PCBP1 interacts with the HTLV-1 Tax oncoprotein to potentiate NF-κB activation.

Human T-cell leukemia virus type 1 (HTLV-1) is the etiological agent of adult T-cell leukemia/lymphoma. The HTLV-1 Tax constitutively activates nuclear factor-κB (NF-κB) to promote the survival and transformation of HTLV-1-infected T cells. Despite extensive study of Tax, how Tax interacts with host factors to regulate NF-κB activation and HTLV-1-driven cell proliferation is not entirely clear. Here, we showed that overexpression of Poly (rC)-binding protein 1 (PCBP1) promoted Tax-mediated IκB kinase (IKK)-NF-κB signaling activation, whereas knockdown of PCBP1 attenuated Tax-dependent IKK-NF-κB activation. However, Tax activation of HTLV-1 long terminal repeat was unaffected by PCBP1. Furthermore, depletion of PCBP1 led to apoptosis and reduced proliferation of HTLV-1-transformed cells. Mechanistically, PCBP1 interacted and co-localized with Tax in the cytoplasm, and PCBP1 KH3 domain was indispensable for the interaction between PCBP1 and Tax. Moreover, PCBP1 facilitated the assembly of Tax/IKK complex. Collectively, our results demonstrated that PCBP1 may exert an essential effect in Tax/IKK complex combination and subsequent NF-κB activation, which provides a novel insight into the pathogenetic mechanisms of HTLV-1.

Mining the accident causes of railway dangerous goods transportation: A Logistics-DT-TFP based approach.

Accurately and quickly mining the hidden information in railway dangerous goods transportation (RDGT) accident reports has great significance for its safety management. In this paper, a data mining method Logistics-DT-TFP is proposed for analysing the causes of RDGT accidents. Firstly, analyse the transportation process, extract the cause of the accident, and classify the severity of the accident. Then, using ordered multi-classification Logistic regression for correlation calculation, qualitatively judge and quantitatively analyse the relationship between each cause and the severity of the accident. The feature tags of the Decision Tree (DT) are screened, the C5.0 algorithm is used to obtain the accident coupling rules. Next, the FP-Growth algorithm is used to mine frequent itemsets, and TOP-K is used to improve it and output effective association rules with the degree of lift as the indicator, which avoids repeated traversal of the database, shortens the time complexity, and reduces the impact of the minimum support setting on the calculation results. The degree of lift among the causes in the coupling chain is calculated as a complement to the extraction of coupling rules. Finally, based on the analysis and mining results of case study, the management strategies for railway dangerous goods are proposed.

Adsorption and Dispersion Effect of Sodium Lignosulfonate on Fine SiC Particles in Aqueous Media.

This study presented a novel modification method for fine SiC powder by using sodium lignosulfonate as a dispersant. The adsorption behavior of sodium lignosulfonate on the SiC/water interface and its effect on the performance of a fine SiC slurry were systematically investigated. The adsorption results showed that sodium lignosulfonate formed monolayer adsorption on the surface of fine SiC and that the saturated adsorption capacity was 1.3263 mg/g. The adsorption reached equilibrium within 3 h and was mainly controlled by active sites on the SiC surface. The dispersion, stability, and zeta potential of modified SiC powder were improved after sodium lignosulfonate adsorption. The zeta potential of modified SiC reached a minimum value of -44.8 mV at pH 12. Modified SiC suspensions had great stability in a wider pH range of 6-12. Modified SiC slurry with 54 vol % solid loading had a low viscosity of 173 mPa·s at pH 10. Subsequently, coarse SiC powder was added for slip casting. A mixed slurry with high solid loading (69 vol %) and low viscosity (583 mPa·s) was prepared using modified SiC and coarse SiC powders at a mass ratio of 2:3. Finally, recrystallized SiC green body with high density (2.6492 g/cm3) was obtained.

The effect of breakfast on childhood obesity: a systematic review and meta-analysis.

Objective: Previous cohort trials have shown that skipping breakfast increases the risk of obesity or overweight in children. However, this finding remains controversial. Through a meta-analysis, this study systematically evaluated the effect of skipping breakfast on the prevalence of obesity or overweight in children. Methods: We performed a literature search for studies published until March 19, 2023. using the Cochrane, PubMed, and Embase databases. Based on the inclusion and exclusion criteria, observational studies on the relationship between skipping breakfast and overweight/obesity in children and adolescents were analyzed. Three investigators independently screened the relevant literature, extracted the data, and assessed the risk of bias. The quality of the included studies was assessed using the Newcastle-Ottawa Scale (NOS). A random-effects model was used. The odds ratio (OR) with its 95% confidence interval (CI) was used to indicate the effect size. Results: A total of 40 retrospective studies with 323,244 children ranging in age from 2 to 20 years were included in this study. The results of this meta-analysis showed that children and adolescents who skipped breakfast had a significantly higher prevalence of obesity or overweight than those who ate breakfast (OR, 1.59; 95% CI, 1.33-1.90; P < 0.001). Skipping breakfast was positively associated with overweight in children and adolescents (OR, 1.37; 95% CI, 1.23-1.54; P < 0.001). Similarly, skipping breakfast was positively associated with obesity in children and adolescents (OR, 1.51; 95% CI, 1.30-1.76; P < 0.001). The effect was also different by sex, with girls being the most affected (OR, 1.47; 95% CI, 1.23-1.76; P < 0.001). There was also a correlation between skipping breakfast and abdominal obesity in children (OR, 0.65; 95% CI, 0.55-0.77; P < 0.001). Conclusion: This meta-analysis suggested that skipping breakfast is associated with an increased risk of overweight/obesity in children and adolescents. The findings provide support for a possible protective role of breakfast against excessive weight gain in children and adolescents. However, more rigorous study designs with validated and standardized measures of relevant variables are needed.

A New Process for Efficient Recovery of Rhodium from Spent Carbonyl Rhodium Catalyst by Microreactor.

Triphenylphosphine acetylacetone carbonyl rhodium (ROPAC) is an important catalyst in the petrochemical industry, and its deactivated waste catalyst holds significant value for recovery. This study focuses on the existing forms of rhodium (Rh) in waste catalysts and the current status of traditional processes. A green, efficient, and continuous recovery technique was developed using a sealed stainless steel microchannel reactor. The influence of reaction temperature, reaction time, and phase ratio on the Rh recovery rate was investigated, and the process parameters were optimized using response surface methodology (RSM). The results indicate that the magnitude of the impact on the Rh recovery rate follows the order: reaction temperature > reaction time > phase ratio. The optimized process parameters were determined as follows: a reaction time of 29 min, a reaction temperature of 110 °C, and a phase ratio of 1:1, with a corresponding maximum recovery rate of Rh of 66.06%. Furthermore, secondary treatment was performed on the organic phase after primary recovery using the same process conditions, resulting in an overall Rh recovery rate of 95.6%, indicating satisfactory recovery efficiency. Moreover, the application of FTIR and ICP-OES analysis provided definitive evidence that the oxidative dissociation of the rhodium-phosphine chemical bond by H2O2 within ROPAC leads to the conversion of Rh+ into Rh3+. Subsequently, Rh forms chloroaquorhodium (III) complexes that enter the aqueous phase, enabling effective recovery of Rh.

Recent Advances in Bioengineering Bone Revascularization Based on Composite Materials Comprising Hydroxyapatite.

The natural healing process of bone is impaired in the presence of tumors, trauma, or inflammation, necessitating external assistance for bone regeneration. The limitations of autologous/allogeneic bone grafting are still being discovered as research progresses. Bone tissue engineering (BTE) is now a crucial component of treating bone injuries and actively works to promote vascularization, a crucial stage in bone repair. A biomaterial with hydroxyapatite (HA), which resembles the mineral makeup of invertebrate bones and teeth, has demonstrated high osteoconductivity, bioactivity, and biocompatibility. However, due to its brittleness and porosity, which restrict its application, scientists have been prompted to explore ways to improve its properties by mixing it with other materials, modifying its structural composition, improving fabrication techniques and growth factor loading, and co-cultivating bone regrowth cells to stimulate vascularization. This review scrutinizes the latest five-year research on HA composite studies aimed at amplifying vascularization in bone regeneration.

Characteristic contrast­enhanced ultrasound findings of hepatic epithelioid haemangioendothelioma: A case report and literature review.

Hepatic epithelioid hemangioendothelioma (HEHE) is a rare liver tumor, which is usually diagnosed by pathological examination, since the diagnostic imaging criteria remain to be defined. However, contrast-enhanced ultrasound (CEUS) may reveal the characteristic features of HEHE to aid diagnosis. In the present study, two-dimensional ultrasound examination of a 38-year-old male patient showed a mass in the right liver. CEUS showed an S5 segment hypoechoic nodule, and imaging features resulted in the diagnosis of HEHE. Surgery was shown to be an appropriate and successful treatment for HEHE. In conclusion, CEUS may be valuable for the diagnosis of HEHE, thereby avoiding the serious consequences of misdiagnosis.

Hydrogen Peroxide/Phosphoric Acid Modification of Hydrochars for Sulfamethoxazole and Carbamazepine Adsorption: The Role of Oxygen-Containing Functional Groups.

Emerging pollutants, such as sulfonamide antibiotics and pharmaceuticals, have been widely detected in water and soils, posing serious environmental and human health concerns. Thus, it is urgent and necessary to develop a technology for removing them. In this work, a hydrothermal carbonization method was used to prepare the hydrochars (HCs) by pine sawdust with different temperatures. To improve the physicochemical properties of HCs, phosphoric acid (H3PO4) and hydrogen peroxide (H2O2) were used to modify these HCs, and they were referred to as PHCs and HHCs, respectively. The adsorption of sulfamethoxazole (SMX) and carbamazepine (CBZ) by pristine and modified HCs was investigated systematically. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) results indicated that the H2O2/H3PO4 modification led to the formation of a disordered carbon structure and abundant pores. X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared (FTIR) spectroscopy results suggested that carboxyl (-COOH) and hydroxyl (-OH) functional groups of HCs increased after modification, which is the main reason for the higher sorption of SMX and CBZ on H3PO4/H2O2-modified HCs when compared with pristine HCs. In addition, the positive correlation between -COOH/C=O and logKd of these two chemicals also suggested that oxygen-containing functional groups played a crucial role in the sorption of SMX and CBZ. The strong hydrophobic interaction and π-π interaction between CBZ and pristine/modified HCs resulted in its higher adsorption when compared with SMX. The results of this study provide a novel perspective on the investigation of adsorption mechanisms and environmental behaviors for organic contaminants by pristine and modified HCs.

FexO4-enhanced degradation of bisphenol A in visible light/peroxydisulfate system: production of singlet state oxygen.

In this study, ferrous composites (FexO4) were prepared by microreactor to activate peroxydisulfate (PDS) for the degradation of bisphenol A (BPA) with visible (Vis) light irradiation. X-ray diffraction (XRD), energy-dispersive spectrometry (EDS), X-ray photoelectron spectroscopy (XPS), and scanning electron microscope (SEM) were used to characterize the morphology and crystal phase of FeXO4. Photoluminescence (PL) spectroscopy combined with amperometric tests were used to determine the role of PDS on the performance of photocatalytic reaction. The main reactive species and intermediates for BPA removal were determined by electron paramagnetic resonance (EPR) measurement and quenching experiments. The result indicated that singlet state oxygen (1O2) contributed more to the BPA degradation than that of other reactive radicals (·OH, SO4·- and ·O2-); these reactive radicals and 1O2 formed by the reaction between photo-generated electrons (e-) and holes (h+) of FexO4 and PDS. During this process, the consumption of e- and h+ also improved their separation efficiency and thus enhanced the degradation of BPA. In addition, the photocatalytic activity of FexO4 in Vis/FexO4/PDS system was 3.2-fold and 6.6-fold higher than that of single FexO4 and PDS under Vis light, respectively. The Fe2+/Fe3+ cycle could effectively drive the photocatalytic activation of PDS through indirect electron transfer and the formation of reactive radicals. This work illustrated that the degradation of BPA was rapidly in Vis/FexO4/PDS system mainly through 1O2, which further improve our understanding on the efficient removal of organic contaminants in the environment.

Effect of metformin on sepsis-associated acute lung injury and gut microbiota in aged rats with sepsis.

Background: Recent studies reported the association between the changes in gut microbiota and sepsis, but there is unclear for the gut microbes on aged sepsis is associated acute lung injury (SALI), and metformin treatment for the change in gut microbiota. This study aimed to investigate the effect of metformin on gut microbiota and SALI in aged rats with sepsis. It also explored the therapeutic mechanism and the effect of metformin on aged rats with SALI. Methods: Aged 20-21 months SD rats were categorized into three groups: sham-operated rats (AgS group), rats with cecal ligation and puncture (CLP)-induced sepsis (AgCLP group), and rats treated with metformin (100 mg/kg) orally 1 h after CLP treatment (AgMET group). We collected feces from rats and analyzed them by 16S rRNA sequencing. Further, the lung samples were collected for histological analysis and quantitative real-time PCR (qPCR) assay and so on. Results: This study showed that some pathological changes occurring in the lungs of aged rats, such as hemorrhage, edema, and inflammation, improved after metformin treatment; the number of hepatocyte death increased in the AgCLP group, and decreased in the AgMET group. Moreover, metformin relieved SALI inflammation and damage. Importantly, the gut microbiota composition among the three groups in aged SALI rats was different. In particular, the proportion of E. coli and K. pneumoniae was higher in AgCLP group rats than AgS group rats and AgMET group rats; while metformin could increase the proportion of Firmicutes, Lactobacillus, Ruminococcus_1 and Lactobacillus_johnsonii in aged SALI rats. Moreover, Prevotella_9, Klebsiella and Escherichia_Shigella were correlated positively with the inflammatory factor IL-1 in the lung tissues; Firmicutes was correlated negatively with the inflammatory factor IL-1 and IL-6 in the lung tissues. Conclusions: Our findings suggested that metformin could improve SALI and gut microbiota in aged rats, which could provide a potential therapeutic treatment for SALI in aged sepsis.

Preparation of Micro-Size Spherical Silver Particles and Their Application in Conductive Silver Paste.

In this paper, micro-size spherical silver particles were prepared by using a wet-chemical reduction method. The silver particles were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and a laser particle-size analyzer. The results indicate that different types and the content of surfactants can be used to prevent the accumulation, and control the morphology and particle size distribution, of silver particles. Moreover, the morphology of silver particles was changed from polyhedral to spherical when the pH was raised from 1 to 3. Under the optimal synthesis conditions (0.1 mol/L silver nitrate, 0.06 mol/L ascorbic acid, gelatin (5% by weight of silver nitrate), pH = 1), the micro-size spherical silver particles with diameter of 5-8 µm were obtained. In addition, the resistivity of conductive silver paste that prepared with the as-synthesized spherical silver particles was discussed in detail and the average resistivity of the conductive silver paste was 3.57 × 10-5 Ω·cm after sintering at 140 °C for 30 min.

Porcine endogenous retrovirus: classification, molecular structure, regulation, function, and potential risk in xenotransplantation.

Xenotransplantation with porcine organs has been recognized as a promising solution to alleviate the shortage of organs for human transplantation. Porcine endogenous retrovirus (PERV), whose proviral DNAs are integrated in the genome of all pig breeds, is a main microbiological risk for xenotransplantation. Over the last decades, some advances on PERVs' studies have been achieved. Here, we reviewed the current progress of PERVs including the classification, molecular structure, regulation, function in immune system, and potential risk in xenotransplantation. We also discussed the problem of insufficient study on PERVs as well as the questions need to be answered in the future work.

SWEmean of Quadriceps, a Potential Index of Complication Evaluation to Patients with Chronic Obstructive Pulmonary Disease.

Purpose: To develop a potential quadriceps' index of complication evaluation for patients with chronic obstructive pulmonary disease (COPD) which is simple, convenient, and quantifiable. Patients and Methods: We conducted a prospective study of 59 patients with COPD and 56 healthy controls recruited by the Chengdu First People's Hospital. Grayscale ultrasound (US) of the rectus femoris was performed to measure thickness (RFthick) and cross-sectional area (RFcsa). Shear wave elastography was used to determine the mean elasticity index (SWEmean) of the rectus femoris (SWERFmean), vastus lateralis (SWEVLmean) and vastus medialis (SWEVMmean). Clinical features included dyspnea index score (modified British Medical Research Council (MMRC) score), COPD Assessment Test (CAT), the Five-Repetition Sit-to-Stand Test (5STS) and the Six-Minute Walk Test (6MWT). We compared the differences between US parameters and SWEmean in healthy controls and COPD patients. We also described the correlation between US parameters, SWEmean and clinical features of patients with COPD. Results: The intra-observer repeatability for the performance of using SWE to measure quadriceps stiffness was excellent (intraclass correlation coefficient (ICC)>0.75, p < 0.001). There was a statistically significant difference in the SWEmean of the quadriceps (p < 0.001), but no significant difference in terms of RFthic and RFcsa (p > 0.05) between healthy controls and COPD patients. The SWERFmean was positively correlated with the 6MWT (r = 0.959, p < 0.001), and negatively related to the mMRC (r=-0.825, p < 0.001), CAT (r=-0.993, p < 0.001) and 5STS (r=-0.936, p < 0.001). However, the RFthic, RFcsa, SWEVLmean and SWEVMmean were not correlated with clinical features (p > 0.05). Conclusion: As a supplement to US, SWE reflects changes of stiffness in the quadriceps of COPD patients, and can expanding the dimension of US for assessing the quadriceps. Furthermore, SWEmean was associated with clinical features, and represents a potential index with which to reflect the clinical features of COPD patients.

[Cross subject personality assessment based on electroencephalogram functional connectivity and domain adaptation].

The research shows that personality assessment can be achieved by regression model based on electroencephalogram (EEG). Most of existing researches use event-related potential or power spectral density for personality assessment, which can only represent the brain information of a single region. But some research shows that human cognition is more dependent on the interaction of brain regions. In addition, due to the distribution difference of EEG features among subjects, the trained regression model can not get accurate results of cross subject personality assessment. In order to solve the problem, this research proposes a personality assessment method based on EEG functional connectivity and domain adaption. This research collected EEG data from 45 normal people under different emotional pictures (positive, negative and neutral). Firstly, the coherence of 59 channels in 5 frequency bands was taken as the original feature set. Then the feature-based domain adaptation was used to map the feature to a new feature space. It can reduce the distribution difference between training and test set in the new feature space, so as to reduce the distribution difference between subjects. Finally, the support vector regression model was trained and tested based on the transformed feature set by leave-one-out cross-validation. What's more, this paper compared the methods used in previous researches. The results showed that the method proposed in this paper improved the performance of regression model and obtained better personality assessment results. This research provides a new method for personality assessment.

Cross-Task Cognitive Workload Recognition Based on EEG and Domain Adaptation.

Cognitive workload recognition is pivotal to maintain the operator's health and prevent accidents in the human-robot interaction condition. So far, the focus of workload research is mostly restricted to a single task, yet cross-task cognitive workload recognition has remained a challenge. Furthermore, when extending to a new workload condition, the discrepancy of electroencephalogram (EEG) signals across various cognitive tasks limits the generalization of the existed model. To tackle this problem, we propose to construct the EEG-based cross-task cognitive workload recognition models using domain adaptation methods in a leave-one-task-out cross-validation setting, where we view any task of each subject as a domain. Specifically, we first design a fine-grained workload paradigm including working memory and mathematic addition tasks. Then, we explore four domain adaptation methods to bridge the discrepancy between the two different tasks. Finally, based on the supporting vector machine classifier, we conduct experiments to classify the low and high workload levels on a private EEG dataset. Experimental results demonstrate that our proposed task transfer framework outperforms the non-transfer classifier with improvements of 3% to 8% in terms of mean accuracy, and the transfer joint matching (TJM) consistently achieves the best performance.

Preparation of N/S doped carbon dots and their application in nitrite detection.

Detection of carcinogens is generally recognized to be meaningful, especially for nitrites (NO2 -). Here blue-green fluorescent carbon dots (CDs) were successfully synthesized by using p-aminobenzenesulfonic acid, and their surfaces were identified to be abundant in the functional groups of amino, hydroxyl, and sulfuric acid. Importantly, the sulfuric acid group and aromatic primary ammonia groups on the surfaces of CDs showed the interactions with the nitrites to cause fluorescence quenching. The novel CDs showed high sensitivity and selectivity for NO2 - detection with a low detection limit of 0.03 mM in water due to the fluorescence quenching effect of the CDs. Consequently, the proposed CDs here may provide a new way of monitoring NO2 - in the target samples.

The role of solvents and oxygen-containing functional groups on the adsorption of Bisphenol A on carbon nanotubes.

The wide application of endocrine disruptors (EDs) has recently created great public concerns because of their toxicities. Previous studies have stated that the effect of oxygen-containing functional groups of carbon nanotubes (CNTs) for Bisphenol A (BPA) sorption, but no study has been quantified the exact contribution of the oxygen-containing functional groups. Moreover, the role of solvents on the adsorption of BPA should be considered. Considering the well properties of CNTs, graphitized (MG), carboxylated (MC) and hydroxylated (MH) multi-walled CNTs were selected as model adsorbents, BPA was used as model adsorbate. Solubility and single point adsorption coefficient (logKd) of BPA were n-hexadecane > water > methanol, suggesting that hydrophobic interaction was the main mechanism for BPA sorption on CNTs. For different functional groups of CNTs, π-π interaction between MH and BPA may be stronger than that of MC, and thus the sorption of BPA on MH was higher than that of MC. Moreover, hydrogen bond resulted in the higher adsorption of BPA on MH when compared with MC. The oxygen-containing functional groups of CNTs played a key role for BPA sorption in methanol because the values of contribution were 20%-45% for -OH and were 5%-25% for -COOH. In n-hexadecane, other factors such as hydrophobic interactions should be considered because the contribution percentages of -OH were ca.15% and the values for -COOH were ca.10%. The results are expected to provide important information on the interaction of EDs and CNTs.

Porcine genome engineering for xenotransplantation.

The extreme shortage of human donor organs for treatment of patients with end-stage organ failures is well known. Xenotransplantation, which might provide unlimited organ supply, is a most promising strategy to solve this problem. Domestic pigs are regarded as ideal organ-source animals owing to similarity in anatomy, physiology and organ size to humans as well as high reproductive capacity and low maintenance cost. However, several barriers, which include immune rejection, inflammation and coagulative dysfunctions, as well as the cross-species transmission risk of porcine endogenous retrovirus, blocked the pig-to-human xenotransplantation. With the rapid development of genome engineering technologies and the potent immunosuppressive medications in recent years, these barriers could be eliminated through genetic modification of pig genome together with the administration of effective immunosuppressants. A number of candidate genes involved in the regulation of immune response, inflammation and coagulation have been explored to optimize porcine xenograft survival in non-human primate recipients. PERV inactivation in pigs has also been accomplished to firmly address the safety issue in pig-to-human xenotransplantation. Many encouraging preclinical milestones have been achieved with some organs surviving for years. Therefore, the clinical trials of some promising organs, such as islet, kidney and heart, are aimed to be launched in the near future.

Exploration of the temporal-spatial expression pattern and DNA methylation-related regulation of the duck telomerase reverse transcriptase gene.

Telomerase reverse transcriptase (TERT) is a catalytic subunit of telomerase that adds TTAGGG repeats to the 3'-overhang of telomeres. In the present study, we detected that the duck TERT (dTERT) gene was highly expressed in small intestine and kidney, followed by heart, leg muscle, spleen, pancreas, gonad, and liver at neonatal stage. From embryonic to neonatal stage, the highest dTERT mRNA in liver appeared at stage E19 (19 days at embryonic stage), while for the leg muscle the maximum expression occurred at E26. We also measured the relative telomerase activity (RTA) and relative telomere length (RTL) in the examined tissues and found that the changed tendency of RTA and RTL was not very consistent with that of TERT. In silico analysis revealed that there were three CpG islands (S1, S2, and S3) within the 5' regulatory region of the dTERT gene. Bisulfite sequencing PCR (BSP) assay showed that liver (D7, 7 days after birth) which expressed significantly lower dTERT mRNA had an obviously higher methylation level of S1 compared with small intestine (D7) or liver (E19). Quantitative real-time PCR analysis revealed that the expression of DNA methyltransferase DNMT1 in liver (D7) was significantly higher than that in small intestine (D7) or in liver (E19). In vitro, dTERT expression was upregulated and the methylation status of S1 decreased in both duck embryonic fibroblasts and small intestinal epithelial cells following treatment with the demethylation reagent, 5-aza-2'-deoxycytidine (5-aza-dC), further suggesting that dTERT is epigenetically regulated by DNA methylation. This work lays a solid foundation for further study of TERT function and regulation in avian species.

The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat.

Arrhythmogenesis in acute myocardial infarction (MI) is associated with depolarization of resting membraine potential (RMP) and decrease of inward rectifier potassium current (IK1) in cardiomyocytes. However, clinical anti-arrhythmic agents that primarily act on RMP by enhancing the IK1 channel are not currently available. We hypothesized that zacopride, a selective and moderate agonist of the IK1/Kir2.1 channels, prevents and cures acute ischemic arrhythmias. To test this viewpoint, adult Sprague-Dawley (SD) rats were subjected to MI by ligating the left main coronary artery. The antiarrhythmic effects of zacopride (i.v. infusion) were observed in the settings of pre-treatment (zacopride given 3 min prior to coronary occlusion), post-treatment (zacopride given 3 min after coronary occlusion) and therapeutic treatment (zacopride given 30 s after the onset of the first sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) post MI). In all the three treatment modes, zacopride (15 µg/kg) inhibited MI-induced ventricular tachyarrhythmias, as shown by significant decreases in the premature ventricular contraction (PVC) and the duration and incidence of VT or VF. In Langendorff perfused rat hearts, the antiarrhythmic effect of 1 µmol/L zacopride were reversed by 1 µmol/L BaCl2, a blocker of IK1 channel. Patch clamp results in freshly isolated rat ventricular myocytes indicated that zacopride activated the IK1 channel and thereby reversed hypoxia-induced RMP depolarization and action potential duration (APD) prolongation. In addition, zacopride (1 µmol/L) suppressed hypoxia- or isoproterenol- induced delayed afterdepolarizations (DADs). In Kir2.x transfected Chinese hamster ovary (CHO) cells, zacopride activated the Kir2.1 homomeric channel but not the Kir2.2 or Kir2.3 channels. These results support our hypothesis that moderately enhancing IK1/Kir2.1 currents as by zacopride rescues ischemia- and hypoxia- induced RMP depolarization, and thereby prevents and cures acute ischemic arrhythmias. This study brings a new viewpoint to antiarrhythmic theories and provides a promising target for the treatment of acute ischemic arrhythmias.