Functionalizing Sgc8-Paclitaxel Conjugates with F-Base Modifications: Targeted Drug Delivery with Optimized Cardiac Safety.

Recent advancements in cancer treatment have improved patient prognoses, but chemotherapy-induced cardiotoxicity remains a prevalent concern. This study explores the potential of F-base-modified aptamers for targeted drug delivery, focusing on their impact on cardiotoxicity. From the phosphoramidite, F-base functionalized Sgc8-F23 was prepared in an automated and programmable way, which was further reacted with Paclitaxel (PTX) to give the F-base modified aptamer Sgc8-paclitaxel conjugates (Sgc8-F23-PTX) efficiently. The conjugate exhibits prolonged circulation time and enhanced efficacy as precision anticancer drug delivery system. Echocardiographic assessments reveal no exacerbation of cardiac dysfunction post-Acute Myocardial Infarction (AMI), and no pathological changes or increased apoptosis in non-infarcted cardiac regions. Autophagy pathway analysis shows no discernible differences in Sgc8-F23-PTX-treated cardiomyocytes compared to controls, contrasting with increased autophagy with Nanoparticle albumin-bound -Paclitaxel (Nab-PTX). Similarly, apoptosis analysis shows no significant distinctions. Moreover, Sgc8-F23-PTX exhibits no inhibitory effects on hERG, hNav1.5, or hCav1.2 channels. These findings suggest the safety and efficacy of F-base-modified Sgc8 aptamers for targeted drug delivery, holding potential clinical applications. Further research is warranted for clinical translation and exploration of other drug carriers.

Unlocking the Potential of Pterostilbene: A Pharmaceutical Element for Aptamer-Based Nanomedicine.

Natural compounds like pterostilbene (PTE) have gained recognition for their various biological activities and potential health benefits. However, challenges related to bioavailability and limited clinical efficacy have prompted efforts to strengthen their therapeutic potential. To meet these challenges, we herein rationally designed and successfully synthesized a pharmaceutical phosphoramidite that allows for the programmable incorporation of PTE into oligonucleotides. The resultant aptamer-PTE conjugate can selectively bind to cancer cells, leading to a specific internalization and drug release. Moreover, compared with free PTE, the conjugate exhibits superior cytotoxicity in cancer cells. Specifically, in a zebrafish xenograft model, the nanomedicine effectively inhibits tumor growth and neovascularization, highlighting its potential for targeted antitumor therapy. This approach presents a promising avenue for harnessing the therapeutic potential of natural compounds via a nanomedicine solution.

Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion: a multicentre randomized controlled trial.

AIMS: This study was performed to compare the usability, efficiency, and safety of a modified angioplasty guidewire-assisted transseptal puncture (TSP) technique vs. the conventional approach in facilitating access into the left atrium during left atrial appendage occlusion (LAAO) procedures for the treatment of atrial fibrillation. METHODS AND RESULTS: The ADVANCE-LAAO trial (Angioplasty Guidewire-Assisted vs. Conventional Transseptal Puncture for Left Atrial Appendage Occlusion) was an investigator-initiated, prospective, multicentre, randomized controlled trial (NCT05125159). Patients with atrial fibrillation who underwent LAAO were prospectively enrolled from four centres and randomly assigned to an angioplasty guidewire-assisted TSP group (n = 131) or to a conventional Brockenbrough needle TSP group (n = 132). The primary endpoint was the one-time success rate of TSP. We also analysed the TSP procedure time, failure rate of the assigned TSP type, radiation dose, contrast dose, and procedural complications in both groups. All patients in the guidewire-assisted group underwent successful TSP, whereas five in the standard conventional group switched to the guidewire-assisted approach. The guidewire-assisted puncture improved the one-time success rate (92.4 vs. 77.3%, P = 0.001), shortened the TSP procedure time (109.2 ± 48.2 vs. 120.5 ± 57.6 s, P = 0.023), and tended to have a higher rate of good coaxial orientation of the sheath with the left atrial appendage during the LAAO procedure (66.4 vs. 54.5%, P = 0.059). No TSP-related complications occurred in the guidewire-assisted TSP group, whereas two complications occurred in the conventional TSP group. There was no significant difference in the failure rate of the assigned TSP type, the total procedure time, the total radiation dose, the rate of successful LAAO implantation, or the procedural complication rate between the two groups (all P > 0.05). CONCLUSION: This study confirmed that angioplasty guidewire-assisted puncture can effectively improve the success rate of TSP during LAAO procedures. This novel technique has high potential for application in interventional therapies requiring TSP.

Pulmonary vein perforation into the respiratory tract with systemic air embolism: a rare complication of left atrial appendage closure.

BACKGROUND: Pulmonary vein perforation is an uncommon complication during cardiac intervention. We present a rare case of pulmonary vein perforation into the respiratory tract with systemic air embolism during left atrial appendage closure (LAAC). CASE PRESENTATION: A 77-year-old man with persistent nonvalvular atrial fibrillation was referred for percutaneous LAAC under local anaesthesia (CHA2DS2-VASc score of 4, HAS-BLED score of 3, and prior ischaemic stroke). During the procedure, after delivering a super-stiff guidewire into the left superior pulmonary vein (LSPV), the patient suddenly developed a severe cough with haemoptysis upon advancement of a delivery sheath along the guidewire. Fluoroscopy showed signs of blood entering the left main bronchus, and fast transthoracic echocardiography revealed bubbles in the left heart without pericardial effusion. The procedure was terminated because of a major complication indicated by the repeated haemoptysis and headache, and haemostatic drugs were immediately administered. Subsequent chest computed tomography angiography (CTA) revealed a filling defect in the LSPV branches and bubbles in the aorta. The patient was transferred to the critical care unit for haemostasis and antibacterial treatment. Transthoracic echocardiography later that day showed no bubbles in the heart. The headache and haemoptysis significantly abated the following day. The bubbles in the aorta disappeared on chest CTA 7 days later. CONCLUSIONS: Interventional cardiologists should pay attention to anatomical variations of the pulmonary vein, which are associated with a high risk of complications of pulmonary vein perforation during LAAC. Preoperative CTA examination and intraoperative transoesophageal echocardiography might be helpful to avoid this complication.

BMP6 knockdown enhances cardiac fibrosis in a mouse myocardial infarction model by upregulating AP-1/CEMIP expression.

BACKGROUND: The cardiac repair process following a myocardial infarction is a key factor in patient prognosis. In this repair process, cardiac fibrosis takes a critically important role. Among those featured genes for fibrosis, transforming growth factor beta (TGF-ß) is known to be involved in the fibrosis in various organs. And bone morphogenetic protein (BMP)6 belongs to the TGF-ß superfamily. Although BMPs are known to play exclusive roles in cardiac repair processes, the character of BMP6 in cardiac remodelling remains unclear. PURPOSE: This study aimed to investigate how BMP6 functioned in cardiac fibrosis following myocardial infarction (MI). RESULTS: In this paper, we demonstrated that BMP6 expression was upregulated after myocardial infarction in wild-type (WT) mice. Furthermore, BMP6-/- mice showed a more significant decline in cardiac function and lower survival curves after MI. An enlarged infarct area, increased fibrosis and more pronounced inflammatory infiltration were observed in BMP6-/- mice compared to WT mice. The expression of collagen I, collagen III and α-SMA was increased in BMP6-/- mice. In vitro, through gain-of-function and loss-of-function experiments, it was demonstrated that BMP6 decreases collagen secretion in fibroblasts. Mechanistically, knocking down BMP6 promoted AP-1 phosphorylation, which in turn promotes CEMIP expression, led to an acceleration in the progression of cardiac fibrosis. Finally, it was found that rhBMP6 would alleviate ventricular remodelling abnormalities after myocardial infarction. CONCLUSION: Therefore, BMP6 may be a novel molecular target for improving myocardial fibrosis and cardiac function after myocardial infarction.

Artificial Base-Directed In Vivo Formulation of Aptamer-Drug Conjugates with Albumin for Long Circulation and Targeted Delivery.

Aptamer-drug conjugates (ApDCs) are potential targeted pharmaceutics, but their clinical applications are hampered by fast clearance in blood. Herein we report the construction of ApDCs modified with artificial base F and the study of biological activities. Two types of F-base-modified ApDCs were prepared, Sgc8-paclitaxel by conjugation and Sgc8-gemcitabine, by automated solid-phase synthesis. In vitro experiments showed that F-base-modified ApDCs retain the specificity of the aptamer to target cells and the biological stability is improved. In vivo studies demonstrated that the circulatory time is increased by up to 55 h or longer, as the incorporated F base leads to a stable ApDC-albumin complex as the formulation for targeted delivery. Moreover, conjugated drug molecules were released efficiently and the drug (paclitaxel) concentration in the tumor site was improved. The results demonstrate that an F-base-directed ApDC-albumin complex is a potential platform for drug delivery and targeted cancer therapy.

An X-linked PLXNB3 mutation identified in patients with congenital heart disease with neurodevelopmental disabilities.

Background: Congenital heart disease (CHD) is the most common birth defect and is often accompanied by neurodevelopmental disabilities (NDD) which increase the associated mortality. Plexin families are known to play a key role in the development of heart and the occurrence of neurodevelopmental anomalies. However, there has been no report of PLXNB3 mutation in isolated CHD or CHD with concomitant NDD. Methods: We performed whole-exome sequencing (WES) on a proband with CHD with neurodevelopmental anomalies and his family members. Targeted sequencing, conservation analysis, AlphaFold, and PyRosetta were performed to identify more pathogenic mutations of PLXNB3. Scratch wound assay, Ki-67 assessment by flow cytometry, and gene expression analysis of heart development related pathway by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were conducted after 24 h transfection in AC16 and HEK293T to investigate the effect of the target mutation. Results: We identified a pathogenic mutation in the X-linked PLXNB3 gene (c.A4319T p.E1440V). In addition, we found 4 other pathogenic mutations in a cohort of 75 patients with sporadic CHD with NDD. AlphaFold and PyRosetta predicted that these 4 mutations could cause dramatic changes of the PLXNB3 protein structure (root-mean-square deviation score >10 Å). Further functional analysis revealed that this p.E1440V variant inhibits cell migration and proliferation, and affects the activity of key factors in the Notch signaling pathway, myocardial contraction pathway, and neurodevelopmental pathways. Conclusions: These findings suggest that PLXNB3 and the p.E1440V variant may be related to the pathogenesis of CHD associated with NDD.

Aptamer-based applications for cardiovascular disease.

Cardiovascular disease (especially atherosclerosis) is a major cause of death worldwide, and novel diagnostic tools and treatments for this disease are urgently needed. Aptamers are single-stranded oligonucleotides that specifically recognize and bind to the targets by forming unique structures in vivo, enabling them to rival antibodies in cardiac applications. Chemically synthesized aptamers can be readily modified in a site-specific way, so they have been engineered in the diagnosis of cardiac diseases and anti-thrombosis therapeutics. Von Willebrand Factor plays a unique role in the formation of thrombus, and as an aptamer targeting molecule, has shown initial success in antithrombotic treatment. A combination of von Willebrand Factor and nucleic acid aptamers can effectively inhibit the progression of blood clots, presenting a positive diagnosis and therapeutic effect, as well as laying a novel theory and strategy to improve biocompatibility paclitaxel drug balloon or implanted stent in the future. This review summarizes aptamer-based applications in cardiovascular disease, including biomarker discovery and future management strategy. Although relevant applications are relatively new, the significant advancements achieved have demonstrated that aptamers can be promising agents to realize the integration of diagnosis and therapy in cardiac research.

NLRP3 inflammasome is involved in ambient PM2.5-related metabolic disorders in diabetic model mice but not in wild-type mice.

AIMS: To explore the role of nucleotide-binding domain and leucine-rich repeat protein 3 (NLRP3) inflammasome in ambient fine particulate matter (PM2.5)-related metabolic disorders. METHODS: In this study, the C57BL/6 and db/db mice were exposed to concentrated PM2.5 or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 12 weeks. Indices of lipid metabolism, glucose metabolism, insulin sensitivity, and protein expression of NLRP3 inflammasome in visceral adipose tissue (VAT) were measured, respectively. RESULTS: The results showed that PM2.5 exposure increased circulatory insulin, triglycerides (TG), and total cholesterol (TC), and decreased high-density lipoprotein (HDL) in both C57BL/6 and db/db mice. The levels of NLRP3-related circulatory inflammatory cytokines including both interleukin (IL)-18 and IL-1ß in serum were increased in the PM2.5-exposed mice and accompanied by the elevation in fasting blood glucose and insulin. The results also showed that exposure to PM2.5 promoted the activation of NLRP3, pro-caspase-1, caspase-1, and apoptosis-associated speck-like protein containing CARD (ASC), simultaneously accompanied by the increase of IL-18 and IL-1ß expression in VAT, but the statistically significant difference only found in the db/db mice, not in C57BL/6 mice. CONCLUSION: The activation of NLRP3 inflammasome might be not the main mechanism of PM2.5-related metabolic disorders in wide type mice but it partly mediated the exacerbation of metabolic disorders in diabetic model mice.

Elevated homocysteine levels in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Elevated homocysteine (Hcy) levels showed increasing significance as the predisposing factor for the pathogenesis of atherosclerotic sequelae, including cardiovascular mortality, coronary artery disease, and stroke. There is increasing evidence linking plasma Hcy levels and heart failure (HF). The association between the elevated level of plasma Hcy and HF was examined by meta-analysis and systematic review in this study. METHODS: The PubMed and ScienceDirect databases until April 2020 were utilized to collect previous literature on plasma Hcy levels and the potential relation to HF. The pooled effects were evaluated depending on standardized mean differences (SMDs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software. Potential sources of heterogeneity were assessed with subgroup analysis and sensitivity analysis. RESULTS: A total of 12 research projects including 5506 subjects were selected. For pooled effect, the results confirmed that patients with HF had higher Hcy levels than the control subjects (SMD,1.148 and 95%CI, [0.715, 1.581]). Based on the classification of New York Heart Association (NYHA), the Hcy levels for the group of NYHA I or II (SMD, 1.484 and 95% CI, [0.442, 2.527]) and the group of NYHA III or IV (SMD, 3.361 and 95% CI, [1.902, 4.820]) were significantly increased compared to controls, while the increase was more intensive for the group of NYHA III or IV. Subgroup analyses revealed similar results. CONCLUSION: Our meta-analysis identified that plasma Hcy levels were significantly elevated in HF patients compared to control subjects, which is positively related to the advancement of NYHA class.

CircMYBL2 regulates the resistance of cervical cancer cells to paclitaxel via miR-665-dependent regulation of EGFR.

Circular RNAs are considered to be associated with cancer resistance. This study aims to investigate the function and mechanism of circMYBL2 in paclitaxel (PTX) resistance of cervical cancer (CC). The expression of circMYBL2, miR-665 and epidermal growth factor receptor (EGFR) was investigated using quantitative real-time polymerase chain reaction assay. Cell viability, cell colony number, cell proliferation, apoptosis and lactate dehydrogenase (LDH) were detected by 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, flow cytometry and LDH release assays, respectively. The interaction between miR-665 and circMYBL2 or EGFR was confirmed by dual-luciferase reporter assay. The protein expression levels were quantified by western blot or immunohistochemistry assay. Mice xenograft models were constructed to investigate the effect of circMYBL2 on CC tumor growth. CircMYBL2 was upregulated in CC tissues and cells, especially in PTX-resistant CC tissues and cells, and it was a stable circRNA mainly distributed in the cytoplasm. CircMYBL2 could enhance the PTX resistance of CC cells in vitro and promote CC tumor growth in vivo. Mechanistically, circMYBL2 could inhibit the PTX sensitivity and promote cell malignant behaviors in PTX-sensitive and PTX-resistant CC cells via upregulating EGFR mediated by miR-665. CircMYBL2 played a positive role in the PTX resistance and malignant activities of PTX-sensitive and PTX-resistant CC cells by regulating the miR-665/EGFR network, providing a novel therapeutic strategy for the treatment of CC patients resistant to PTX.

Parental PM2 .5 exposure changes Th17/Treg cells in offspring, is associated with the elevation of blood pressure.

Epidemiological evidences have indicated that fine particulate matter (PM2.5 ) exposure is associated with the occurrence and development of hypertension. The present study aims to explore the effects of parental PM2.5 exposure on blood pressure in offspring and elucidate the potential mechanism. The parental male and female C57BL/6 mice were exposed to concentrated PM2.5 or filtered air (FA) using Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) for 16 weeks. At week 12, the mice were assigned to breed offspring. The male offspring mice were further exposed to PM2.5 or FA as above method. During the parental exposure, the average PM2.5 concentration was 133.7 ± 53.32 µg/m3 in PM chamber, whereas the average concentration in FA chamber was 9.4 ± 0.23 µg/m3 . Similarly, during the offspring exposure, the average concentration in PM and FA chamber were 100.76 ± 26.97 µg/m3 and 9.15 ± 0.15 µg/m3 , respectively. The PM2.5 -exposed offspring mice displayed the elevation of blood pressure, the increase of angiotensin II (Ang II), the decrease of angiotensin converting enzyme 2 (ACE2) and Ang (1-7) in serum when compared with the FA-exposed offspring mice. The similar results displayed in the proteins expression of ACE2, AT1R, and Ang (1-7) in vessel and kidney. More importantly, parental PM exposure further induced the increase in serous Ang II and the protein expression of AT1R in vessel, but decrease in ACE2 and Ang (1-7). The serous Ang II was positively associated with splenic T helper type 17 (Th17) cell population and serous IL (interleukin)-17A, but negatively associated with T regular (Treg) cell population and serous IL-10. The results suggested that parental air pollution exposure might induce the elevation of offspring blood pressure via mediate Th17- and Treg-related immune microenvironment.

Base Editing Mediated Generation of Point Mutations Into Human Pluripotent Stem Cells for Modeling Disease.

Human pluripotent stem cells (hPSCs) are a powerful platform for disease modeling and drug discovery. However, the introduction of known pathogenic mutations into hPSCs is a time-consuming and labor-intensive process. Base editing is a newly developed technology that enables facile introduction of point mutations into specific loci within the genome of living cells. Here, we design an all-in-one episomal vector that expresses a single guide RNA (sgRNA) with an adenine base editor (ABE) or a cytosine base editor (CBE). Both ABE and CBE can efficiently introduce mutations into cells, A-to-G and C-to-T, respectively. We introduce disease-specific mutations of long QT syndrome into hPSCs to model LQT1, LQT2, and LQT3. Electrophysiological analysis of hPSC-derived cardiomyocytes (hPSC-CMs) using multi-electrode arrays (MEAs) reveals that edited hPSC-CMs display significant increases in duration of the action potential. Finally, we introduce the novel Brugada syndrome-associated mutation into hPSCs, demonstrating that this mutation can cause abnormal electrophysiology. Our study demonstrates that episomal encoded base editors (epi-BEs) can efficiently generate mutation-specific disease hPSC models.

MFGE8 is down-regulated in cardiac fibrosis and attenuates endothelial-mesenchymal transition through Smad2/3-Snail signalling pathway.

Endothelial-mesenchymal transition (EndMT) is a major source of transformed cardiac fibroblasts, which is reported to play a key role in cardiac fibrosis (CF), a pathogenesis of cardiovascular diseases such as heart failure, myocardial infarction and atrial fibrillation. Nonetheless, the specific mechanism underlying the progression of EndMT to CF is still largely unknown. In this study, we aimed to investigate the role of milk fat globule-EGF factor 8 (MFGE8), a kind of soluble glycoprotein, in TGF-ß1-induced EndMT. In animal experiments, the expression of MFGE8 was found down-regulated in the left ventricle and aorta of rats after transverse aortic constriction (TAC) compared with the sham group, especially in endothelial cells (ECs). In in vitro cultured ECs, silencing MFGE8 with small interfering RNA (siRNA) was found to promote the process of TGF-ß1-induced EndMT, whereas administration of recombinant human MFGE8 (rh-MFGE8) attenuated the process. Moreover, activated Smad2/3 signalling pathway after TGF-ß1 treatment and EndMT-related transcription factors, such as Snail, Twist and Slug, was potentiated by MFGE8 knock-down but inhibited by rh-MFGE8. In conclusion, our experiments indicate that MFGE8 might play a protective role in TGF-ß1-induced EndMT and might be a potential therapeutic target for cardiac fibrosis.

Ambient fine particulate matter induced the elevation of blood pressure through ACE2/Ang(1-7) pathway: The evidence from urine metabolites.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.

CARD9 mediates T cell inflammatory response in Coxsackievirus B3-induced acute myocarditis.

Cardiac inflammation in Coxsackievirus B3 (CVB3)-induced myocarditis is a consequence of viral-related cardiac injury and immune response. Caspase-associated recruitment domain 9 (CARD9) is a critical adaptor protein involved in transduction of signals from various innate pattern recognition receptors. In this study, the role of CARD9 in acute viral myocarditis was evaluated. CARD9-/- and C57BL/6 mice were infected with CVB3. On day 7 postinfection, myocardial tissue and blood samples were collected and examined. After CARD9 knockout, mRNA and protein levels of transforming growth factor-ß(TGF-ß), interleukin-17A(IL-17A), and CARD domain of B-cell CLL/lymphoma 10(BCL-10) in the myocardium were markedly lower in CARD9-/- mice than in C57BL/6 mice with CVB3-induced viral myocarditis. This trend was similar for the pathological scores for inflammation and serum levels of cytokines interleukin-6(IL-6), interleukin-10(IL-10), interferon -γ(IFN-γ), TGF-ß, and IL-17A. These results suggest that the CARD9-mediated secretion of pro-inflammatory cytokines plays an important role in the immune response to acute viral myocarditis.

Elevated Homocysteine Levels Associated with Atrial Fibrillation and Recurrent Atrial Fibrillation.

There is increasing evidence linking plasma homocysteine levels and atrial fibrillation (AF). The association between an elevated level of plasma homocysteine and AF was examined by meta-analysis in this study.The PubMed and ScienceDirect databases until August 2019 were utilized to collect previous literature on homocysteine and the potential relation to AF. The pooled effects were evaluated depending on standardized mean differences (SMDs) or odds ratios (ORs) with 95% confidence intervals (CIs), and the calculation was performed using Stata 12 software.A total of 11 validated articles were included in the meta-analysis. For pooled effect, the results confirmed that AF patients had higher homocysteine levels than control subjects (SMD: 0.58, 95%CI: 0.09-1.06). Compared with control subjects, homocysteine levels were higher in paroxysmal AF (SMD: 0.45, 95%CI: 0.18-0.72) and persistent AF patients (SMD: 1.21, 95%CI: 0.50-1.92). The pooled analysis suggested that patients with elevated homocysteine levels had markedly higher risk of AF compared with lower homocysteine levels in the categorical variable (OR: 2.21, 95%CI: 1.16-4.21) and continuous variable analyses (OR: 1.13, 95%CI: 1.00-1.27), respectively. In addition, the pooled analysis indicated that recurrent AF patients had significantly higher homocysteine levels than those without recurrence (SMD: 0.65, 95%CI: 0.42-0.88). The pooled analysis of the categorical variables indicated that elevated homocysteine levels were associated with increased risk of AF recurrence (OR: 3.81, 95%CI: 3.11-4.68). However, the association was weak in the pooled analysis of continuous variables (OR: 1.88, 95%CI: 0.74-4.81).Our meta-analysis identified that plasma homocysteine levels were significantly elevated in AF and recurrent AF patients. Elevated homocysteine is associated with increased risk of AF and AF recurrence.

NLRC5 deficiency ameliorates cardiac fibrosis in diabetic cardiomyopathy by regulating EndMT through Smad2/3 signaling pathway.

Diabetic cardiomyopathy (DCM) is one of the main causes of heart failure in patients with diabetes. Cardiac fibrosis caused by endothelial mesenchymal transformation (EndMT) plays an important role in the pathogenesis of DCM. NLRC5 is a recently discovered immune and inflammatory regulatory molecule in the NOD-like receptor family, and is involved in organ fibrosis. In this study, we found that the expression of NLRC5 was up-regulated in endothelial cells (ECs) and cardiac fibroblasts (CFs) in diabetes models both in vivo and in vitro. NLRC5 knockdown significantly inhibited high glucose-induced EndMT. In addition, NLRC5 deficiency inhibited the expression of phosphorylated Smad2/3 and the activation of EndMT-related transcription factors in ECs induced by high glucose. However, the effect of NLRC5 deficiency on CFs was not obvious. In summary, our results suggest that NLRC5 deficiency ameliorates cardiac fibrosis in DCM by inhibiting EndMT through Smad2/3 signaling pathway and related transcription factors. NLRC5 is likely to be a biomarker and therapeutic target of cardiac fibrosis in diabetic cardiomyopathy.