, enzyme-responsive nanoparticles for controlled drug release, dendrimers as nanoparticle drug carriers, quantum dot nanocarrier systems for precise drug delivery, solid lipid nanoparticles, and polymeric nanoparticles designed for targeted drug delivery. Additionally, nanotechnology has been explored in cancer treatment through gene therapy. Despite these advances, the complex nature of carrier materials and functional integration presents challenges in preparing these candidates for clinical translation. Nanotechnology, with its unique features at the nanoscale, offers novel possibilities for developing cancer therapies while increasing efficacy and safety. Although only a few nanotherapeutics have obtained clinical approval, exciting uses for nanotechnology are on the horizon. Nanoparticles possess unique transport, biological, optical, magnetic, electrical, and thermal capabilities due to their small size within the light wavelength spectrum. This results in high surface area-to-volume ratios, allowing for the incorporation of various supporting components in addition to active medicinal substances. These properties aid in solubilization, degradation protection, delayed release, immune response evasion, tissue penetration, imaging, targeted distribution, and triggered activation. In summary, the future of nanomedicine holds promise for introducing innovative platforms in cancer treatment. The research presented underscores the potential for nanoparticles to revolutionize anticancer therapies, enhancing the overall therapeutic approach.

Fluorescence assay for aflatoxin B1 based on aptamer-binding triggered DNAzyme activity.

As a kind of mycotoxin, aflatoxin B1 (AFB1), which is often found in agricultural products, poses a threat to human health. Developing asimple sensitive method for AFB1 detection is in great demand. Here, we reported an aptamer-based fluorescence assay for AFB1 detection by using DNAzyme to generate and amplify asignal. We redesigned a pair of DNA sequences, which originated from the anti-AFB1 aptamer and RNA-cleaving DNAzyme 10-23. In the absence of AFB1, the aptamer hybridized with the region of thesubstrate-binding arm of the DNAzyme, inhibiting the activity of theDNAzyme. In the presence of AFB1, the binding of AFB1 to theaptamer led to the displacement of theDNAzyme from theaptamer. The substrate-binding arm was unblocked, and the activity of theDNAzyme was restored for the hydrolysis of thefluorophore and quencher-labeled substrate, causing asignificant fluorescence increase. This assay could detect AFB1 in the dynamic range from 0.98 to 2000nmol/L with high selectivity, and the detection limit was 0.98nmol/L. Moreover, the assay was able to detect AFB1 in acomplex sample matrix. This work provides a useful tool for the analysis of AFB1.