Faecalibacterium prausnitzii as a potential Antiatherosclerotic microbe.

BACKGROUND: The gut microbiota plays a crucial role in coronary artery disease (CAD) development, but limited attention has been given to the role of the microbiota in preventing this disease. This study aimed to identify key biomarkers using metagenomics and untargeted metabolomics and verify their associations with atherosclerosis. METHODS: A total of 371 participants, including individuals with various CAD types and CAD-free controls, were enrolled. Subsequently, significant markers were identified in the stool samples through gut metagenomic sequencing and untargeted metabolomics. In vivo and in vitro experiments were performed to investigate the mechanisms underlying the association between these markers and atherosclerosis. RESULTS: Faecal omics sequencing revealed that individuals with a substantial presence of Faecalibacterium prausnitzii had the lowest incidence of CAD across diverse CAD groups and control subjects. A random forest model confirmed the significant relationship between F. prausnitzii and CAD incidence. Notably, F. prausnitzii emerged as a robust, independent CAD predictor. Furthermore, our findings indicated the potential of the gut microbiota and gut metabolites to predict CAD occurrence and progression, potentially impacting amino acid and vitamin metabolism. F. prausnitzii mitigated inflammation and exhibited an antiatherosclerotic effect on ApoE-/- mice after gavage. This effect was attributed to reduced intestinal LPS synthesis and reinforced mechanical and mucosal barriers, leading to decreased plasma LPS levels and an antiatherosclerotic outcome. CONCLUSIONS: Sequencing of the samples revealed a previously unknown link between specific gut microbiota and atherosclerosis. Treatment with F. prausnitzii may help prevent CAD by inhibiting atherosclerosis.

Silencing EIF3A ameliorates pulmonary arterial hypertension through HDAC1 and PTEN/PI3K/AKT pathway in vitro and in vivo.

Pulmonary vascular remodeling caused by the excessive proliferation of pulmonary arterial smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Eukaryotic initiation factor 3 subunit A (EIF3A) exhibited proliferative activity in multiple cell types. The present study investigated the role of EIF3A in the progression of PAH. A monocrotaline (MCT)-induced PAH rat model was constructed, and adeno-associated virus type 1 (AAV1) carrying EIF3A shRNA was intratracheally delivered to PAH rats to block EIF3A expression. PASMCs were isolated from rats and treated with PDGF-BB to simulate PASMC proliferation, and shRNA for EIF3 was conducted to investigate the mechanism behind the role of EIF3A in PASMC function in vitro. EIF3A expression was upregulated in pulmonary arteries, and EIF3A inhibition effectively improved pulmonary hypertension and right ventricular hypertrophy and suppressed MCT-induced vascular remodeling in vivo. In addition, we found that genetic knockdown of EIF3A reduced PDGF-triggered proliferation and arrested cell cycle, accompanied by downregulated proliferation-related protein expression in PASMCs. Mechanistically, the histone deacetylase 1 (HDAC1)-mediated PTEN/PI3K/AKT pathway was recognized as a primary mechanism in PAH progression. Silencing EIF3A decreased HDAC1 expression, and further inhibited the excessive proliferation of PASMCs by increasing the phosphatase and tension homolog (PTEN) expression and suppressing the AKT phosphorylation. Notably, HDAC1 expression reversed the effect of silencing EIF3A on PAH and PTEN/PI3K/AKT pathway. Collectively, silencing EIF3A improved PAH by decreasing PASMC proliferation through the HDAC1-mediated PTEN/PI3K/AKT pathway. These findings suggest that targeting EIF3A may represent a potential approach for the treatment of PAH.

Mutated CYP17A1 promotes atherosclerosis and early-onset coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) is a multi-factor complex trait and is heritable, especially in early-onset families. However, the genetic factors affecting the susceptibility of early-onset CAD are not fully characterized. METHODS: In the present study, we identified a rare nonsense variant in the CYP17A1 gene from a Chinese Han family with CAD. To validate the effect of this variation on atherosclerosis and early-onset coronary artery disease, we conducted studies on population, cells, and mice. RESULTS: The mutation precisely congregated with the clinical syndrome in all the affected family members and was absent in unaffected family members and unrelated controls. Similar to the human phenotype, the CYP17A1-deficient mice present the phenotype of metabolic syndrome with hypertension, increased serum glucose concentration, and presentation of central obesity and fatty liver. Furthermore, CYP17A1 knockout mice or CYP17A1 + ApoE double knockout mice developed more atherosclerotic lesions than wild type (WT) with high fat diary. In cell models, CYP17A1 was found to be involved in glucose metabolism by increasing glucose intake and utilization, through activating IGF1/mTOR/HIF1-α signaling way, which was consistent in CYP17A1 knockout mice with impaired glucose tolerance and insulin resistance. CONCLUSIONS: Through our study of cells, mice and humans, we identified CYP17A1 as a key protein participating in the pathophysiology of the atherosclerotic process and the possible mechanism of CYP17A1 C987X mutation induced atherosclerosis and early-onset CAD involving glucose homeostasis regulation was revealed. Video Abstract.

Association between complete right bundle branch block and atrial fibrillation development.

BACKGROUND: Complete right bundle branch block (CRBBB) is an important predictor of atrial fibrillation (AF) recurrence after pulmonary vein isolation. However, the association between CRBBB and AF development remains unclear. METHODS: We performed a retrospective study of 2639 patients (male, n = 1549; female, n = 1090; mean age, 58 ± 13 years). CRBBB was defined as a late R (R') wave in lead V1 or V2 with a slurred S wave in lead I and/or lead V6 with a prolonged QRS duration (≥120 ms). RESULTS: Among the 2639 patients, CRBBB was detected in 40 patients (1.5%), and the prevalence of AF was 7.4% (196/2639). The proportion of patients with AF and CRBBB was higher than the proportion of patients with AF without CRBBB (22.5% vs. 7.2%; p = 0.001). In the forward multivariate logistic analysis, CRBBB (odds ratio [OR], 3.329; 95% confidence interval [CI], 1.350-8.211; p = 0.009), complete left bundle branch block (OR, 2.209; 95% CI, 1.238-3.940; p = 0.007), age (OR, 1.020; 95% CI, 1.005-1.035; p = 0.009), valvular heart disease (OR, 2.332; 95% CI, 1.531-3.552; p < 0.001), left atrial diameter (OR, 1.133; 95% CI, 1.104-1.163; p < 0.001), left ventricular ejection fraction (OR, 1.023; 95% CI, 1.006-1.041; p = 0.007), and class I or III anti-arrhythmic drug use (OR, 10.534; 95% CI, 7.090-15.651; p < 0.001) were associated with AF. CONCLUSION: Complete right bundle branch block was significantly associated with AF development in hospitalized patients with cardiovascular diseases.

High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3ß/TXNIP Pathway.

High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1ß is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1ß secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1ß production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3ß phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3ß shRNA knockdown study further revealed that GSK-3ß played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.

PU.1 inhibition attenuates atrial fibrosis and atrial fibrillation vulnerability induced by angiotensin-II by reducing TGF-ß1/Smads pathway activation.

Fibrosis serves a critical role in driving atrial remodelling-mediated atrial fibrillation (AF). Abnormal levels of the transcription factor PU.1, a key regulator of fibrosis, are associated with cardiac injury and dysfunction following acute viral myocarditis. However, the role of PU.1 in atrial fibrosis and vulnerability to AF remain unclear. Here, an in vivo atrial fibrosis model was developed by the continuous infusion of C57 mice with subcutaneous Ang-II, while the in vitro model comprised atrial fibroblasts that were isolated and cultured. The expression of PU.1 was significantly up-regulated in the Ang-II-induced group compared with the sham/control group in vivo and in vitro. Moreover, protein expression along the TGF-ß1/Smads pathway and the proliferation and differentiation of atrial fibroblasts induced by Ang-II were significantly higher in the Ang-II-induced group than in the sham/control group. These effects were attenuated by exposure to DB1976, a PU.1 inhibitor, both in vivo and in vitro. Importantly, in vitro treatment with small interfering RNA against Smad3 (key protein of TGF-ß1/Smads signalling pathway) diminished these Ang-II-mediated effects, and the si-Smad3-mediated effects were, in turn, antagonized by the addition of a PU.1-overexpression adenoviral vector. Finally, PU.1 inhibition reduced the atrial fibrosis induced by Ang-II and attenuated vulnerability to AF, at least in part through the TGF-ß1/Smads pathway. Overall, the study implicates PU.1 as a potential therapeutic target to inhibit Ang-II-induced atrial fibrosis and vulnerability to AF.

The dissection of R genes and locus Pc5.1 in Phytophthora capsici infection provides a novel view of disease resistance in peppers.

BACKGROUND: Phytophthora capsici root rot (PRR) is a disastrous disease in peppers (Capsicum spp.) caused by soilborne oomycete with typical symptoms of necrosis and constriction at the basal stem and consequent plant wilting. Most studies on the QTL mapping of P. capsici resistance suggested a consensus broad-spectrum QTL on chromosome 5 named Pc.5.1 regardless of P. capsici isolates and resistant resources. In addition, all these reports proposed NBS-ARC domain genes as candidate genes controlling resistance. RESULTS: We screened out 10 PRR-resistant resources from 160 Capsicum germplasm and inspected the response of locus Pc.5.1 and NBS-ARC genes during P. capsici infection by comparing the root transcriptomes of resistant pepper 305R and susceptible pepper 372S. To dissect the structure of Pc.5.1, we anchored genetic markers onto pepper genomic sequence and made an extended Pc5.1 (Ext-Pc5.1) located at 8.35 Mb-38.13 Mb on chromosome 5 which covered all Pc5.1 reported in publications. A total of 571 NBS-ARC genes were mined from the genome of pepper CM334 and 34 genes were significantly affected by P. capsici infection in either 305R or 372S. Only 5 inducible NBS-ARC genes had LRR domains and none of them was positioned at Ext-Pc5.1. Ext-Pc5.1 did show strong response to P. capsici infection and there were a total of 44 differentially expressed genes (DEGs), but no candidate genes proposed by previous publications was included. Snakin-1 (SN1), a well-known antimicrobial peptide gene located at Pc5.1, was significantly decreased in 372S but not in 305R. Moreover, there was an impressive upregulation of sugar pathway genes in 305R, which was confirmed by metabolite analysis of roots. The biological processes of histone methylation, histone phosphorylation, DNA methylation, and nucleosome assembly were strongly activated in 305R but not in 372S, indicating an epigenetic-related defense mechanism. CONCLUSIONS: Those NBS-ARC genes that were suggested to contribute to Pc5.1 in previous publications did not show any significant response in P. capsici infection and there were no significant differences of these genes in transcription levels between 305R and 372S. Other pathogen defense-related genes like SN1 might account for Pc5.1. Our study also proposed the important role of sugar and epigenetic regulation in the defense against P. capsici.

Copper-Catalyzed Cascade Annulation of Malonate-Tethered O-Acyl Oximes with Cyclic 1,3-Dicarbonyl Compounds for the Synthesis of Spiro-Pentacyclic Derivatives.

A copper-catalyzed cascade annulation of malonate-tethered O-acyl oximes with cyclic 1,3-dicarbonyl compounds has been developed for the rapid synthesis of spiro-pentacyclic derivatives. This reaction allows the one-step formation of five C-C/N/O bonds and an angular tricyclic core under very mild conditions and shows excellent regioselectivity and stereoselectivity.

Effect of catheter ablation on clinical outcomes in patients with atrial fibrillation and significant functional mitral regurgitation.

BACKGROUND: In patients with atrial fibrillation (AF) and functional mitral regurgitation (MR), catheter ablation reduces the severity of MR and improves cardiac remodeling. However, its effects on prognosis are uncertain. METHODS: This retrospective study included 151 consecutive patients with AF and functional MR, 82 (54.3%) of whom were treated by catheter ablation (Ablation group) and 69 (45.7%) with drug therapy without ablation (Non-ablation group). Forty-three pairs of these patients were propensity matched on the basis of age, CHA2DS2-VASc scores, and left ventricular ejection fraction. The primary outcome evaluated was severity of MR, cardiac remodeling and the combined incidence of subsequent heart failure-related hospitalization and strokes/transient ischemic attacks. RESULTS: Patients in the Ablation group showed a significant decrease in the severity of MR (p < 0.001), a significant decrease in the left atrial diameter (p = 0.010), and significant improvement in the left ventricular ejection fraction (p = 0.015). However, patients in the Non-ablation group showed only a significant decrease in the severity of MR (p = 0.004). The annual incidence of the studied events was 4.9% in the Ablation group and 16.7% in the Non-ablation group, the incidence being significantly lower in the ablation than Non-ablation group (p = 0.026) according to Kaplan-Meier curve analyses. According to multivariate Cox regression analysis, catheter ablation therapy (hazard ratio [HR] 0.27, 95% confidence interval [CI] 0.09-0.84; p = 0.024) and heart failure at baseline (HR 3.84, 95% CI 1.07-13.74; p = 0.038) were independent predictors of the incidence of the studied events. CONCLUSIONS: Among patients with AF and functional MR, catheter ablation was associated with a significantly lower combined risk of heart failure-related hospitalization and stroke than in a matched cohort of patients receiving drug therapy alone.

Cu(OAc)2-Promoted Oxidative Cross-Dehydrogenative Coupling Reaction of α-Acylmethyl Malonates with Indole Derivatives to Access 3-Functionalized Indoles and Polycyclic Indoles.

A Cu(OAc)2-promoted oxidative cross-dehydrogenative coupling reaction of α-acylmethyl malonates with indole derivatives was developed. In the case of indoles, the regioselective coupling products were formed through a sequential dehydrogenation-addition-dehydrogenation process. When a second nucleophilic center was located in the 2-position of indoles, further successive nucleophilic cyclization occurred to give polycyclic indole derivatives. The Cu(OAc)2 was proved to act as not only an oxidant but also a catalyst.

Delayed PCI 12 Hours after the Onset of Symptoms Is Associated with Improved Outcomes for Patients with ST-Segment Elevation Myocardial Infarction: A Real-World Study.

BACKGROUND: Primary percutaneous coronary intervention (PPCI) plays a pivotal role in the treatment of ST-segment elevation myocardial infarction (STEMI). However, it remains controversial whether PCI delayed beyond the recommended time window of 12 h after the onset of symptoms is applicable to STEMI. OBJECTIVE: The acute myocardial infarction (AMI) registration study in Xinjiang, China, is a real-world clinical trial (retrospective cohort study) that includes hospitalized patients. The purpose of this study was to compare delayed PCI and medication therapy beyond the recommended time window of 12 h after the onset of symptoms on the outcomes of STEMI patients. METHODS AND RESULTS: From May 2012 to December 2015, a total of 1072 STEMI patients received delayed PCI (n=594) or standard medication therapy (MT) (n=478) more than 12 h after the onset of symptoms. The number of all-cause deaths in the delayed PCI group and that in the MT group were 55 (9.3%) and 138 (28.9%), respectively, and a significant difference between the groups was indicated for this variable (P<0.001). The number of cardiac deaths in the delayed PCI group and that in the medication therapy group were 47 (7.9%) and 120 (25.1%), respectively, and a significant difference between the groups was indicated for this variable (P<0.001). We also found that the MACE incidence in the delayed PCI group was significantly higher than it was in the MT group (32.2% versus 43.5%, P<0.001). Propensity score matching (PSM) analyses remained significant differences between the delayed PCI group and the MT group, respectively, in all-cause deaths (9.3% versus 25.8%, P<0.001) and cardiac death (8.7% versus 21.6%, P<0.001). CONCLUSION: Compared to medication therapy, PCI for STEMI delayed beyond 12 h after the onset of symptoms can better reduce mortality and the incidence of MACEs. TRIAL REGISTRATION: This study is registered with the following: Trial Registration: clinicaltrials.gov; Identifier: NCT02737956.

Copper-Catalyzed Reaction of C60 with Tertiary Amines for the Preparation of Spiro-Linked Methanofullerenes and Fullerenoalkanals.

CuI-catalyzed reaction of C60 with tertiary amines by using air as the sole oxidant has been developed. Spiro-linked methanofullerenes bearing cyclic amides and fullerenoalkanals can be obtained selectively using the cyclic and acyclic amines as starting materials, respectively. The reactions show a wide functional group tolerance. In addition, four ([6,6]-phenyl-C61-butyric acid methyl ester) analogues can be easily prepared through the developed method.

Tunable Copper-Catalyzed Reaction of C60 with 2-Ethoxycarbonylacetamides and Subsequent BF3·Et2O-Mediated Isomerization of the Generated Dihydrofuran-Fused Fullerenes to Fulleropyrrolidinones.

A tunable copper-catalyzed reaction of C60 with 2-ethoxycarbonylacetamides using air as the oxidant has been explored, which selectively affords methanofullerenes (2) and dihydrofuran-fused fullerenes (3) under the CuI/DMAP and CuCl/NMI catalytic systems, respectively. Furthermore, the generated dihydrofuran-fused fullerenes could be transformed to fulleropyrrolidinones (4 and 5) upon treatment with BF3·Et2O.

Effects of erythropoietin on the clinical outcomes of patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention: A meta-analysis
.

AIMS: To investigate the effects of erythropoietin (EPO) on the clinical outcomes of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI). MATERIAL AND METHODS: We collected randomized controlled studies conducted before April 15, 2017, and performed a meta-analysis using RevMan5.3 software. RESULTS: Compared with the conventional revascularization group, mortality (RR = 0.79; 95% Cl, 0.42 - 1.50; p = 0.47), stroke events (RR = 2.63; 95% Cl, 0.70 - 9.85; p = 0.15), recurrent myocardial infarction (RR = 0.99; 95% Cl, 0.44 - 2.20; p = 0.98), and other clinical endpoints were not significantly different in the EPO group. However, subgroup analysis showed a marginally significant difference between the high-dose EPO group and the control group (MD = 1.29; 95% CI, 0.02 - 2.56; p = 0.05) in ejection fraction. CONCLUSION: The administration of EPO has no effects on the clinical outcomes of patients with acute STEMI after PCI, whilst a high dose of EPO may increase patients' ejection fraction.
.

Association Between CHADS2 Score and the Development of Interatrial Block.

Interatrial block (IAB) is associated with a multitude of medical conditions. The aim of this retrospective study was to investigate whether CHADS2 (congestive heart failure, hypertension, age ≥ 75 years, diabetes mellitus, prior stroke) score is positively associated with the development of IAB. A total of 1072 patients (men, 555; women, 517; mean age, 61 ± 14 years) were included in the study. P-wave duration was measured manually using a caliper. IAB was defined as a P-wave duration of ≥ 120 ms on a 12-lead electrocardiogram. CHADS2 scores were calculated retrospectively. Among the 1072 patients, the prevalence of IAB was 36.1% (387/1072). In multivariate analysis, increased CHADS2 score (odds ratio [OR], 1.810; 95% confidence interval [CI], 1.577-2.077; P < 0.001), coronary artery disease (OR, 1.536; 95% CI, 1.065-2.216; P = 0.022), and increased left atrial diameter (OR, 1.039; 95% CI, 1.008-1.071; P = 0.013) were independently associated with IAB. The percentages of patients with IAB among those with a CHADS2 score of 0, 1, 2, 3, 4, 5, and 6 were 20.6%, 33.0%, 45.0%, 55.9%, 61.9%, 77.8%, and 100%, respectively (P < 0.001). There was a greater percentage of patients with a CHADS2 score of ≥ 2 with IAB compared with a CHADS2 score of < 2 (26.5% vsrsus 52.0%; P < 0.001). In receiver operating curve (ROC) analysis, CHADS2 score (area under the curve, 0.670; 95% CI, 0.636-0.704; P < 0.001) was predictive of IAB. In conclusion, CHADS2 score was significantly associated with the development of IAB in this study population.

Copper-Catalyzed Functionalizations of C60 with Amino Alcohols.

CuI-catalyzed diverse functionalizations of C60 with amino alcohols with aerobic oxygen as the sole oxidant have been explored. For 2-/3-amino alcohols, an aminooxygenation reaction occurs to generate fulleromorpholine and fullerooxazepane derivatives. When a tethered furan ring exists, a further intramolecular [4 + 2] reaction with the neighboring double bond occurs to furnish the cis-1 products. In the case of 4-/5-amino alcohols, methanofullerenes linking with cyclic amides are obtained through cyclic enamine intermediates.

The Cs2CO3-Catalyzed Reaction of 2-Oxindoles with Enones for the Preparation of Indolin-3-Ones and Their Further Transformation.

The Cs2CO3-catalyzed reaction of 2-oxindoles with enones affords 2,2-disubstituted indolin-3-ones through domino "Michael addition-oxidation-ring-cleavage-C-N coupling" process. O2 acts as the sole oxidant to accomplish the oxidative process. The indolin-3-ones can be further transformed to pyridazine, azirdine-fused 3-oxindoles, 4-quinolone derivatives easily.

Cu(OAc)2-Mediated Reaction of C60 with Ureas for the Preparation of Fulleroimidazolidinones.

The Cu(OAc)2-mediated intermolecular diamination reaction of C60 with ureas allows the concise and efficient preparation of fulleroimidazolidinones involving the cleavage of two N-H bonds and formation of two C-N bonds. Both dialkylated and diarylated fulleroimidazolidinones can be synthesized using this method.

2-Oxindole Acts as a Synthon of 2-Aminobenzoyl Anion in the K2CO3-Catalyzed Reaction with Enones: Preparation of 1,4-Diketones Bearing an Amino Group and Their Further Transformations.

A convenient approach for the synthesis of 1,4-diketones bearing an amino group has been developed through the K2CO3-catalyzed reaction of 2-oxindoles with enones with the assistance of atmospheric O2 via sequential Michael addition-oxidation-ring-cleavage process. The further intramolecular reaction leads to the formation of benzoazepinone, quinoline, and 3-oxindole derivatives.

Reaction of C60 with Inactive Secondary Amines and Aldehydes and the Cu(OAc)2-Promoted Regioselective Intramolecular C-H Functionalization of the Generated Fulleropyrrolidines.

The thermal reaction of C60 with aromatic aldehydes and inactive secondary amines for the stereoselective synthesis of trans-1,2,5-trisubstituted fulleropyrrolidines has been developed. Moreover, when an o-hydroxyl group was located at the phenyl ring of the generated fulleropyrrolidines, the Cu(OAc)2-promoted regioselective intramolecular C-O coupling reaction occurred to generate unique tricycle-fused fullerene derivatives.