PEX3 promotes regenerative repair after myocardial injury in mice through facilitating plasma membrane localization of ITGB3.

The peroxisome is a versatile organelle that performs diverse metabolic functions. PEX3, a critical regulator of the peroxisome, participates in various biological processes associated with the peroxisome. Whether PEX3 is involved in peroxisome-related redox homeostasis and myocardial regenerative repair remains elusive. We investigate that cardiomyocyte-specific PEX3 knockout (Pex3-KO) results in an imbalance of redox homeostasis and disrupts the endogenous proliferation/development at different times and spatial locations. Using Pex3-KO mice and myocardium-targeted intervention approaches, the effects of PEX3 on myocardial regenerative repair during both physiological and pathological stages are explored. Mechanistically, lipid metabolomics reveals that PEX3 promotes myocardial regenerative repair by affecting plasmalogen metabolism. Further, we find that PEX3-regulated plasmalogen activates the AKT/GSK3ß signaling pathway via the plasma membrane localization of ITGB3. Our study indicates that PEX3 may represent a novel therapeutic target for myocardial regenerative repair following injury.

Checkpoint Kinase 1 Stimulates Endogenous Cardiomyocyte Renewal and Cardiac Repair by Binding to Pyruvate Kinase Isoform M2 C-Domain and Activating Cardiac Metabolic Reprogramming in a Porcine Model of Myocardial Ischemia/Reperfusion Injury.

BACKGROUND: The regenerative capacity of the adult mammalian hearts is limited. Numerous studies have explored mechanisms of adult cardiomyocyte cell-cycle withdrawal. This translational study evaluated the effects and underlying mechanism of rhCHK1 (recombinant human checkpoint kinase 1) on the survival and proliferation of cardiomyocyte and myocardial repair after ischemia/reperfusion injury in swine. METHODS AND RESULTS: Intramyocardial injection of rhCHK1 protein (1 mg/kg) encapsulated in hydrogel stimulated cardiomyocyte proliferation and reduced cardiac inflammation response at 3 days after ischemia/reperfusion injury, improved cardiac function and attenuated ventricular remodeling, and reduced the infarct area at 28 days after ischemia/reperfusion injury. Mechanistically, multiomics sequencing analysis demonstrated enrichment of glycolysis and mTOR (mammalian target of rapamycin) pathways after rhCHK1 treatment. Co-Immunoprecipitation (Co-IP) experiments and protein docking prediction showed that CHK1 (checkpoint kinase 1) directly bound to and activated the Serine 37 (S37) and Tyrosine 105 (Y105) sites of PKM2 (pyruvate kinase isoform M2) to promote metabolic reprogramming. We further constructed plasmids that knocked out different CHK1 and PKM2 amino acid domains and transfected them into Human Embryonic Kidney 293T (HEK293T) cells for CO-IP experiments. Results showed that the 1-265 domain of CHK1 directly binds to the 157-400 amino acids of PKM2. Furthermore, hiPSC-CM (human iPS cell-derived cardiomyocyte) in vitro and in vivo experiments both demonstrated that CHK1 stimulated cardiomyocytes renewal and cardiac repair by activating PKM2 C-domain-mediated cardiac metabolic reprogramming. CONCLUSIONS: This study demonstrates that the 1-265 amino acid domain of CHK1 binds to the 157-400 domain of PKM2 and activates PKM2-mediated metabolic reprogramming to promote cardiomyocyte proliferation and myocardial repair after ischemia/reperfusion injury in adult pigs.

TRPV1 signaling of perirenal adipose tissue promotes DOCA-Salt-induced hypertension and kidney injury.

BACKGROUND: Denervation of renal or perirenal adipose tissue (PRAT) can reduce arterial blood pressure in various hypertensive experimental models. Trpv1 (transient receptor potential vanillin 1) channel is highly expressed in the renal sensory nerves and the dorsal root ganglias (DRGs) projected by PRAT. However, it is currently unclear whether Trpv1 in DRGs projected from PRAT can regulate renal hypertension. METHODS: We used resintoxin (RTX) to block the afferent sensory nerves of rat PRAT. We also constructed Trpv1 -/- mice and Trpv1 +/- mice or used the injection of AAV2-retro-shTrpv1 to detect the effects of Trpv1 knockout or knockdown of PRAT-projected DRGs on deoxycorticosterone acetate (DOCA)-Salt-induced hypertension and kidney injury. RESULTS: Blocking the afferent sensory nerves of PRAT with RTX can alleviate DOCA-Salt-induced hypertension and renal injury in rats. And this blockade reduces the expression of Trpv1 in the DRGs projected by PRAT. Injecting AAV2-retro-shTrpv1 into the PRAT of DOCA-Salt mice also achieved the same therapeutic effect. However, DOCA-Salt-induced hypertension and renal injury can be treated in Trpv1 +/- mice but not alleviated or even worsened in Trpv1 -/- mice, possibly because of compensatory increase of Trpv5 in DRG of Trpv1 -/- mice. CONCLUSION: Reducing, rather than eliminating, Trpv1 in DRG from PRAT-projection can reduce blood pressure and kidney damage in DOCA-Salt in rats or mice. Trpv1 in PRAT-DRGs may serve as a therapeutic target for salt-sensitive hypertension and its renal complications.

Gut microbial genomes with paired isolates from China illustrate probiotic and cardiometabolic effects.

The gut microbiome displays genetic differences among populations, and characterization of the genomic landscape of the gut microbiome in China remains limited. Here, we present the Chinese Gut Microbial Reference (CGMR) set, comprising 101,060 high-quality metagenomic assembled genomes (MAGs) of 3,707 nonredundant species from 3,234 fecal samples across primarily rural Chinese locations, 1,376 live isolates mainly from lactic acid bacteria, and 987 novel species relative to worldwide databases. We observed region-specific coexisting MAGs and MAGs with probiotic and cardiometabolic functionalities. Preliminary mouse experiments suggest a probiotic effect of two Faecalibacillus intestinalis isolates in alleviating constipation, cardiometabolic influences of three Bacteroides fragilis_A isolates in obesity, and isolates from the genera Parabacteroides and Lactobacillus in host lipid metabolism. Our study expands the current microbial genomes with paired isolates and demonstrates potential host effects, contributing to the mechanistic understanding of host-microbe interactions.

MAP4K4 exacerbates cardiac microvascular injury in diabetes by facilitating S-nitrosylation modification of Drp1.

Dynamin-related protein 1 (Drp1) is a crucial regulator of mitochondrial dynamics, the overactivation of which can lead to cardiovascular disease. Multiple distinct posttranscriptional modifications of Drp1 have been reported, among which S-nitrosylation was recently introduced. However, the detailed regulatory mechanism of S-nitrosylation of Drp1 (SNO-Drp1) in cardiac microvascular dysfunction in diabetes remains elusive. The present study revealed that mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) was consistently upregulated in diabetic cardiomyopathy (DCM) and promoted SNO-Drp1 in cardiac microvascular endothelial cells (CMECs), which in turn led to mitochondrial dysfunction and cardiac microvascular disorder. Further studies confirmed that MAP4K4 promoted SNO-Drp1 at human C644 (mouse C650) by inhibiting glutathione peroxidase 4 (GPX4) expression, through which MAP4K4 stimulated endothelial ferroptosis in diabetes. In contrast, inhibition of MAP4K4 via DMX-5804 significantly reduced endothelial ferroptosis, alleviated cardiac microvascular dysfunction and improved cardiac dysfunction in db/db mice by reducing SNO-Drp1. In parallel, the C650A mutation in mice abolished SNO-Drp1 and the role of Drp1 in promoting cardiac microvascular disorder and cardiac dysfunction. In conclusion, our findings demonstrate that MAP4K4 plays an important role in endothelial dysfunction in DCM and reveal that SNO-Drp1 and ferroptosis activation may act as downstream targets, representing potential therapeutic targets for DCM.

Molecular mechanisms and potential therapeutic targets in the pathogenesis of hypertension in visceral adipose tissue induced by a high-fat diet.

Background: Hypertension (HTN) presents a significant global public health challenge with diverse causative factors. The accumulation of visceral adipose tissue (VAT) due to a high-fat diet (HFD) is an independent risk factor for HTN. While various studies have explored pathogenic mechanisms, a comprehensive understanding of impact of VAT on blood pressure necessitates bioinformatics analysis. Methods: Datasets GSE214618 and GSE188336 were acquired from the Gene Expression Omnibus and analyzed to identify shared differentially expressed genes between HFD-VAT and HTN-VAT. Gene Ontology enrichment and protein-protein interaction analyses were conducted, leading to the identification of hub genes. We performed molecular validation of hub genes using RT-qPCR, Western-blotting and immunofluorescence staining. Furthermore, immune infiltration analysis using CIBERSORTx was performed. Results: This study indicated that the predominant characteristic of VAT in HTN was related to energy metabolism. The red functional module was enriched in pathways associated with mitochondrial oxidative respiration and ATP metabolism processes. Spp1, Postn, and Gpnmb in VAT were identified as hub genes on the pathogenic mechanism of HTN. Proteins encoded by these hub genes were closely associated with the target organs-specifically, the resistance artery, aorta, and heart tissue. After treatment with empagliflozin, there was a tendency for Spp1, Postn, and Gpnmb to decrease in VAT. Immune infiltration analysis confirmed that inflammation and immune response may not be the main mechanisms by which visceral adiposity contributes to HTN. Conclusions: Our study pinpointed the crucial causative factor of HTN in VAT following HFD. Spp1, Postn, and Gpnmb in VAT acted as hub genes that promote elevated blood pressure and can be targets for HTN treatment. These findings contributed to therapeutic strategies and prognostic markers for HTN.

The diagnostic efficiency of artificial intelligence based 2 hours Holter monitoring in premature ventricular and supraventricular contractions detection.

BACKGROUND: Electrocardiography (ECG) and 24 hours Holter monitoring (24 h-Holter) provided valuable information for premature ventricular and supraventricular contractions (PVC and PSVC). Currently, artificial intelligence (AI) based 2 hours single-lead Holter (2 h-Holter) monitoring may provide an improved strategy for PSVC/PVC diagnosis. HYPOTHESIS: AI combined with single-lead Holter monitoring improves PSVC/PVC detection. METHODS: In total, 170 patients were enrolled between August 2022 and 2023. All patients wore both devices simultaneously; then, we compared diagnostic efficiency, including the sensitivity/specificity/positive predictive-value (PPV) and negative predictive-value (NPV) in detecting PSVC/PVC by 24 h-Holter and 2 h-Holter. RESULTS: The PPV and NPV in patients underwent 2 h-Holter were 76.00%/87.50% and 96.35%/98.55, respectively, and the sensitivity and specificity were 79.17%/91.30%, and 95.65%/97.84% in PSVC/PVC detection compared with 24 h-Holter. The areas under the ROC curves (AUCs) for PSVC and PVC were 0.885 and 0.741, respectively (p < .0001). CONCLUSIONS: The potential advantages of the 2 h-Holter were shortened wearing period, improved convenience, and excellent consistency of diagnosis.

Temporal colonization and metabolic regulation of the gut microbiome in neonatal oxen at single nucleotide resolution.

The colonization of microbes in the gut is key to establishing a healthy host-microbiome symbiosis for newborns. We longitudinally profiled the gut microbiome in a model consisting of 36 neonatal oxen from birth up to 2 months postpartum and carried out microbial transplantation to reshape their gut microbiome. Genomic reconstruction of deeply sequenced fecal samples resulted in a total of 3931 metagenomic-assembled genomes from 472 representative species, of which 184 were identified as new species when compared with existing databases of oxen. Single nucleotide level metagenomic profiling shows a rapid influx of microbes after birth, followed by dynamic shifts during the first few weeks of life. Microbial transplantation was found to reshape the genetic makeup of 33 metagenomic-assembled genomes (FDR < 0.05), mainly from Prevotella and Bacteroides species. We further linked over 20 million microbial single nucleotide variations to 736 plasma metabolites, which enabled us to characterize 24 study-wide significant associations (P < 4.4 × 10-9) that identify the potential microbial genetic regulation of host immune and neuro-related metabolites, including glutathione and L-dopa. Our integration analyses further revealed that microbial genetic variations may influence the health status and growth performance by modulating metabolites via structural regulation of their encoded proteins. For instance, we found that the albumin levels and total antioxidant capacity were correlated with L-dopa, which was determined by single nucleotide variations via structural regulations of metabolic enzymes. The current results indicate that temporal colonization and transplantation-driven strain replacement are crucial for newborn gut development, offering insights for enhancing newborn health and growth.

The potential mechanisms underlying the modulating effect of perirenal adipose tissue on hypertension: Physical compression, paracrine, and neurogenic regulation.

Hypertension, a prevalent global cardiovascular disease, affects approximately 45.4 % of adults worldwide. Despite advances in therapy, hypertension continues to pose a significant health risk due to inadequate management. It has been established that excessive adiposity contributes majorly to hypertension, accounting for 65 to 75 % of primary cases. Fat depots can be categorised into subcutaneous and visceral adipose tissue based on anatomical and physiological characteristics. The metabolic impact and the risk of hypertension are determined more significantly by visceral fat. Perirenal adipose tissue (PRAT), a viscera enveloping the kidney, is known for its superior vascularisation and abundant innervation. Although traditionally deemed as a mechanical support tissue, recent studies have indicated its contributing potential to hypertension. Hypertensive patients tend to have increased PRAT thickness compared to those without, and there is a positive correlation between PRAT thickness and elevated systolic blood pressure. This review encapsulates the anatomical characteristics and biogenesis of PRAT. We provide an overview of the potential mechanisms where PRAT may modulate blood pressure, including physical compression, paracrine effects, and neurogenic regulation. PRAT has become a promising target for hypertension management, and continuous effort is required to further explore the underlying mechanisms.

Single Bolus r-SAK Before Primary PCI for ST-Segment-Elevation Myocardial Infarction.

BACKGROUND: It is uncertain whether adjunctive thrombolysis is beneficial for patients with ST-segment-elevation myocardial infarction undergoing percutaneous coronary intervention (PCI) within 120 minutes of presentation. This study was to determine whether in patients presenting with ST-segment-elevation myocardial infarction a single bolus recombinant staphylokinase (r-SAK) before timely PCI leads to improved patency of the infarct-related artery and reduces the infarct size. METHODS: This is an open-label, prospective, multicenter, randomized study. We enrolled patients aged 18 to 75 years who were within 12 hours of symptom onset of ST-segment-elevation myocardial infarction and expected to undergo PCI within 120 minutes. Patients were administered loading doses of aspirin and ticagrelor and intravenous heparin and were randomized to receive 5 mg bolus of r-SAK or normal saline intravenously before PCI. The primary end point was Thrombolysis in Myocardial Infarction flow grade 2 to 3 or grade 3 in the infarct-related artery 60 minutes after thrombolysis. The infarct size was detected by cardiac magnetic resonance 5 days after randomization. The safety end point was major bleeding (Bleeding Academic Research Consortium ≥3) during 30-day follow-up. RESULTS: A total of 283 patients were screened from 8 centers and 200 were randomized (median age, 58.5 years; 14% female). The median symptom to thrombolysis time was 252.5 (interquartile range, 142.8-423.8) minutes and thrombolysis to coronary arteriography was 50.0 (interquartile range, 37.0-66.0) minutes. Patients randomized to r-SAK compared with normal saline more often had Thrombolysis in Myocardial Infarction flow grade 2 to 3 (69.0% versus 29.0%; P<0.001) and Thrombolysis in Myocardial Infarction flow grade 3 (51.0% versus 18.0%; P<0.001) and had smaller infarct size (21.91±10.84% versus 26.85±12.37%; P=0.016). There was no increase in major bleeding (r-SAK, 1.0% versus control, 3.0%; P=0.616). CONCLUSIONS: A single bolus r-SAK before primary PCI for ST-segment-elevation myocardial infarction improves infarct-related artery patency and reduces infarct size without increasing major bleeding. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05023681.

The positive association between the atherogenic index of plasma and the risk of new-onset hypertension: a nationwide cohort study in China.

BACKGROUND: The atherogenic index of plasma (AIP) is a novel metabolic biomarker of atherosclerosis. Nevertheless, the association between the AIP and new-onset hypertension has not been elucidated in the Chinese population. METHODS: Prospective data were obtained from 3150 participants aged ≥ 18 years in the China Health and Nutrition Survey from 2009 to 2015. The AIP is a logarithmically transformed ratio of triglycerides to high-density lipoprotein cholesterol in molar concentration. Cox regression analysis was used to determine the association of AIP index with new-onset hypertension. RESULTS: After the six-year follow-up, 1054 (33.4%) participants developed new-onset hypertension. The participants were divided into AIP quartile groups (Q1-Q4). Compared with those in Q1, subjects in Q3-4 had nearly 1.35 times the risk of new-onset hypertension after full adjustment [Q3: hazard ratio (HR): 1.35, 95% confidence interval (CI): 1.13-1.62; Q4: HR: 1.35, 95% CI: 1.13-1.64]. The risks of new-onset hypertension were nearly 1.30 times higher in subjects in Q2-4 than in subjects in Q1 (p < .01) after the full adjustment when we excluded subjects with diabetes and/or chronic kidney diseases. There was a significant difference [HR (CI): 1.27 (1.04-1.54) vs. 0.90 (0.69-1.18)] when subjects were divided into two groups according to body mass index (BMI) level (<24 vs. ≥24 kg/m2). CONCLUSIONS: The present study suggested that individuals with a higher AIP index are associated with new-onset hypertension, independent of kidney function and glucose levels. The association was stronger in subjects with normal BMI, which may provide early screening of metabolomics in hypertension prevention.

Gender differences in the association between healthy eating index-2015 and hypertension in the US population: evidence from NHANES 1999-2018.

BACKGROUND: Diet has long been recognized as an important modifiable risk factor for hypertension. Herein, our research goal was to decipher the association of healthy eating index-2015 (HEI-2015) with hypertension, and to explore potential gender differences. METHODS: We collected the cross-sectional data of 42,391 participants of the National Health and Nutrition Examination Survey (NHANES) 1999-2018. The association of HEI-2015 with hypertension was estimated using weighted multivariate logistic regression, with restricted cubic spline (RCS) regression being adopted to examine the nonlinearity of this association in both genders, and the stability of the results were examined by sensitivity analysis. We also performed subgroup analysis to detect potential difference in the link between HEI-2015 and hypertension stratified by several confounding factors. RESULTS: After eliminating potential confounding bias, the adjusted odds ratios (ORs) with 95% confidence intervals (CIs) for hypertension across higher HEI-2015 quartiles were 0.93 (0.85-1.03), 0.84 (0.77-0.93), and 0.78 (0.72-0.86) compared to the lowest quartile, respectively. HEI-2015 was nonlinearly and inversely associated with hypertension in all participants. The gender-specific RCS curves presented a U-shaped correlation in males, while showed a linear and inverse correlation in females. Besides, subgroup analyses showed a lower risk of hypertension in participants who were females, younger than 40 years, Whites, obese, and diabetic patients. CONCLUSIONS: We determined a nonlinear and inverse association between HEI-2015 and hypertension in the US general population, and revealed a remarkable gender difference when adhering to a HEI-2015 diet for preventing hypertension.

Effectiveness and safety of ivabradine in Chinese patients with chronic heart failure: an observational study.

AIMS: A therapeutic strategy for chronic heart failure (HF) is to lower resting heart rate (HR). Ivabradine is a well-known HR-lowering agent, but limited prospective data exist regarding its use in Chinese patients. This study aimed to evaluate the effectiveness and safety of ivabradine in Chinese patients with chronic HF. METHODS AND RESULTS: This multicentre, single-arm, prospective, observational study enrolled Chinese patients with chronic HF. The primary outcome was change from baseline in HR at 1 and 6 months, measured by pulse counting. Effectiveness was also evaluated using laboratory tests, the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (CSS) and overall summary score (OSS), and New York Heart Association (NYHA) class. Treatment-emergent adverse events (TEAEs) were assessed. A post hoc analysis examined the effectiveness and safety of ivabradine combined with an angiotensin receptor-neprilysin inhibitor (ARNI) or beta-blocker. A total of 1003 patients were enrolled [mean age 54.4 ± 15.0 years, 773 male (77.1%), mean baseline HR 88.5 ± 11.3 b.p.m., mean blood pressure 115.7/74.4 ± 17.2/12.3 mmHg, mean left ventricular ejection fraction 30.9 ± 7.6%, NYHA Classes III and IV in 48.8% and 22.0% of patients, respectively]. HR decreased by a mean of 12.9 and 16.1 b.p.m. after 1 and 6 months, respectively (both P < 0.001). At Month 6, improvements in the KCCQ CSS and OSS of ≥5 points were observed in 72.1% and 74.1% of patients, respectively (both P < 0.001). Left ventricular ejection fraction increased by 12.1 ± 11.6 (P < 0.001), and 66.7% of patients showed improvement in NYHA class (P < 0.001). At Month 6, the overall proportion of patients in NYHA Classes III and IV was reduced to 13.5% and 2.1%, respectively. Serum brain natriuretic peptide (BNP) and N-terminal pro-BNP changed by -331.9 ng/L (-1238.6, -134.0) and -1113.8 ng/L (-2202.0, -297.2), respectively (P < 0.001). HR reductions and improvements in NYHA and KCCQ scores with ivabradine were similar with and without use of ARNIs or beta-blockers. Of 498 TEAEs in 296 patients (29.5%), 73 TEAEs in 55 patients (5.5%) were considered related to ivabradine [most frequent sinus bradycardia (n = 7) and photopsia (n = 7)]. TEAEs were reported in a similar number of patients in ARNI and beta-blocker subgroups (21.9-35.6%). CONCLUSIONS: Ivabradine treatment reduced HR and improved cardiac function and health-related quality of life in Chinese patients with chronic HF. Benefits were seen irrespective of whether or not patients were also taking ARNIs or beta-blockers. Treatment was well tolerated with a similar profile to previous ivabradine studies.

Comparison of arterial stiffness indices measured by pulse wave velocity and pulse wave analysis for predicting cardiovascular and all-cause mortality in a Chinese population.

Arterial stiffness measured by pulse wave velocity and pulse wave analysis has been widely studied in different populations in terms of its correlation with cardiovascular events and all-cause mortality. It remains unknown which arterial stiffness index is better for risk stratification in the general population. We included 4129 participants from Gaoyou County, Jiangsu Province, China, with a median follow-up of 11 years. The primary endpoint was cardiovascular mortality, and the secondary endpoint was all-cause mortality. Harrell's C-index, net reclassification improvement (NRI) and integrated discrimination improvement (IDI) based on the Cox proportional hazards regression model were evaluated to assess predictive discrimination and accuracy. The associations between the 4 indices and cardiovascular mortality remained significant after adjusting for the Framingham Risk Score (FRS) and/or associated risk factors. Considering reclassification based on the newly integrated models (FRS model combined with the 4 indices), NRI for cardiovascular mortality showed that haPWV and baPWV had more significant improvement in reclassification compared with C1 and C2 [NRI with 95% CI: haPWV 0.410 (0.293, 0.523); baPWV 0.447 (0.330, 0.553); C1 0.312 (0.182, 0.454); C2 0.328 (0.159, 0.463); all P < 0.05]. This study showed that pulse wave velocity (haPWV and baPWV) provides better discrimination of long-term risk than arterial elasticity indices (C1 and C2) in the general population.

NAT10 Is Involved in Cardiac Remodeling Through ac4C-Mediated Transcriptomic Regulation.

BACKGROUND: Heart failure, characterized by cardiac remodeling, is associated with abnormal epigenetic processes and aberrant gene expression. Here, we aimed to elucidate the effects and mechanisms of NAT10 (N-acetyltransferase 10)-mediated N4-acetylcytidine (ac4C) acetylation during cardiac remodeling. METHODS: NAT10 and ac4C expression were detected in both human and mouse subjects with cardiac remodeling through multiple assays. Subsequently, acetylated RNA immunoprecipitation and sequencing, thiol-linked alkylation for the metabolic sequencing of RNA (SLAM-seq), and ribosome sequencing (Ribo-seq) were employed to elucidate the role of ac4C-modified posttranscriptional regulation in cardiac remodeling. Additionally, functional experiments involving the overexpression or knockdown of NAT10 were conducted in mice models challenged with Ang II (angiotensin II) and transverse aortic constriction. RESULTS: NAT10 expression and RNA ac4C levels were increased in in vitro and in vivo cardiac remodeling models, as well as in patients with cardiac hypertrophy. Silencing and inhibiting NAT10 attenuated Ang II-induced cardiomyocyte hypertrophy and cardiofibroblast activation. Next-generation sequencing revealed ac4C changes in both mice and humans with cardiac hypertrophy were associated with changes in global mRNA abundance, stability, and translation efficiency. Mechanistically, NAT10 could enhance the stability and translation efficiency of CD47 and ROCK2 transcripts by upregulating their mRNA ac4C modification, thereby resulting in an increase in their protein expression during cardiac remodeling. Furthermore, the administration of Remodelin, a NAT10 inhibitor, has been shown to prevent cardiac functional impairments in mice subjected to transverse aortic constriction by suppressing cardiac fibrosis, hypertrophy, and inflammatory responses, while also regulating the expression levels of CD47 and ROCK2 (Rho associated coiled-coil containing protein kinase 2). CONCLUSIONS: Therefore, our data suggest that modulating epitranscriptomic processes, such as ac4C acetylation through NAT10, may be a promising therapeutic target against cardiac remodeling.

Oxidative stress biomarker triggered multiplexed tool for auxiliary diagnosis of atherosclerosis.

Oxidative stress is integral in the development of atherosclerosis, but knowledge of how oxidative stress affects atherosclerosis remains insufficient. Here, we design a multiplexed diagnostic tool that includes two functions (photoacoustic imaging and urinalysis), for assessing intraplaque and urinary malondialdehyde (MDA), a well-recognized end-product of oxidative stress. Molecular design is conducted to develop the first near-infrared MDA-responsive molecule (MRM). Acid-unlocked ratiometric photoacoustic nanoprobe is designed to report intraplaque MDA, enabling it to reflect plaque burden. Furthermore, MRM is tailored for urinary MDA detection with excellent specificity in a blind study. Moreover, we found a significant difference in urinary MDA between healthy adults and atherosclerotic patients (more than 600 participants). Combining these two functions, such a multiplexed diagnostic tool can dynamically report intraplaque and systemic oxidative stress levels during atherosclerosis progression, pneumonia infection, and drug treatment in atherosclerotic mice, which is promising for the auxiliary diagnosis of atherosclerosis.

Recycling of Silicomanganese Slag and Fly Ash for Preparation of Environment-Friendly Foamed Ceramics.

In order to reduce the manufacturing cost of foamed ceramics and expand the application scope of industrial solid waste, in this study, a new type of environment-friendly foamed ceramics was prepared using direct high-temperature foaming with waste silicomanganese slag (SMS) and fly ash (FA) as raw materials and silicon carbide (SiC) as a foaming agent. The influence of SMS content, SiC content, and sintering temperature on the characteristics and microstructure of the specimen were explored. More concretely, the compressive strength, pore morphology, bulk density, and crystalline composition of the foamed ceramics were discussed. The foaming mechanism was also further analyzed. The results showed that including 20% SMS significantly reduced the melt's viscosity and stimulated bubble expansion. This, in turn, facilitated the creation of a porous structure. Moreover, it was noted that samples containing 20% SMS exhibited an anorthite phase when sintered at 1110 °C, resulting in enhanced compressive strength. The bulk density and compressive strength of the foamed ceramics decreased with an increase in the sintering temperature and SiC content. This trend was primarily attributed to the higher total porosity and the insufficient support of the pore wall to the matrix. The best all-around performance was achieved with 20 wt% SMS, 80 wt% FA as raw material, SiC addition of 1.0 wt%, and a sintering temperature of 1100 °C. Under these conditions, the compressive strength, bulk density, and total porosity of the foamed ceramics were 8.09 MPa, 0.57 g/cm3, and 71.04%, respectively. Taken together, the outstanding porous structure and mechanical properties of this foamed ceramic make it suitable for use as insulation or for building partition materials.