Search Results (24)

p190RhoGAP, which exists in two paralogs, p190RhoGAP-A (p190A) and p190RhoGAP-B (p190B), is a GTPase activating protein (GAP) contributing to the regulation of the cellular activity of RhoGTPases. Recent data showed that M₂ muscarinic acetylcholine receptor (M₂R) stimulation in neonatal rat cardiac myocytes (NRCM) induces the binding of p190RhoGAP to the long isoform of the regulator of G protein signaling 3 (RGS3L). This complex formation alters the substrate preference of p190RhoGAP from RhoA to Rac1. By analyzing carbachol-stimulated GAP activity, we show herein that p190A, but not p190B, alters its substrate preference in NRCM. Based on data that the RhoGAP activity of p190A in endothelial cells is diminished upon nitration by endothelial nitric oxide synthase (eNOS)-derived peroxynitrite, we studied whether carbachol-induced NO/peroxynitrite formation contributes to the carbachol-induced RhoA activation in NRCM. Interestingly, the carbachol-induced RhoA activation in NRCM was suppressed by the eNOS-preferring inhibitor L-NIO as well as the non-selective NOS inhibitor L-NAME. Using L-NIO, we firstly verified the carbachol-induced NO production concurrent with eNOS activation and, secondly, the carbachol-induced nitration of p190A in NRCM. By co-immunoprecipitation, the carbachol-induced complex formation of eNOS, p190A, RGS3L and caveolin-3 was detected. We thus conclude that the NO production by M₂R-induced eNOS activation in caveolae in NRCM is required for the nitration of p190A, leading to the binding to RGS3L and the change in substrate preference from RhoA to Rac1. In line with this interpretation, the disruption of caveolae in NRCM by methyl-β-cyclodextrin suppressed carbachol-induced RhoA activation in NRCM to a similar extent as the inhibition of NO production. Full article

Previous studies indicated long non-coding RNAs (lncRNAs) participated in the pathogenesis of atrial fibrillation (AF). However, little is known about the role of lncRNAs in AF-induced electrical remodeling. This study aimed to investigate the regulatory effect of lncRNA GAS5 (GAS5) on the electrical remodeling of neonatal rat cardiomyocytes (NRCMs) induced by rapid pacing (RP). RNA microarray analysis yielded reduced GAS5 level in NRCMs after RP. RT-qPCR, western blot, and immunofluorescence yielded downregulated levels of Nav1.5, Kv4.2, and Cav1.2 after RP, and whole-cell patch-clamp yielded decreased sodium, potassium, and calcium current. Overexpression of GAS5 attenuated electrical remodeling. Bioinformatics tool prediction analysis and dual luciferase reporter assay confirmed a direct negative regulatory effect for miR-27a-3p on lncRNA-GAS5 and HOXa10. Further analysis demonstrated that either miR-27a-3p overexpression or the knockdown of HOXa10 further downregulated Nav1.5, Kv4.2, and Cav1.2 expression. GAS5 overexpression antagonized such effects in Nav1.5 and Kv4.2 but not in Cav1.2. These results indicate that, in RP-treated NRCMs, GAS5 could restore Nav1.5 and Kv4.2 expression via the miR-27a-3p/HOXa10 pathway. However, the mechanism of GAS5 restoring Cav1.2 level remains unclear. Our study suggested that GAS5 regulated cardiac ion channels via the GAS5/miR-27a-3p/HOXa10 pathway and might be a potential therapeutic target for AF. Full article

On the climate-health issue, studies have already attempted to understand the influence of climate change on the transmission of malaria. Extreme weather events such as floods, droughts, or heat waves can alter the course and distribution of malaria. This study aims to understand the impact of future climate change on malaria transmission using, for the first time in Senegal, the ICTP’s community-based vector-borne disease model, TRIeste (VECTRI). This biological model is a dynamic mathematical model for the study of malaria transmission that considers the impact of climate and population variability. A new approach for VECTRI input parameters was also used. A bias correction technique, the cumulative distribution function transform (CDF-t) method, was applied to climate simulations to remove systematic biases in the Coupled Model Intercomparison Project Phase 5 (CMIP5) global climate models (GCMs) that could alter impact predictions. Beforehand, we use reference data for validation such as CPC global unified gauge-based analysis of daily precipitation (CPC for Climate Prediction Center), ERA5-land reanalysis, Climate Hazards InfraRed Precipitation with Station data (CHIRPS), and African Rainfall Climatology 2.0 (ARC2). The results were analyzed for two CMIP5 scenarios for the different time periods: assessment: 1983–2005; near future: 2006–2028; medium term: 2030–2052; and far future: 2077–2099). The validation results show that the models reproduce the annual cycle well. Except for the IPSL-CM5B model, which gives a peak in August, all the other models (ACCESS1–3, CanESM2, CSIRO, CMCC-CM, CMCC-CMS, CNRM-CM5, GFDL-CM3, GFDL-ESM2G, GFDL-ESM2M, inmcm4, and IPSL-CM5B) agree with the validation data on a maximum peak in September with a period of strong transmission in August–October. With spatial variation, the CMIP5 model simulations show more of a difference in the number of malaria cases between the south and the north. Malaria transmission is much higher in the south than in the north. However, the results predicted by the models on the occurrence of malaria by 2100 show differences between the RCP8.5 scenario, considered a high emission scenario, and the RCP4.5 scenario, considered an intermediate mitigation scenario. The CanESM2, CMCC-CM, CMCC-CMS, inmcm4, and IPSL-CM5B models predict decreases with the RCP4.5 scenario. However, ACCESS1–3, CSIRO, NRCM-CM5, GFDL-CM3, GFDL-ESM2G, and GFDL-ESM2M predict increases in malaria under all scenarios (RCP4.5 and RCP8.5). The projected decrease in malaria in the future with these models is much more visible in the RCP8.5 scenario. The results of this study are of paramount importance in the climate-health field. These results will assist in decision-making and will allow for the establishment of preventive surveillance systems for local climate-sensitive diseases, including malaria, in the targeted regions of Senegal. Full article

Preterm birth is a risk factor for cardiometabolic disease. The preterm heart before terminal differentiation is in a phase that is crucial for the number and structure of cardiomyocytes in further development, with adverse effects of hypoxic and hyperoxic events. Pharmacological intervention could attenuate the negative effects of oxygen. Dexmedetomidine (DEX) is an α2-adrenoceptor agonist and has been mentioned in connection with cardio-protective benefits. In this study, H9c2 myocytes and primary fetal rat cardiomyocytes (NRCM) were cultured for 24 h under hypoxic condition (5% O₂), corresponding to fetal physioxia (pO₂ 32–45 mmHg), ambient oxygen (21% O₂, pO₂ ~150 mmHg), or hyperoxic conditions (80% O₂, pO₂ ~300 mmHg). Subsequently, the effects of DEX preconditioning (0.1 µM, 1 µM, 10 µM) were analyzed. Modulated oxygen tension reduced both proliferating cardiomyocytes and transcripts (CycD2). High-oxygen tension induced hypertrophy in H9c2 cells. Cell-death-associated transcripts for caspase-dependent apoptosis (Casp3/8) increased, whereas caspase-independent transcripts (AIF) increased in H9c2 cells and decreased in NRCMs. Autophagy-related mediators (Atg5/12) were induced in H9c2 under both oxygen conditions, whereas they were downregulated in NRCMs. DEX preconditioning protected H9c2 and NRCMs from oxidative stress through inhibition of transcription of the oxidative stress marker GCLC, and inhibited the transcription of both the redox-sensitive transcription factors Nrf2 under hyperoxia and Hif1α under hypoxia. In addition, DEX normalized the gene expression of Hippo-pathway mediators (YAP1, Tead1, Lats2, Cul7) that exhibited abnormalities due to differential oxygen tensions compared with normoxia, suggesting that DEX modulates the activation of the Hippo pathway. This, in the context of the protective impact of redox-sensitive factors, may provide a possible rationale for the cardio-protective effects of DEX in oxygen-modulated requirements on survival-promoting transcripts of immortalized and fetal cardiomyocytes. Full article

Background: Elderly population is particularly vulnerable to socioeconomic disparities. This study assessed inequalities in health care utilization among the elderly in China and identified contributing factors. Methods: This study used data from the 2018 China Health and Retirement Longitudinal Study survey. A non-linear probit regression model based on the Andersen Health Care Utilization Model was used to identify determinants of health care utilization among the elderly. The concentration index (CI) and the decomposition of the CI were calculated to evaluate inequalities in health care utilization among the elderly and identify related contributors. Results: The CI for actual and standardized outpatient visits was 0.0889 and 0.0945, respectively, and the corresponding values for inpatient service utilization were 0.1134 and 0.1176, respectively. Factors that contributed to greater inequalities in the utilization of outpatient and inpatient service included income (73.68% for outpatient service; 85.20% for inpatient service), Urban Employee Basic Medical Insurance (UEBMI) (40.75% for outpatient service; 32.03% for inpatient service) and non-agricultural Hukou status (12.63% for outpatient service; 18.73% for inpatient service). New Rural Cooperative Medical Scheme (NRCMS) (−34.30% for outpatient service; −33.18% for inpatient service) and poor health status (−7.36% for outpatient service; −8.30% for inpatient service) reduced inequalities in outpatient and inpatient utilization. Conclusions: This study found that a key contributor to these inequalities was income, followed by UEBMI coverage. Meanwhile, health care coverage through NRCMS was associated with fewer disparities in health care utilization. Full article

Particulate matter with a diameter less than 2.5 (PM_2.5) is one of the major threats posed by air pollution to human health. It penetrates the respiratory system, particularly the lungs. In northern Thailand, the PM_2.5 concentrations have significantly increased in the past decade, becoming a major concern for the health of children. This study aimed to assess the health risk of PM_2.5 in different age groups of children in northern Thailand between 2020 and 2029. Based on the PM_2.5 data from the simulation of the Nested Regional Climate Model with Chemistry (NRCM-Chem), the hazard quotient (HQ) was used to estimate the possible risk from PM_2.5 exposure in children. In general, all age groups of children in northern Thailand will tend to experience the threat of PM_2.5 in the future. In the context of age-related development periods, infants are at a higher risk than other groups (toddlers, young children, school age and adolescents), but adolescents also have a lower risk of exposure to PM_2.5, albeit maintaining a high HQ value (>1). Moreover, the analysis of risk assessment in different age groups of children revealed that PM_2.5 exposure might indeed affect adolescent risk differently depending on gender, with males generally at a heightened risk than females in adolescence. Full article

Infants exposed to diabetic pregnancy are at higher risk of cardiomyopathy at birth and early onset cardiovascular disease (CVD) as adults. Using a rat model, we showed how fetal exposure to maternal diabetes causes cardiac disease through fuel-mediated mitochondrial dysfunction, and that a maternal high-fat diet (HFD) exaggerates the risk. Diabetic pregnancy increases circulating maternal ketones which can have a cardioprotective effect, but whether diabetes-mediated complex I dysfunction impairs myocardial metabolism of ketones postnatally remains unknown. The objective of this study was to determine whether neonatal rat cardiomyocytes (NRCM) from diabetes- and HFD-exposed offspring oxidize ketones as an alternative fuel source. To test our hypothesis, we developed a novel ketone stress test (KST) using extracellular flux analyses to compare real-time ß-hydroxybutyrate (βHOB) metabolism in NRCM. We also compared myocardial expression of genes responsible for ketone and lipid metabolism. NRCM had a dose-dependent increase in respiration with increasing concentrations of βHOB, demonstrating that both control and combination exposed NRCM can metabolize ketones postnatally. Ketone treatment also enhanced the glycolytic capacity of combination exposed NRCM with a dose-dependent increase in the glucose-mediated proton efflux rate (PER) from CO2 (aerobic glycolysis) alongside a decreased reliance on PER from lactate (anaerobic glycolysis). Expression of genes responsible for ketone body metabolism was higher in combination exposed males. Findings demonstrate that myocardial ketone body metabolism is preserved and improves fuel flexibility in NRCM from diabetes- and HFD-exposed offspring, which suggests that ketones might serve a protective role in neonatal cardiomyopathy due to maternal diabetes. Full article

Myocardial damage caused by the newly emerged coronavirus (SARS-CoV-2) infection is one of the key determinants of COVID-19 severity and mortality. SARS-CoV-2 entry to host cells is initiated by binding with its receptor, angiotensin-converting enzyme (ACE) 2, and the ACE2 abundance is thought to reflect the susceptibility to infection. Here, we report that ibudilast, which we previously identified as a potent inhibitor of protein complex between transient receptor potential canonical (TRPC) 3 and NADPH oxidase (Nox) 2, attenuates the SARS-CoV-2 spike glycoprotein pseudovirus-evoked contractile and metabolic dysfunctions of neonatal rat cardiomyocytes (NRCMs). Epidemiologically reported risk factors of severe COVID-19, including cigarette sidestream smoke (CSS) and anti-cancer drug treatment, commonly upregulate ACE2 expression level, and these were suppressed by inhibiting TRPC3-Nox2 complex formation. Exposure of NRCMs to SARS-CoV-2 pseudovirus, as well as CSS and doxorubicin (Dox), induces ATP release through pannexin-1 hemi-channels, and this ATP release potentiates pseudovirus entry to NRCMs and human iPS cell-derived cardiomyocytes (hiPS-CMs). As the pseudovirus entry followed by production of reactive oxygen species was attenuated by inhibiting TRPC3-Nox2 complex in hiPS-CMs, we suggest that TRPC3-Nox2 complex formation triggered by panexin1-mediated ATP release participates in exacerbation of myocardial damage by amplifying ACE2-dependent SARS-CoV-2 entry. Full article

The opening of the ATP-sensitive mitochondrial potassium channel (mitok-ATP) is a common goal of cardioprotective strategies in the setting of acute and chronic myocardial disease. The biologically active thyroid hormone (TH), 3-5-3-triiodothyronine (T3), has been indicated as a potential activator of mitoK-ATP but the underlying mechanisms are still elusive. Here we describe a novel role of T3 in the transcriptional regulation of mitoK and mitoSur, the recently identified molecular constituents of the channel. To mimic human ischemic heart damage, we used a rat model of a low T3 state as the outcome of a myocardial ischemia/reperfusion event, and neonatal rat cardiomyocytes (NRCM) challenged with hypoxia or H₂O₂. Either in the in vivo or in vitro models, T3 administration to recover the physiological concentrations was able to restore the expression level of both the channel subunits, which were found to be downregulated under the stress conditions. Furthermore, the T3-mediated transcriptional activation of mitoK-ATP in the myocardium and NRCM was associated with the repression of the TH-inactivating enzyme, deiodinase 3 (Dio3), and an up-regulation of the T3-responsive miR-133a-3p. Mechanistically, the loss and gain of function experiments and reporter gene assays performed in NRCM, have revealed a new regulatory axis whereby the silencing of Dio3 under the control of miR-133a-3p drives the T3-dependent modulation of cardiac mitoK and mitoSur transcription. Full article

Increased heat stress affects well-being, comfort, and economic activities across the world. It also causes a significant decrease in work performance, as well as heat-related mortality. This study aims to investigate the impacts of the projected climate change scenario under RCP8.5 on heat stress and associated work performance in Thailand during the years 2020–2029. The model evaluation shows exceptional performance in the present-day simulation (1990–1999) of temperature and relative humidity, with R² values ranging from 0.79 to 0.87; however, the modeled temperature and relative humidity are all underestimated when compared to observation data by −0.9 °C and −27%, respectively. The model results show that the temperature change will tend to increase by 0.62 °C per decade in the future. This could lead to an increase in the heat index by 2.57 °C if the temperature increases by up to 1.5 °C in Thailand. The effect of climate change is predicted to increase heat stress by 0.1 °C to 4 °C and to reduce work performance in the range of 4% to >10% across Thailand during the years 2020 and 2029. Full article

Throughout the year, particularly during the dry season, the northern peninsula of Southeast Asia struggles with air pollution from PM_2.5. In this study, we used the Nested Regional Climate and Chemistry Model (NRCM-Chem) to predict the PM_2.5 concentrations over Southeast Asia’s northern peninsula during the years 2020–2029 under the Representative Concentration Pathway (RCP)8.5. In general, the model reasonably shows a good result, including temperature, precipitation, and PM_2.5 concentration, compared to the observation with an Index of Agreement (IOA) in the range of 0.63 to 0.80. However, there were some underestimations for modeled precipitation and temperature and an overestimation for modeled PM_2.5 concentration. As a response to changes in climatic parameters and the emission of PM_2.5’s precursors, PM_2.5 concentrations tend to increase across the region in the range of (+1) to (+35) µg/m³ during the dry season (November to April) and decline in the range of (−3) to (−30) µg/m³ during the wet season (May to October). The maximum increase in PM_2.5 concentrations were found in March by >40 µg/m³. Full article

Injectable decellularized matrix hydrogels derived from either myocardium or small intestinal submucosa (pDMYO-gel, pDSIS-gel) have been successfully used for myocardial injury repair. However, the relationship between tissue-specific biological functions and protein composition in these two materials is not clear yet. In this study, the protein composition, mechanical properties, and morphology of these two hydrogels and their effects on the behavior of neonatal rat cardiomyocytes (NRCMs) and human umbilical vein endothelial cells (HUVECs), are investigated. The results show that pDMYO-gel is more conducive to growth, adhesion, spreading, and maintenance of normal NRCM beating, due to its higher proportion of extracellular matrix (ECM) glycoproteins (49.55%) and some unique functional proteins such as annexin-6 (ANXA6), agrin (AGRN), cathepsin D (CTSD) and galectin-1 (LGALS1), whereas pDSIS-gel is more conducive to the proliferation of HUVECs. Animal study shows that pDMYO-gel has a better effect on improving cardiac function, inhibiting myocardial fibrosis and maintaining ventricular wall thickness in acute myocardial infarction models in vivo. Therefore, it is proposed that injectable pDMYO-gel hydrogel may be more suitable for functional recovery of myocardial injuries. Full article

With the deepening of health insurance reform in China, the integration of social health insurance schemes was put on the agenda. This paper aims to illustrate the achievements and the gaps in integration by demonstrating the trends in benefits available from the three social health insurance schemes, as well as the influencing factors. Data were drawn from the three waves of the China Health and Nutrition Survey (2009, 2011, 2015) undertaken since health reforms commenced. χ², Kruskal–Wallis test, and the Two-Part model were employed in the analysis. The overall reimbursement rate of the Urban Employee Basic Medical Insurance (UEBMI) is higher than that of Urban Resident Basic Medical Insurance (URBMI) or the New Rural Cooperative Medical Scheme (NRCMS) (p < 0.001), but the gap has narrowed since health reform began in 2009. Both the outpatient and inpatient reimbursement amounts have increased through the URBMI and NRCMS. Illness severity, higher institutional level, and inpatient service were associated with significant increases in the amount of reimbursement received across the three survey waves. The health reform improved benefits covered by the URBMI and NRCMS, but gaps with the UEBMI still exist. The government should consider more the release of health benefits and how to lead toward healthcare equity. Full article

Ventricular arrhythmia induced by ischemia/reperfusion (I/R) injury is a clinical problem in reperfusion therapies for acute myocardial infarction. Ca²⁺ overload through reactive oxygen species (ROS) production is a major cause for I/R-induced arrhythmia. We previously demonstrated that canstatin, a C-terminal fragment of type IV collagen α2 chain, regulated Ca²⁺ handling in rat heart. In this study, we aimed to clarify the effects of canstatin on I/R-induced ventricular arrhythmia in rats. Male Wistar rats were subjected to I/R injury by ligating the left anterior descending artery followed by reperfusion. Ventricular arrhythmia (ventricular tachycardia and ventricular fibrillation) was recorded by electrocardiogram. Nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity and ROS production in neonatal rat cardiomyocytes (NRCMs) stimulated with oxygen glucose deprivation/reperfusion (OGD/R) were measured by lucigenin assay and 2′,7′-dichlorodihydrofluorescein diacetate staining, respectively. The H₂O₂-induced intracellular Ca²⁺ ([Ca²⁺]_i) rise in NRCMs was measured by a fluorescent Ca²⁺ indicator. Canstatin (20 µg/kg) inhibited I/R-induced ventricular arrhythmia in rats. Canstatin (250 ng/mL) inhibited OGD/R-induced NOX activation and ROS production and suppressed the H₂O₂-induced [Ca²⁺]_i rise in NRCMs. We for the first time demonstrated that canstatin exerts a preventive effect against I/R-induced ventricular arrhythmia, perhaps in part through the suppression of ROS production and the subsequent [Ca²⁺]_i rise. Full article

China’s rural older are the threat from chronic diseases, making it important to evaluate the effect of public health insurance on the health care utilization and expenditures with chronic diseases. In 2003, China initiated a public health insurance, which was called the New Rural Cooperative Medical System (NRCMS). NRCMS is a voluntary program, targeting rural residents with government subsidies and individual contribution. Using the two-stage residual inclusion approach (2SRI), we analyzed the impact of NRCMS on health-care service utilization and expenditure of rural older with chronic diseases by using the 2011 and 2013 China Health and Retirement Survey (CHARLS) data. The results showed NRCMS did not play an effective role on improving the medical services utilization of rural older with chronic diseases. Although NRCMS immediate reimbursement significantly reduced the outpatient service fee, the actual outpatient reimbursement is the opposite. In addition, NRCMS did not significantly decrease their hospitalization expense. Policy makers should pay attention to health management about chronic diseases in rural China, and some measures should be taken to deepen the medical security system reform and improve the public health service system. Full article