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A copper-catalyzed [3 + 2] annulation of O-acyl oximes with 4-sulfonamidophenols is developed. The advantage of this method lies in the concurrent double activation of two substrates to form nucleophilic enamines and electrophilic quinone monoimines. The substituent on the α-carbon of O-acyl oxime determines two different reaction pathways, thereby leading to the selective generation of 5-sulfonamidoindoles and 2-amido-5-sulfonamidobenzofuran-3(2H)-ones.
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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.
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Aterosclerosis , Microbioma Gastrointestinal , Humanos , Animales , Ratones , Faecalibacterium prausnitzii/metabolismo , LipopolisacáridosRESUMEN
AIMS: The relation between hypoalbuminemia and coronary artery disease (CAD) has been established. However, the association of increased albumin level and outcomes of CAD has not been investigated. METHODS: There were 14 994 CAD patients from the PRACTICE study, which is a large, single center prospective cohort study based on case records and follow-up registry performed in the First Affiliated Hospital of Xinjiang Medical University from Dec. 2016 to Oct. 2021 in the present study. All the 14 994 patients were divided into five categories according albumin levels: <35 g/L group (n = 1 478), 35-40 g/L group (n = 5 007), 40-45 g/L group (n = 6 076), 45-50 g/L group (n = 1 835), and ≥50 g/L group (n = 598). RESULTS: A total of 448 all-cause deaths(ACD), 333 cardiac deaths (CD), 1 162 MACEs and 1 276 MACCEs were recorded during up to 60-months follow-up period. After adjusting for confounders, we observed a non-linear relation for either MACE or MACCE with the lowest risk at 45 g/L of albumin levels. A threshold value of albumin ≥50 g/L was associated with an increased risk for either MACE (adjusted HR=1.617, 95%CI:1.130-2.315, P = 0.009) or MACCE (adjusted HR= 1.439, 95%CI: 1.007-2.056, P = 0.045) in multivariable Cox regression model. For mortality, we only found decreased (<35 g/L) but not increased albumin level was associated with either ACD (HR=2.744, 95%CI: 1.631-4.617, P<0.001) or CD (HR=2.736, 95%CI: 1.484-5.045, P = 0.001). CONCLUSIONS: In the present study, a U-shaped curve relation was identified between albumin levels and MACE and MACCE in CAD patients, with the lowest risk at 45 g/L levels.
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AIMS: Chronic heart failure (CHF) remains a major health issue worldwide. In the present study, we aimed to identify novel circulating biomarkers for CHF using serum proteomics technology and to validate the biomarker in three independent cohorts. METHODS AND RESULTS: The isobaric tags for relative and absolute quantitation technology was utilized to identify the potential biomarkers of CHF. The validation was conducted in three independent cohort. Cohort A included 223 patients with ischaemic heart disease (IHD) and 321 patients with ischaemic heart failure (IHF) from the CORFCHD-PCI study. Cohort B recruited 817 patients with IHD and 1139 patients with IHF from the PRACTICE study. Cohort C enrolled 559 non-ischaemic heart disease patients with CHF (n = 316) or without CHF (n = 243). We found the expression of a-1 antitrypsin (AAT) was elevated significantly in patients with CHF compared with that in the patients with stable IHD using statistical and bioinformatics analyses. In a validation study, there was a significant difference between patients with stable IHD and patients with IHF in AAT concentration either in cohort A (1.35 ± 0.40 vs. 1.64 ± 0.56, P < 0.001) or in cohort B (1.37 ± 0.42 vs. 1.70 ± 0.48, P < 0.001). The area under the receiver operating characteristic curve was 0.70 [95% confidence interval (CI): 0.66 to 0.74, P < 0.001] in cohort A and 0.74 (95% CI: 0.72 to 0.76, P < 0.001) in cohort B. Furthermore, AAT was negative correlated with left ventricular ejection fraction (r = -0.261, P < 0.001). After adjusting for confounders using a multivariate logistic regression analysis, AAT remained an independent association with CHF in both cohort A (OR = 3.14, 95% CI: 1.667 to 5.90, P < 0.001) and cohort B (OR = 4.10, 95% CI: 2.97 to 5.65, P < 0.001). This association was also validated in cohort C (OR = 1.86, 95% CI: 1.02 to 3.38, P = 0.043). CONCLUSIONS: The present study suggests that serum AAT is a reliable biomarker for CHF in a Chinese population.
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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.
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Aterosclerosis , Enfermedad de la Arteria Coronaria , Animales , Humanos , Ratones , Aterosclerosis/genética , Enfermedad de la Arteria Coronaria/genética , Ratones Noqueados , Ratones Noqueados para ApoE , Transducción de Señal , Esteroide 17-alfa-Hidroxilasa/genéticaRESUMEN
We aimed to evaluate the association of the fibrinogen-to-albumin ratio (FAR) with the clinical outcomes of coronary artery disease (CAD). All 14,944 patients with CAD evaluated in the present study were from a prospective cohort that recruited 15,250 patients admitted in the First Affiliated Hospital of Xinjiang Medical University between December 2016 and October 2021. The all-cause mortality (ACM) and cardiac mortality (CM) were selected as the primary endpoints. The secondary endpoints were major adverse cardiovascular events (MACEs), major adverse cardiac and cerebrovascular events (MACCEs), and non-fatal myocardial infarction (NFMI). The optimal FAR cutoff value was determined by using a receiver operating characteristic (ROC) curve analysis. Using 0.1 as the cutoff value, all the patients were divided into two groups: a low-FAR group (FAR < 0.1, n = 10,076) and a high-FAR group (FAR ≥ 0.1, n = 4918). The incidence of outcomes between the two groups was compared. The high-FAR group exhibited a higher incidence of ACM (5.3% vs. 1.9%), CM (3.9% vs. 1.4%), MACEs (9.8% vs. 6.7%), MACCEs (10.4% vs. 7.6%), and NFMI (2.3% vs. 1.3%) than the low-FAR group. To adjust the confounders, multivariate Cox regression analyses showed that the risk in the high-FAR group was increased 2.182 fold in ACM (HR = 2.182, 95% CI: 1.761 ~ 2.704, P < 0.001), 2.116 fold in CM (HR = 2.116, 95% CI: 1.761 ~ 2.704, P < 0.001), 1.327 fold in MACEs (HR = 1.327, 95% CI: 1.166 ~ 1.510, P < 0.001), 1.280 fold in MACCEs (HR = 1.280, 95% CI: 1.131 ~ 1.448, P < 0.001), and 1.791 fold in NFMI (HR = 1.791, 95% CI:1.331 ~ 2.411, P < 0.001), compared to the low-FAR group. The present study suggested that the high-FAR group was an independent and powerful predictor of adverse outcomes in CAD patients.
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Enfermedad de la Arteria Coronaria , Infarto del Miocardio , Intervención Coronaria Percutánea , Humanos , Estudios Prospectivos , Infarto del Miocardio/etiología , Pronóstico , Fibrinógeno , Albúminas , Factores de Riesgo , Intervención Coronaria Percutánea/efectos adversosRESUMEN
BACKGROUND: We sought to examine the dose-response relationship between high-density lipoprotein cholesterol (HDL-C) and bleeds in coronary artery disease (CAD) patients who underwent percutaneous coronary intervention (PCI). METHODS: All the 15,250 participants were from the Personalized Antiplatelet Therapy According to CYP2C19 Genotype in Coronary Artery Disease (PRACTICE) study, which is a large, single-center, prospective cohort study based on case records and a follow-up registry performed in the First Affiliated Hospital of Xinjiang Medical University from December 2016 to October 2021. We divided all the patients into five groups according to their HDL-C levels: the ≤35 mg/dL group (n = 4,732), 35 to 45 mg/dL group (n = 6,049), 45 to 55 mg/dL group (n = 2,826), 55 and 65 mg/dL group (n = 1,117), and >65 mg/dL group (n = 526). The incidence of bleeds, mortality, ischemic events, and net adverse clinical events (NACEs) among the five groups was compared. RESULTS: A total of 713 bleeds, 1,180 ischemic events, 456 deaths, and 1,893 NACEs were recorded during the up to 60-month follow-up period. After adjusting for confounders, we observed a nonlinear relation for bleeds, with the highest risk at intermediate HDL-C levels (45-55 mg/dL). We also identified a dose-response relationship for ischemic events. A threshold value of HDL-C ≤35 mg/dL (adjusted hazard ratio = 0.560, 95% confidence interval: 0.360-0.872, p = 0.010) was associated with a decreased risk for bleeds in the multivariable Cox regression model. The results were consistent in multiple sensitivity analyses and propensity score-matching analysis. CONCLUSION: In the present study, a nonlinear association was identified between HDL-C levels and bleeds in CAD patients who underwent PCI, with a higher risk at intermediate levels. However, further multicenter studies are warranted.
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A copper-catalyzed [3+2] annulation of O-acyl ketoximes with 2-aryl malonates for the concise synthesis of 3-aryl-4-pyrrolin-2-ones has been developed. The advantage of this method lies in the use of O-acyl oximes as an internal oxidant to generate the nucleophilic enamines and electrophilic p-quinone methides concurrently. The subsequent nucleophilic addition undergoes selectively on the α-C of malonates.
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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.
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Factor 3 de Iniciación Eucariótica , Hipertensión Arterial Pulmonar , Animales , Ratas , Proliferación Celular/genética , Eucariontes/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 1/metabolismo , Miocitos del Músculo Liso/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Arteria Pulmonar/metabolismo , ARN Interferente Pequeño/metabolismo , Remodelación Vascular , Factor 3 de Iniciación Eucariótica/genética , Factor 3 de Iniciación Eucariótica/metabolismoRESUMEN
Objective: Anti-Ro60 and anti-Ro52 antibodies are associated with different connective tissue diseases (CTDs). However, the clinical significance of anti-Ro antibodies is not always consistent among different global regions. The aim of this study was to investigate the clinical characteristics of patients with anti-Ro antibodies. Methods: A total of 1596 inpatients with anti-Ro antibodies were included in the study. Demographic, clinical, and serological data were compared between individuals with different profiles of anti-Ro antibodies: patients with anti-Ro52 antibodies alone, patients with anti-Ro60 antibodies alone, and patients with combined anti-Ro52 and anti-Ro60 antibodies. Results: Of the 1596 patients, 1362 (85.3%) were female, the mean age was 45.5 years, and systemic lupus erythematosus (SLE) (46.0%) and Sjogren's syndrome (SS) (19.0%) were the most common CTD diagnoses. Among the patients with anti-Ro52 antibodies alone, idiopathic inflammatory myopathy (18.8%) and SLE (17.6%) were the most common CTD diagnoses. The coexistent autoantibodies of this group were significantly lower compared with those of the other two groups, while the presence of anti-Jo1 antibodies were significantly higher compared with those of the other two groups (3.7% vs. 0.6% vs. 1.9%, p = 0.029). In addition, the patients with isolated anti-Ro52 antibodies were more likely to suffer from interstitial lung disease (35.5% vs. 11.3% vs. 13.7%, p < 10-4) and pulmonary arterial hypertension (10.1% vs. 5.3% vs. 3.6%, p = 0.001) compared with the other two groups of patients. Compared with patients with isolated anti-Ro52 or anti-Ro60 antibodies, the patients with combined anti-Ro52 and anti-Ro60 antibodies were more likely to suffer from xerophthalmia and xerostomia. Furthermore, hypocomplementemia, hyperglobulinemia, and proteinuria were particularly prevalent in patients with anti-Ro60 antibodies. Conclusion: Different profiles of anti-Ro antibodies were significantly associated with clinical phenotypic features in CTDs, indicating the potential diagnostic and prognostic value of these antibodies in clinical practice.
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Lupus Eritematoso Sistémico , Miositis , Síndrome de Sjögren , Humanos , Femenino , Persona de Mediana Edad , Masculino , Relevancia Clínica , Anticuerpos Antinucleares , Síndrome de Sjögren/diagnóstico , Autoanticuerpos , AutoantígenosRESUMEN
A copper-catalyzed annulation of O-acyl oximes with cyclic 1,3-diones has been developed for the concise synthesis of 7,8-dihydroindolizin-5(6H)-ones and cyclohexanone-fused furans through the substituent-controlled selective radical coupling process. 2-Alkyl cyclic 1,3-diones undergo C-C radical coupling, while 2-unsubstituted cyclic 1,3-diones undergo C-O radical coupling.
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Dipeptidyl peptidase III (DPP3), a zincdependent metallopeptidase, is upregulated in a variety of malignancies. However, little is known about its roles in the pathogenesis of these malignancies. The present study was designed to investigate the roles of DPP3 in the pathogenesis and progression of oesophageal cancer (EC). The expression level of DPP3 in EC tissues and adjacent normal tissues was detected in 93 cases of tissue biopsies collected from patients diagnosed with oesophageal carcinoma by immunohistochemistry. The effect of DPP3 expression on cell proliferation, migration or apoptosis was determined in DPP3depleted EC cells created by infection with lentivirus containing short hairpin RNA specific to the human DPP3 mRNA sequence, followed by detection at the cellular level using a Celigo cell count assay, flow cytometry, woundhealing assay and Transwell assay as well as chip screening with a Human Apoptosis Antibody Array kit, which enables the quantitative detection of 43 apoptosisrelated genes. A xenograft model was applied to detect the tumour growth and invasion of DPP3depleted cancer cells in nude mice. The results revealed that DPP3 expression was elevated in EC tissues compared with adjacent nontumour tissues, and high DPP3 expression was significantly associated with poor prognosis. DPP3 depletion resulted in reduced cell proliferation and migration and enhanced cell cycle arrest and apoptosis of EC cells and led to the inhibition of tumour growth and invasion in a xenograft model. In addition, DPP3 depletion was associated with the upregulation of the proapoptotic proteins SMAC and p53 and the downregulation of the antiapoptotic proteins clAP2, IGFBP2 and TRAILR4. Finally, DPP3 may promote cell proliferation, migration and survival of EC cells in vitro and tumour growth and invasion of oesophageal carcinoma in vivo, and thus may serve as a molecular target for tumour therapy.
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Carcinoma de Células Escamosas , Neoplasias Esofágicas , Animales , Humanos , Ratones , Apoptosis/genética , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Movimiento Celular/genética , Proliferación Celular/genética , Dipeptidil-Peptidasas y Tripeptidil-Peptidasas/genética , Neoplasias Esofágicas/patología , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , PronósticoRESUMEN
Background: Coronary heart disease is one of the main causes of Mortality. Many biological indicators have been used to predict the prognosis of patients with coronary heart disease. The ratio of serum globulin to albumin (GAR) has been used to predict the prognosis of patients with various cancers. It has been proven that GAR is related to the prognosis of patients with stroke. However, GAR's role in cardiovascular disease remains unclear. Our purpose was to investigate the predictive value of GAR on clinical outcomes in post-percutaneous coronary intervention (PCI) patients with coronary artery disease (CAD). Methods: From Dec. 2016 to Oct. 2021, a total of 14,994 patients undergoing PCI patients admitted to the First Affiliated Hospital of Xinjiang Medical University were divided into high GAR group (GAR ≥ 0.76, n = 4087) and low GAR group (GAR < 0.76, n = 10,907). The incidence of adverse outcomes including all-cause mortality (ACM), cardiovascular mortality (CM), major adverse cardiovascular events (MACE) and major adverse cardiovascular and cerebrovascular events (MACCE) was compared between the two groups. Multivariate Cox regression was used to adjust for the effects of confounding factors, while hazard ratios (HRs) and 95% confidence intervals (95% CI) were calculated. Median follow-up time was 24 months. Results: Compared with the low GAR group, the high GAR group had significantly higher incidence of ACM (6.5% vs. 1.7%, p < 0.001); CM (4.9% vs. 1.2%, p < 0.001), MACE (10.5% vs. 6.7%, p < 0.001), and MACCE (11.3% vs. 7.5%, p < 0.001). Cox regression analysis showed the patients in the high GAR group had a 1.62-fold increased risk for ACM (HR = 2.622, 95% CI: 2.130-3.228, p < 0.01), a 1.782-fold increased risk for CM (HR = 2.782, 95% CI: 2.180-3.550, p < 0.01). There was a 37.2% increased risk for MACE (HR = 1.372, 95% CI: 1.204-1.564, p < 0.01), and 32.4% increased risk for MACCE (HR = 1.324, 95% CI: 1.169-1.500, p < 0.01), compared to the patients in the low GAR group. Conclusions: The present study suggested that post-PCI CAD patients with higher GAR presented significantly increased mortality and adverse events GAR level at admission may 296 be considered as part of risk stratification when PCI is possible in patients with coronary heart disease. Clinical Trial Registration: The detailed information of the PRACTICE study has been registered on http://Clinicaltrials.gov (Identifier: NCT05174143).
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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.
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Diabetes Mellitus Tipo 2 , Ácidos Grasos Omega-3 , Resistencia a la Insulina , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Proteínas Portadoras , Dieta Alta en Grasa/efectos adversos , Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos/farmacología , Ácidos Grasos Omega-3/farmacología , Glucógeno Sintasa Quinasa 3 beta , Inflamasomas/metabolismo , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ácido Palmítico/farmacología , Proteínas Proto-Oncogénicas c-akt , ARN Interferente Pequeño , Especies Reactivas de Oxígeno , TiorredoxinasRESUMEN
Strategies for treating osteoarthritis (OA) have become a research focus because an effective treatment for OA is unavailable. The objective of this study was to explore the effects and underlying mechanisms of glutamine (Gln) in OA. First, the chondrocytes were identified and a standard IL-1ß-induced OA model was established. After treatment with Gln or saline, the viability and apoptosis of chondrocytes were evaluated using a CCK-8 assay and flow cytometry analysis, which revealed that Gln can improve the IL-1ß-induced OA cells. Meanwhile, Gln can enhance the expression of aggrecan and collagen II, which are protective proteins for articular cartilage. Instead, Gln inhibited the expression of matrix metalloproteinase-1 (MMP-1) and matrix metalloproteinase-13 (MMP-13), which can degrade cartilage. To better understand the underlying mechanisms of Gln in IL-1ß-induced chondrocytes, the classical OA pathways of JNK and NF-κB were examined at the protein and mRNA levels using western blot and qRT-PCR analyses. We found that JNK and NF-κB were downregulated gradually depending on the Gln dose and protective and destructive factors changed based on changes of JNK and NF-κB. The effects of high-dose Gln were more effective than low-dose. Moreover, Gln was applied to the animal OA model to check the effects in vivo. The results showed that Gln attenuated cartilage degeneration and decreased OARSI scores, which demonstrated that Gln can improve OA. The experiments showed that Gln can benefit mice with OA by inhibiting the JNK and NF-κB signaling pathways.
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Cartílago Articular , Osteoartritis , Animales , Cartílago Articular/metabolismo , Células Cultivadas , Condrocitos/metabolismo , Modelos Animales de Enfermedad , Glutamina/metabolismo , Interleucina-1beta/metabolismo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Ratones , FN-kappa B/metabolismo , Osteoartritis/tratamiento farmacológico , Osteoartritis/metabolismo , Transducción de SeñalRESUMEN
Background: Degradation of pro-inflammatory macrophage-mediated connexin 43 (Cx43) plays an important role in post-myocardial infarction (MI) arrhythmogenesis, microRNA (miR)-155 produced by macrophages has been shown to mediate post-MI effects. We hypothesized that miR-155 inhibition attenuated MI-induced Cx43 degradation by reducing pro-inflammatory macrophage activation. Methods: MI was induced by permanent ligation of the left anterior descending coronary artery in male C57BL/6 mice. Lipopolysaccharide (LPS)-stimulated mice bone marrow-derived macrophages (BMDMs) and hypoxia-induced neonatal rat cardiomyocytes (NRCMs) were used in vitro models. qRT-PCR, Western-blot and immunofluorescence were used to analyze relevant indicators. Results: The expression levels of miR-155, interleukin-1 beta (IL-1ß), and matrix metalloproteinase (MMP)7 were higher in MI mice and LPS-treated BMDMs than in the sham/control groups, treatment with a miR-155 antagomir reversed these effects. Moreover, miR-155 inhibition reduced ventricular arrhythmias incidence and improved cardiac function in MI mice. Cx43 expression was decreased in MI mice and hypoxia-exposed NRCMs, and hypoxia-induced Cx43 degradation in NRCMs was reduced by application of conditioned medium from LPS-induced BMDMs treated with the miR-155 antagomir, but increased by conditioned medium from BMDMs treated with a miR-155 agomir. Importantly, NRCMs cultured in conditioned medium from LPS-induced BMDMs transfected with small interfering RNA against IL-1ß and MMP7 showed decreased hypoxia-mediated Cx43 degradation, and this effect also was diminished by BMDM treatment with the miR-155 agomir. Additionally, siRNA-mediated suppressor of cytokine signaling 1 (SOCS1) knockdown in LPS-induced BMDMs promoted Cx43 degradation in hypoxia-exposed NRCMs, and the effect was reduced by the miR-155 inhibition. Conclusions: MiR-155 inhibition attenuated post-MI Cx43 degradation by reducing macrophage-mediated IL-1ß and MMP7 expression through the SOCS1/nuclear factor-κB pathway.
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A copper-catalyzed annulation of α,ß-unsaturated O-acyl ketoximes with isoquinolinium N-ylides has been developed for the concise synthesis of stable N-H imines with a benzo[7,8]indolizine core. When ß-(2-bromoaryl)-α,ß-unsaturated O-acyl ketoximes are used as the starting materials, a cascade cyclization occurs to afford the benzo[7,8]indolizino[1,2-c]quinolines.
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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.
Asunto(s)
Fibrilación Atrial , Bloqueo de Rama , Anciano , Fibrilación Atrial/complicaciones , Fibrilación Atrial/epidemiología , Bloqueo de Rama/complicaciones , Bloqueo de Rama/diagnóstico , Bloqueo de Rama/epidemiología , Electrocardiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
Background: The influence of the albumin/derived neutrophil and lymphocyte ratio (ALB-dNLR) on the outcomes of patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI) is not known. Here, we aimed to determine the association between the ALB-dNLR score and post-PCI CAD patient outcomes. Methods: A total of 6,050 patients from the First Affiliated Hospital of Xinjiang Medical University were enrolled between January 2008 and December 2016. These patients were divided into three groups according to their ALB-dNLR scores (0 points, n = 1,121; 1 point, n = 3,119; 2 points, n = 1,810). Mortality after PCI [all-cause (ACM) and cardiac (CM)] was taken as the primary endpoint. The prognostic value of the ALB-dNLR score was determined with the Cox proportional hazard model after adjustment for covariates. Results: The ACM and CM rates differed among participants in the three groups (P = 0.007 and P = 0.034, respectively). Multivariate Cox analysis showed that the ALB-dNLR score independently predicted both ACM [1 point vs. 0 points, HR = 1.249 (95% CI: 0.79-1.774), P = 0.215; 2 points vs. 0 points, HR = 1.777 (95% CI: 1.239-2.549), P = 0.002] and CM [1 point vs. 0 points, HR = 1.294 (95% CI: 0.871-1.922), P = 0.202; 2 points vs. 0 points, HR = 1.782 (95% CI: 1.185-1.782), P = 0.027]. We also found that among male patients in the three groups, both ACM and CM rates differed (P = 0.006 and P = 0.017, respectively). Multivariate Cox analysis showed that the ALB-dNLR score independently predicted both ACM [1 point vs. 0 points, HR = 1.237 (95% CI: 0.806-0.330), P = 0.330; 2 points vs. 0 points, HR = 1.790 (95% CI: 1.159-2.764), P = 0.009] and CM [1 point vs. 0 points HR = 1.472 (95% CI: 0.892-2.430), P = 0.130; 2 points vs. 0 points, HR = 1.792 (95% CI: 1.182-3.289), P = 0.009]. Conclusion: The ALB-dNLR score is a credible predictor for mortality in patients with CAD who have undergone PCI.