Cardiovascular disease represents a significant global cause of mortality, with its development and progression closely associated with pathological remodeling of cardiac tissue. Increasing attention has been directed towards environmental pollutants, particularly persistent organic pollutants (POPs), for their potential toxicity to the cardiovascular system. The effects of perfluorodecanoic acid (PFDA) on cardiac health remain inadequately understood. This study investigated the impact of PFDA exposure on cardiomyocyte aging and myocardial fibrosis, alongside the underlying mechanisms involved. Results indicated that PFDA treatment significantly induced cellular senescence and fibrosis-associated phenotypes in both rat H9c2 and mouse HL1 cardiomyocyte cell lines. CCK-8 assays demonstrated a reduction in cardiomyocyte viability following PFDA exposure. Western blot analyses revealed elevated senescence-associated markers, as well as a significant increase in the expression of key fibrotic markers. Additionally, PFDA exposure compromised mitochondrial function in cardiomyocytes, as evidenced by a decline in mitochondrial membrane potential and intracellular ATP levels. ELISA assays confirmed an increase in the secretion of inflammatory cytokines due to PFDA exposure. In vivo experiments utilizing C57BL/6 mice exposed to long-term low-dose PFDA displayed comparable pathological alterations in myocardial tissue. Immunohistochemical analysis revealed a significant increase in collagen fiber deposition within the myocardial interstitium of PFDA-exposed mice, alongside elevated expression levels of COLI and α-SMA compared to the control group. Mechanistically, PFDA exposure resulted in hyperactivation of the MTORC1 signaling axis, characterized by increased phosphorylation of its downstream substrates S6K1 and 4E-BP1 both in vitro and in vivo. Furthermore, activation of AKT was identified as an upstream event that contributes to MTORC1 hyperactivation. In summary, the environmental pollutant PFDA exacerbates cardiomyocyte senescence and activates cardiac fibroblasts through mechanisms that include mitochondrial dysfunction, inflammation promotion, and hyperactivation of the MTORC1 signaling cascade. This research provides novel experimental evidence supporting the role of PFDA pollutants in age-related cardiac diseases.

Objective: Diabetic cardiomyopathy (DCM) is characterized by metabolic dysfunction and lipotoxicity. The roles of acyl-CoA thioesterase 1 (ACOT1) and the novel post-translational modification lactylation in its pathogenesis remain unclear. This study aimed to investigate the stage-specific function of ACOT1 and the mechanism by which lactylation of SREBP1c regulates lipid metabolism in DCM. Methods: Key genes were screened via bioinformatic analysis. ACOT1 was functionally assessed in early and decompensated DCM mouse models using gain- and loss-of-function strategies, evaluated by echocardiography and hemodynamics. SREBP1c lactylation was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and validated via site-directed mutagenesis. Results: ACOT1 exhibited a biphasic expression pattern: protective upregulation in early DCM improved cardiac function and attenuated oxidative stress, whereas its downregulation in decompensated DCM exacerbated remodeling and dysfunction. Mechanistically, ACOT1 physically interacted with SREBP1c and facilitated its lactylation under high-lactate conditions. This modification was essential for SREBP1c transcriptional activity, driving its nuclear translocation and subsequent upregulation of the fatty acid transporter CD36. The enhanced CD36-mediated uptake led to free fatty acid accumulation, aggravating myocardial lipotoxicity and DCM progression. Conclusion: This study reveals a dual-stage regulatory role of ACOT1 in DCM and identifies a novel ACOT1-SREBP1c(lactylation)-CD36 axis linking metabolic reprogramming to lipotoxic injury. These findings establish lactylation as a key regulatory mechanism in diabetic heart metabolism and propose ACOT1 and SREBP1c lactylation as potential therapeutic targets for mitigating myocardial lipotoxicity in DCM.

Cancer remains a major health threat, driving the need for new treatments. Phototherapy, a minimally invasive method for targeting tumors, shows promise but faces issues like uneven photosensitizer distribution and heat dispersion, leading to incomplete treatment and tumor recurrence. To address this, we developed genetically engineered bacteria that produce PCSK9 nanobodies and combined them with photothermal liposomes for solid tumor treatment. These engineered bacteria, DPIR@EcN/PCSK9nb, effectively convert light into heat under near-infrared irradiation, boosting the photodynamic impact on tumors while sparing normal tissues. When activated, these bacteria release PCSK9 nanobodies and bacterial antigens, modulating cholesterol levels and activating key signaling pathways in the tumor environment. Photoactivation further triggers the cGAS–STING–NF-κB pathway and regulates the CXCR1/2 axis, reshaping the tumor immune microenvironment, boosting local immune responses, and inducing tumor cell apoptosis. In vivo studies showed significant tumor growth inhibition without major organ toxicity, underscoring the safety and effectiveness of this dual-modality therapy. Combining phototherapy with PCSK9 nanobody-engineered bacteria offers a novel cancer treatment strategy, enhancing anti-tumor effects through coordinated photothermal, immune, and metabolic actions while minimizing side effects, thus providing a promising targeted therapy approach.

Salivary adenoid cystic carcinoma (ACC) is a common type of salivary gland cancer, and the mechanisms underlying its progression still remain poorly understood without efficient therapies. NOTCH1, an evolutionally conserved cell-cell signaling pathway, is involved in the progression of ACC. In our study, we attempted to explore whether NOTCH1 suppression using the monoclonal anti-NOTCH1 antibody OMP-52 M51 could be of potential for ACC treatment. Here, we identified NOTCH1 elevation in human ACC tissues compared with the matched normal samples. Patients with metastasis expressed much higher NOTCH1. We then found that OMP-52 M51 markedly reduced the expression of NOTCH1 and its intracellular active form NICD1 (NOTCH1 intracellular domain). Importantly, OMP-52 M51 markedly reduced the proliferation, migration and invasion of ACC cells. RNA-Seq and in vitro studies further showed that OMP-52 M51 significantly induced ferroptosis in ACC cells, indicated by the increased cellular malondialdehyde (MDA), iron contents and lipid ROS production, and decreased glutathione (GSH) levels. Further, remarkable glutathione peroxidase 4 (GPX4) reduction was detected in ACC cells with OMP-52 M51 treatment. However, promoting NOTCH1 expression markedly abolished the function of OMP-52 M51 to induce ferroptosis. Intriguingly, low-dose OMP-52 M51 strongly facilitated the capacity of ferroptosis inducer erastin to trigger ferroptotic cell death, revealing that OMP-52 M51 could improve the sensitivity of ACC cells to ferroptosis. In vivo, OMP-52 M51 administration suppressed tumor growth and induced ferroptosis in the constructed ACC xenograft mouse model. Collectively, our findings demonstrated that NOTCH1 inhibition by OMP-52 M51 represses the proliferation and epithelial-mesenchymal transition (EMT) in ACCs, and promotes ferroptosis, revealing the potential therapeutical application of OMP-52 M51 in ACC.

THE HEADINGS AIMS:DEAD-box helicase 27 (DDX27), a member of the DEAD-Box nucleic acid helicase family, holds an elusive role in oral squamous cell carcinoma (OSCC). This study aims to unravel the regulatory functions of DDX27 in OSCC and explore its downstream targets.MATERIALS AND METHODS:A commercial oral squamous cell carcinoma (OSCC) tissue microarray (TMA) was utilized. We analyzed differentially expressed genes in OSCC through the GEO database. Target gene silencing was achieved using the shRNA-mediated lentivirus method. Coexpedia analysis identified co-expressed genes associated with DDX27. Additionally, a Co-Immunoprecipitation (Co-IP) experiment confirmed the protein interaction between DDX27 and CSE1L. Xenograft tumor models were employed to evaluate DDX27's role in OSCC tumor formation.KEY FINDINGS:Elevated DDX27 expression in OSCC correlated with a higher pathological grade. DDX27 knockdown resulted in decreased cell proliferation, increased apoptosis, inhibited cell migration, and induced G2/M phase cell cycle arrest, as well as impaired tumor outgrowth. Coexpedia analysis identified STAU1, NELFCD, and CSE1L as top co-expressed genes. Lentiviral vectors targeting STAU1, NELFCD, and CSE1L revealed that silencing CSE1L significantly impaired cell growth, indicating it as a downstream target of DDX27. Cell rescue experiments demonstrated that increased DDX27 levels ameliorated cell proliferation, attenuated apoptosis, and CSE1L depletion blocked cell development induced by DDX27 overexpression.SIGNIFICANCES:This study highlighted DDX27 as a potential therapeutic target for OSCC treatment, shedding light on its crucial role in OSCC development. Targeting DDX27 or its downstream effector, CSE1L, holds promise for innovative OSCC therapies.

BACKGROUND:The non-exercise estimated cardiorespiratory fitness (eCRF) has been recognized as an important predictor of mortality among the general population. This study sought to evaluate the relationship between eCRF and mortality from all causes, cardiovascular disease (CVD), and cancer in hypertensive adults. METHODS:We included 27,437 adults with hypertension from the National Health and Nutrition Examination Survey (NHANES) III and 10 NHANES cycles from 1999 to 2018. Multivariate Cox proportional hazard models were used to assess the hazard ratios and 95% confidence intervals (CIs) of eCRF for mortality. RESULTS:A total of 8,023 deaths were recorded throughout a median 8.6-year follow-up, including 2,338 from CVD, and 1,761 from cancer. The eCRF with per 1 metabolic equivalent increase was linked to decreased risk of all-cause (adjusted HR 0.78, 95% CI: 0.75-0.81) and CVD mortality (adjusted HR 0.79, 95% CI: 0.74-0.84), rather than cancer mortality (adjusted HR 0.94, 95% CI: 0.86-1.03). Moreover, a stronger protective effect of eCRF was observed for females (HR 0.66 (95% CI: 0.62-0.72) versus HR 0.78 (95% CI: 0.73-0.83), Pinteraction < 0.001 for all-cause mortality; HR 0.70 (95% CI: 0.61-0.80;) versus HR 0.82 (95% CI: 0.73-0.92), Pinteraction = 0.026 for CVD mortality) compared with males. Findings did not significantly differ in subgroup analyses and sensitivity analyses. CONCLUSIONS:Among adults with hypertension, eCRF was inversely related to all-cause and CVD mortality, but not cancer mortality. A significant interaction effect existed between sex and eCRF. Further studies are needed to verify this association in different populations.

BackgroundAs a device for percutaneous coronary intervention, drug-coated balloon (DCB) is widely used to treat in-stent restenosis. However, data regarding the use of DCB in treating de novo saphenous vein graft (SVG) lesions are limited. This study aimed to explore the outcomes of using the DCB in the treatment of de novo SVG lesions of coronary heart disease (CHD).MethodsThis retrospective and observational study analyzed CHD patients with de novo SVG lesions treated with DCB or the new-generation drug-eluting stent (DES) between January 2018 and December 2020. Restenosis was the primary endpoint, whereas target lesion revascularization (TLR), major adverse cardiac events, restenosis, cardiac death, target vessel revascularization, and myocardial infarction were the secondary outcomes.ResultsWe enrolled 31 and 23 patients treated with DCB and DES, respectively. The baseline clinical data, lesion characteristics, and procedural characteristics were similar between the two groups. Twenty-eight (90.3%) patients in the DCB group and 21 (91.3%) in the DES group completed follow-up angiography after 1 year. The quantitative coronary angiography measurements at angiographic follow-up showing late lumen loss were −0.07 ± 0.95 mm for the DCB group and 0.86 ± 0.71 mm for the DES group (P = 0.039), and the rates of restenosis were 13.3% and 21.7% for the DCB and DES groups, respectively (P = 0.470). No significant differences were observed in the rates of MACE (16.7% vs. 26.1%, P = 0.402) and TLR (13.3% vs. 4.3%, P = 0.374) during clinical follow-up.ConclusionOur findings suggest that when pre-dilatation was successful, DCB might be safe and effective in treating de novo SVG lesions.

BackgroundData on drug-coated balloons (DCB) for de novo coronary chronic total occlusion (CTO) are limited. We aimed to investigate the long-term outcomes of substitution of drug-eluting stents (DES) by DCB.MethodsWe compared the outcomes of less DES strategy (DCB alone or combined with DES) and DES-only strategy in treating de novo coronary CTO in this prospective, observational, multicenter study. The primary endpoints were major adverse cardiovascular events (MACE), target vessel revascularization, myocardial infarction, and death during 3-year follow-up. The secondary endpoints were late lumen loss (LLL) and restenosis until 1-year after operation.ResultsOf the 591 eligible patients consecutively enrolled between January 2015 and December 2019, 281 (290 lesions) were treated with DCB (DCB-only or combined with DES) and 310 (319 lesions) with DES only. In the DCB group, 147 (50.7%) lesions were treated using DCB-only, and the bailout stenting rate was relatively low (3.1%). The average stent length per lesion in the DCB group was significantly shorter compared with the DES-only group (21.5 ± 25.5 mm vs. 54.5 ± 26.0 mm, p < 0.001). A total of 112 patients in the DCB group and 71 patients in the DES-only group (38.6% vs. 22.3%, p < 0.001) completed angiographic follow-up until 1-year, and LLL was much less in the DCB group (−0.08 ± 0.65 mm vs. 0.35 ± 0.62 mm, p < 0.001). There were no significant differences in restenosis occurrence between the two groups (20.5% vs. 19.7%, p > 0.999). The Kaplan–Meier estimates of MACE at 3-year (11.8% vs. 12.0%, log-rank p = 0.688) was similar between the groups.ConclusionPercutaneous coronary intervention with DCB is a potential “stent-less” therapy for de novo CTO lesions with satisfactory long-term clinical results compared to the DES-only approach.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are a new class of potent lipid-lowering drugs. Oxidized low-density lipoprotein (ox-LDL) is the key pathogenic factor leading to atherosclerosis. However, its effect on ox-LDL levels has not been clinically reported. The clinical data of 290 very high-risk atherosclerotic cardiovascular disease (ASCVD) patients diagnosed in the First Affiliated Hospital of Zhengzhou University from May 2022 to October 2022 were collected retrospectively. According to whether evolocumab (a PCSK9 inhibitor) was used after percutaneous coronary intervention (PCI), they were divided into evolocumab group (153 cases) and statin monotherapy group (137 cases). At hospital admission, ox-LDL, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoproteinA1 (apoA1), apolipoprotein B-100 (apoB), lipoprotein (a) [Lp(a)], and high-sensitivity reactive protein (hs-CRP) levels were collected and used as baseline data. After two weeks of treatment, ox-LDL in the evolocumab group and statin monotherapy group were significantly lower than those before treatment (p<0.05). The decrease of ox-LDL in the evolocumab group was more than in the stain monotherapy group (p<0.05). In conclusion, PCSK9 inhibitors reduce ox-LDL levels in very high-risk ASCVD patients in a short time.

BackgroundCardiac-resident or -enriched microRNAs (miRNAs) could be released into the bloodstream becoming circulating cardiac miRNAs, which are increasingly recognized as non-invasive and accessible biomarkers of multiple heart diseases. However, dilated cardiomyopathy (DCM)-associated circulating miRNAs (DACMs) and their roles in DCM pathogenesis remain largely unexplored. MethodsTwo human cohorts, consisting of healthy individuals and DCM patients, were enrolled for serum miRNA sequencing (10 vs. 10) and quantitative polymerase chain reaction validation (46 vs. 54), respectively. Rigorous screening strategy was enacted to define DACMs and their potentials for diagnosis. DCM mouse model, different sources of cardiomyocytes, adeno-associated virus 9 (AAV9), gene knockout, RNAscope miRNA in situ hybridization, mRFP-GFP-LC3B reporter, echocardiography and transmission electron microscopy were adopted for mechanistic explorations. ResultsSerum miRNA sequencing revealed a unique expression pattern for DCM circulating miRNAs. DACMs miR-26a-5p, miR-30c-5p, miR-126-5p and miR-126-3p were found to be depleted in DCM circulation as well as heart tissues. Their expressions in circulation and heart tissues were proven to be correlated significantly, and a combination of these miRNAs was suggested potential values for DCM diagnosis. FOXO3, a predicted common target, was experimentally demonstrated to be co-repressed within cardiomyocytes by these DACMs except miR-26a-5p. Delivery of a combination of miR-30c-5p, miR-126-5p and miR-126-3p into the murine myocardium via AAV9 carrying an expression cassette driven by cTnT promoter, or cardiac-specific knockout of FOXO3 (Myh6-Cre(ERT2), FOXO3 flox(+/+)) dramatically attenuated cardiac apoptosis and autophagy involved in DCM progression. Moreover, competitively disrupting the interplay between DACMs and FOXO3 mRNA by specifically introducing their interacting regions into murine myocardium crippled the cardioprotection of DACMs against DCM. ConclusionsCirculating cardiac miRNA-FOXO3 axis plays a pivotal role in safeguarding against myocardial apoptosis and excessive autophagy in DCM development, which may provide serological cues for DCM non-invasive diagnosis and shed light on DCM pathogenesis and therapeutic targets.

Background Current research results show that drug-coated balloons (DCB) have unique advantages in the treatment of in-stent restenosis, small vessel disease, bifurcation lesions, and de novo lesions, but the data regarding rotational atherectomy (RA) followed by DCB treatment in calcified lesions, especially severe coronary artery calcification (CAC), are limited. Methods A retrospective study was conducted on 318 individuals with severe CAC who underwent RA-assisted PCI at the First Affiliated Hospital of Zhengzhou University from May 2018 to July 2021. Among them, 57 patients (RA/DCB group) were treated with DCB, and 261 patients (RA/DES group) were treated with drug-eluting stents (DES). The two groups' clinical baseline data, lesion characteristics, intraoperative complications, in-hospital adverse events, and major adverse cardiovascular and cerebrovascular events (MACCE) were compared throughout the follow-up period. Results The baseline clinical data, intraoperative complications, and in-hospital adverse events were not significantly different between the two groups. The anatomical categories in the RA/DES group were more complex and included left main coronary disease, bifurcation disease, and multivessel disease. Although target lesion revascularization (13.79% vs. 7.02%) and MACCE (18.77% vs. 12.28%) occurred more frequently in the RA/DES group than in the RA/DCB group, there was no statistically significant difference ( p > 0.05). Multivariate Cox regression analysis showed that bifurcation lesions (HR 2.284, 95% CI 1.063–4.908, p = 0.034), total length of DCB/DES (HR 1.023, 95% CI 1.005–1.047, p = 0.014) and SYNTAX score (HR 1.047, 95% CI 1.013–1.082, p = 0.006) were independent risk factors for MACCE during the follow-up period. Conclusion Drug-coated balloon treatment after rotational atherectomy appears safe and effective in selected severe coronary artery calcification.

Background:Coronary artery calcification (CAC) is associated with high rates of restenosis and adverse clinical events after percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Objectives:The aim of this study was to evaluate the long-term clinical outcomes of drug-coated balloon (DCB)-only treatment for de novo lesions with and without CAC. Methods:Patients with de novo coronary disease treated with the DCB-only strategy were retrospectively enrolled from three centers and categorized into a CAC group and a non-CAC group. The primary endpoint was the target lesion failure (TLF) rate during the 3-year follow-up. Secondary endpoints included the occurrence of major adverse cardiac events (MACEs), target lesion revascularization (TLR), cardiac death, myocardial infarction (MI) and any revascularization. Propensity score matching (PSM) was conducted to assemble a cohort of patients with similar baseline characteristics. Results:A total of 1,263 patients with 1,392 lesions were included, and 243 patients were included in each group after PSM. Compared with the non-CAC group, the incidence rates of TLF (9.52% vs. 4.94%, odds ratio [OR]: 2.080; 95% confidence interval [CI]: 1.083-3.998, P = 0.034) and TLR (7.41% vs. 2.88%, OR: 2.642; 95% CI: 1.206-5.787, P = 0.020) in the CAC group were higher. The incidence rates of MACE (12.35% vs. 7.82%, OR: 1.665; 95% CI: 0.951-2.916, P = 0.079), cardiac death (2.06% vs. 2.06%, OR: 0.995; 95% CI: 0.288-3.436, P = 0.993), MI (1.23% vs. 0.82%, OR: 2.505; 95% CI: 0.261-8.689, P = 0.652) and any revascularization (12.76% vs. 9.67%, OR: 1.256; 95% CI: 0.747-2.111, P = 0.738) were similar between groups. Conclusions:CAC increased the incidence of TLF and TLR without a substantial increase in the risk of MACE, cardiac death, MI, or any revascularization in patients treated with DCB-only angioplasty during the 3-year follow-up.

目的:探索冠状动脉(冠脉)旋磨术(RA)联合药物涂层球囊(DCB)治疗严重冠脉钙化病变的疗效.方法:连续入选2018年5月—2021年7月就诊于郑州大学第一附属医院因冠脉严重钙化行RA的患者318例,根据不同治疗方案分为RA/DCB组(57例)和RA/药物洗脱支架(DES)组(261例).比较两组一般临床资料、冠脉病变特征、术中并发症、院内不良事件、随访期间主要心脑血管不良事件(MACCE)发生率.结果:两组基线临床资料、术中并发症、院内不良事件均差异无统计学意义.RA/DES组较多合并左主干病变、分叉病变、弥漫性病变等复杂解剖类型(均P＜0.05).随访期间RA/DES组MACCE(18.77％vs.12.28％)及靶病变血运重建(13.79％vs.7.02％)发生率较RA/DCB组升高,但差异无统计学意义.多因素Cox回归分析显示,分叉病变(HR=2.284,95％CI:1.063～4.908,P=0.034)、植入物总长度(HR=1.023,95％CI:1.005～1.047,P=0.014)、SNYT AX 评分(HR:1.047,95％CI:1.013～1.082,P=0.006)是 RA-PCI 术后远期 MACCE 发生的危险影响因素.结论:RA联合DCB可对部分适合的钙化病变进行安全有效的治疗.

目的:探究冠心病患者服用氯吡格雷后血小板抑制作用达到稳态的时间,为氯吡格雷药效学研究提供借鉴.方法:入选接受经皮冠状动脉介入治疗且服用氯吡格雷3d后的冠心病患者,采用光比浊法检测二磷酸腺苷诱导的血小板聚集率(PLADP).分别比较检测时已服用氯吡格雷不同天数患者住院期间和服用氯吡格雷30d后的PLADP水平.结果:入选240例患者,住院期间及出院后检测PLADP距离首次服用氯吡格雷的时间分别为6(5,8)d和39(35,47)d,患者住院期间PLADP水平显著高于服用氯吡格雷≥30 d的PLADP水平[36(25,46)％vs 29(20,44)％,P＜0.01].入选患者中未服用负荷剂量(仅予维持剂量75 mg/d)氯吡格雷者156例,住院期间PLADP水平显著高于服用氯吡格雷≥30 d PLADP水平[36(25,46)％vs 28(19,42)％,P＜0.01];此类患者中住院期间服用氯吡格雷≥6 d者,住院期间与服用氯吡格雷30 d的PLADP水平差异无统计学意义(P＞0.05).入选患者中服用氯吡格雷负荷剂量(150 mg或300 mg)者84例,住院期间与服用氯吡格雷≥30 d的PLADP水平差异无统计学意义[(35.99±15.38)％vs(32.61±16.30)％,P＞0.05];检测时已服用氯吡格雷不同天数患者住院期间与服用氯吡格雷30 d的PLADP水平差异均无统计学意义(P＞0.05).结论:冠心病患者服用维持量氯吡格雷≥6 d或负荷加维持量氯吡格雷≥3 d时残余血小板聚集功能与服用氯吡格雷30 d后相当;在以上时间窗检测的PLADP水平可准确体现氯吡格雷的长期抗血小板疗效.

Doxorubicin (DOX) is a chemotherapeutic agent that can cause cardiotoxicity leading to progressive, chronic, life-threatening cardiomyopathy, called DOX-induced cardiomyopathy (DIC). DIC is a fatal cardiomyopathy with a worse prognosis compared to other cardiomyopathies and limits the use of DOX in malignancies due to its cardiotoxicity. DIC has been proven to be associated with reactive oxygen species (ROS)-induced side effect damage in cardiac myocytes. Currently, scavenging of reactive oxygen species is a practical strategy to reduce chemotherapy-associated DIC. Although quercetin has already been reported to have superior antioxidant activity, its clinical application is severely limited due to its rapid degradation and poor tissue absorption. Herein, we reported the preparation of a novel enzyme mimic via coordinated albumin, Zinc Ion (Zn2+) and quercetin. The enzyme mimics were capable of simultaneously increasing the biocompatibility and efficiently overcame the drawbacks of free quercetin, and were achieved by long circulation in vivo. Most importantly, these quercetin-based enzyme mimics had no effect on the antioxidant activity of quercetin. These beneficial therapeutic properties, together with high drug-carrying capacity and redox stimuli, will significantly improve quercetin's alleviation of chemotherapeutic cardiotoxicity without causing significant side effects. Therefore, nanoparticles of albumin-based Zn (II)-Quercetin have a promising clinical application as an effective agent for mitigating the cardiotoxicity of chemotherapy.

Objective:To investigate the value of a SnapECG monitoring in diagnosing arrhythmias compared with the conventional management. Methods:In the first phase, the SnapECG and 12-lead electrocardiogram (ECG) were simultaneously adopted to detect arrhythmias in 439 hospitalized patients. The accuracies of the SnapECG in detecting different arrhythmias were assessed. In the second phase, 62 patients with palpitations were randomized to receive the SnapECG monitoring or conventional management for 3 months. The diagnosis rate, time of diagnosis, episodes before diagnosis, associated expenses, and scores of the modified European Heart Rhythm Association (EHRA), Self-rating Anxiety Scale (SAS), and the 36-item short-form health survey questionnaire (SF-36) were compared between groups. Results:In the first phase, the SnapECG monitoring showed a sensitivity of 83.55% and specificity of 96.79% in identifying tachyarrhythmias, and a sensitivity of 95.29% and specificity of 97.54% in identifying bradyarrhythmias. In the second phase, 1642 ECGs were recorded by the SnapECG, among which 290 abnormal ECGs were identified. Compared with the conventional management, the SnapECG monitoring increased the diagnosis rate of symptomatic arrhythmias (70.97% vs. 19.35%, P < 0.05), shortened the time of diagnosis (48.26 ± 36.78 days vs. 71.45 ± 30.01 days, P < 0.05) and consequently reduced the episodes of symptomatic arrhythmias prior to establishing diagnosis. The scores of modified EHRA, SAS, SF-36 significantly improved at 3-month compared with their baseline levels in the SnapECG group. Conclusions:Remote monitoring with the SnapECG can achieve early diagnosis of symptomatic arrhythmias. However, its sensitivity in identifying P-wave-related arrhythmias warrants further improvement.

Introduction: Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear.Objective: In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload.Methods: Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes.Results: LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1 (+/-) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes Conclusion: LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.(c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University.. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Cold-inducible RNA-binding protein (CIRBP) is documented to be required for maintaining cardiac function, however, its role in chemotherapy-induced cardiotoxicity remains obscured.Herein, we report that CIRBP decreases cardiomyocyte apoptosis and attenuates cardiotoxicity through disrupting OGF-OGFR signal.CIRBP deficiency is involved in diverse chemotherapeutic agents induced cardiomyocyte apoptosis.Delivery of exogenous CIRBP to the mouse myocardium significantly mitigated doxorubicin-induced cardiac apoptosis and dysfunction.Specifically, OGFR was identified as a downstream core effector responsible for chemotherapy-induced cardiomyocyte apoptosis.CIRBP was shown to interact with OGFR mRNA and to repress OGFR expression by reducing mRNA stability.CIRBP-mediated cytoprotection against doxorubicin-induced cardiac apoptosis was demonstrated to largely involve OGFR repression by CIRBP.NTX as a potent antagonist of OGFR successfully rescued CIRBP ablation-rendered susceptibility to cardiac dyshomeostasis upon exposure to doxorubicin, whereas another antagonist ALV acting only on opioid receptors did not.Taken together, our results demonstrate that CIRBP confers myocardium resistance to chemotherapy-induced cardiac apoptosis and dysfunction by dampening OGF/OGFR axis, shedding new light on the mechanisms of chemo-induced cardiotoxicity and providing insights into the development of an efficacious cardioprotective strategy for cancer patients.

LRRK2 is a Ser/Thr kinase with multiple functional domains. Studies have shown that LRRK2 mutations are closely related to hereditary Parkinson's disease. However, its role in cardiovascular disease, especially in myocardial infarction, is unclear. The aim of this study was to explore the functional role of LRRK2 in myocardial infarction. Wild-type and LRRK2-knockout mice were subjected to coronary artery ligation (left anterior descending) to establish a myocardial infarction model. Neonatal rat cardiomyocytes were subjected to hypoxia to induce hypoxic injury in vitro. We found increased LRRK2 expression levels in the infarct periphery in mouse hearts and hypoxic cardiomyocytes. LRRK2-deficient mice exhibited decreased death rates and reduced infarction areas compared to wild-type controls 14 days after infarction. LRRK2-deficient mice showed reduced left ventricular fibrosis and inflammatory responses, as well as improved cardiac function. In the in vitro study, LRRK2 silencing decreased cleaved caspase-3 activity, reduced cardiomyocyte apoptosis, and diminished hypoxia-induced inflammation. However, LRRK2 overexpression enhanced cleaved caspase-3 activity, increased the number of apoptotic cardiomyocytes, and caused remarkable hypoxia-induced inflammation. When examining the underlying mechanisms, we found that hypoxia increased HIFα expression, which enhanced LRRK2 expression. LRRK2 induced high expression of HMGB1 via P53. When HMGB1 was blocked using an anti-HMGB1 antibody, the deleterious effects caused by LRRK2 overexpression following hypoxia were inhibited in cardiomyocytes. In summary, LRRK2 deficiency protects the heart against myocardial infarction injury. The mechanism underlying this effect involves the P53-HMGB1 pathway.

Background: Previous studies have suggested that proton pump inhibitors could impair the antiplatelet effect of clopidogrel. It is uncertain whether ilaprazole affects the antiplatelet effect of clopidogrel. This study aimed to determine the drug-drug interaction between ilaprazole and clopidogrel. Methods: A randomized crossover trial of 40 healthy subjects was performed. Clopidogrel was administered alone or in combination with ilaprazole for 7 days. The maximal platelet aggregation (MPA) to 5 μmol/L adenosine diphosphate was measured by light transmission aggregometry and the platelet reactivity index (PRI) was determined by vasodilator-stimulated phosphoprotein P2Y 12 assay. High on-treatment platelet reactivity (HOPR) was defined as a MPA of >40%. The inhibition of platelet aggregation (IPA) and PRI in the two phases were compared between two regimens after the last dosing. Results: IPA was comparable between the two regimens at 0, 10 and 24 h ( p > 0.05), but higher at 4 h in the clopidogrel alone regimen compared with that in the combined treatment regimen (75.66 ± 18.44% vs. 70.18 ± 17.67%, p = 0.031). The inhibition of PRI was comparable between the two regimens at 0 and 24 h. There were no significant differences in the area under the time-IPA% curve (AUC) or the incidence of HOPR at all time-points between the two regimens. Conclusion: In healthy subjects, ilaprazole has limited effect on the pharmacodynamics of clopidogrel and it may not be clinically relevant. Clinical Trial Registration : [ www.chictr.org.cn ], identifier [ChiCTR2000031482].