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Objective: To study the effect of predictive early nutritional care intervention on gastrointestinal function, Subjective global nutritional assessment (SGA) score, serum albumin (ALB) and high-sensitivity C-reactive protein (hs CRP), quality of life and quality of sleep in patients on maintenance haemodialysis. Methods: A total of 90 cases of maintenance hemodialysis patients in our hospital were collected from March 2020 and randomly divided into two groups of 45 cases each. The control group was cared for according to routine procedures. The study group added predictive early nutritional care intervention to this control group, i.e., nutritional personalized care was adjusted according to the patient's own disease, adherence, and comorbidities. The nursing effects, improvement of gastrointestinal function, and serum indexes when the two groups were compared. Results: Before the intervention, there was no difference between the two groups regarding the improvement of gastrointestinal function, pg-sga score, or serum indexes (P > .05). After the intervention, the gastrointestinal function, pg-sga score and serum indexes in the two groups were improved, and the calorie and protein intake, the total effective rate of gastrointestinal function improvement, ALB level and quality of life score in the control group were significantly lower than those in the study group; BMI, AC, and TSF were significantly higher compared with study group; The level of hs CRP and sleep quality score in the study group were smaller than those in the study group (P < .05). Conclusion: Through predictive early nutritional care intervention, maintenance hemodialysis patients can increase food intake and improve protein and calorie intake. In turn, it effectively improves gastrointestinal function, malnutrition and microinflammation, and improves life and sleep, which is worthy of clinical promotion.
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Interleukin 37 (IL-37), a member of the IL-1 family, is considered a suppressor of innate and adaptive immunity and, hence is a regulator of tumor immunity. However, the specific molecular mechanism and role of IL-37 in skin cancer remain unclear. Here, we report that IL-37b-transgenic mice (IL-37tg) treated with the carcinogenic 7,12-dimethylbenzoanthracene (DMBA)/12-o-tetradecylphorbol-13-acetate (TPA) exhibited enhanced skin cancer and increased tumor burden in the skin by inhibiting the function of CD103+ dendritic cells (DCs). Notably, IL-37 induced rapid phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK), and via single immunoglobulin IL-1-related receptor (SIGIRR), inhibited the long-term Akt activation. Specifically, by affecting the SIGIRR-AMPK-Akt signaling axis, which is related to the regulation of glycolysis in CD103+DCs, IL-37 inhibited their anti-tumor function. Our results show that a marked correlation between the CD103+DC signature (IRF8, FMS-like tyrosine kinase 3 ligand, CLEC9A, CLNK, XCR1, BATF3, and ZBTB46) and chemokines C-X-C motif chemokine ligand 9, CXCL10, and CD8A in a mouse model with DMBA/TPA-induced skin cancer. In a word, our results highlight that IL-37 as an inhibitor of tumor immune surveillance through modulating CD103+DCs and establishing an important link between metabolism and immunity as a therapeutic target for skin cancer.
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Glycerolipids are the most abundant lipids in microalgae, and glycerol-3-phosphate:acyl-CoA acyltransferase (GPAT) plays an important role in their biosynthesis. However, the biochemical and biological functions of algal GPAT remain poorly characterized. Here, we characterized the endoplasmic reticulum (ER)-associated GPAT of the model unicellular green alga Chlamydomonas reinhardtii (CrGPATer). Enzymatic assays indicated that CrGPATer is an sn-1 acyltransferase using a variety of acyl-CoAs as the acyl donor. Subcellular localization revealed that CrGPATer was associated with ER membranes and lipid droplets. We constructed overexpression (OE) and knockdown (KD) transgenic C. reinhardtii lines to investigate the in vivo function of CrGPATer. Lipidomic analysis indicated that CrGPATer OE enhanced the cellular content of galactolipids, especially monogalactosyldiacylglycerol, under nitrogen deficiency stress. Correspondingly, CrGPATer KD lines contained lower contents of galactolipids than the control. Feeding experiments with labeled phosphatidic acid revealed that the intermediate of the eukaryotic Kennedy pathway could be used for galactolipid biosynthesis in the chloroplasts. These results provided multiple lines of evidence that the eukaryotic Kennedy pathway mediated by CrGPATer may be involved in galactolipid biosynthesis in C. reinhardtii. OE of CrGPATer significantly increased the content of triacylglycerol and the yield of biomass. Moreover, the content and yield of 1, 3-olein-2-palmitin, a high-value lipid that can be used as an alternative for human milk fat in infant formula, were significantly enhanced in the OE transgenic lines. Taken together, this study provided insights into the biochemical and biological functions of CrGPATer and its potential as a genetic engineering target in functional lipid manufacturing.
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Galactolipídeos , Microalgas , Humanos , Aciltransferases/metabolismo , Galactolipídeos/metabolismo , Glicerol/metabolismo , Glicerol-3-Fosfato O-Aciltransferase/genética , Glicerol-3-Fosfato O-Aciltransferase/química , Glicerol-3-Fosfato O-Aciltransferase/metabolismo , Microalgas/genética , Microalgas/metabolismo , Fosfatos/metabolismo , Plantas/metabolismo , Triglicerídeos/metabolismo , Metabolismo dos LipídeosRESUMO
Cheap and available formate can be seen formally as a carbon dioxide radical anion (CO2â¢-) combined with a hydrogen atom, where the CO2â¢- is not only a highly active radical but also a very powerful reductant. In this paper, we successfully realized a visible-light-driven carboxylation of benzyl bromides with carbon dioxide to prepare high-value arylacetic acids using potassium formate as a terminal reductant. This reaction is characterized by mild reaction conditions and a wide range of substrates. Moreover, under nitrogen atmosphere, the reaction can also achieve the carboxylation of benzyl bromides utilizing an excess of potassium formate. Mechanistic experiments indicate this carboxylation proceeded through CO2â¢-, which was generated from the oxidation of 1,4-diazabicyclo[2.2.2]octane with excited photosensitizer Ir(ppy)2(dtbbpy)PF6 in the presence of the potassium formate.
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[This corrects the article DOI: 10.3389/fcimb.2021.701820.].
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Patients with psoriasis tend to have significant comorbidities, such as hyperlipemia, diabetes mellitus, and obesity, which belong to metabolic disorders. The specific mechanism through which psoriasis increases the metabolic disorder risk is uncertain. In this study, we demonstrated that the dysbiotic gut microbiota of 6-month-old psoriasis-like model mice (K14-VEGF-A-transgenic) exacerbated psoriasis disease and induced metabolic disorder when transferred into 2-month-old mice. By 16S rRNA gene sequencing, we confirmed that the Parabacteroides distasonis decreased with age in K14-VEGF mice, and P. distasonis also decreased in the transferred mice. Metabolomic screening identified an altered bile acid profile, including a decrease in chenodeoxycholic acid (CDCA) in the feces of transferred mice. Additionally, CDCA supplements prevented metabolic disorders in K14-VEGF-A-transgenic mice. Consequently, we found that aberrant bile acid metabolism may contribute to metabolic disorder in K14-VEGF-A-transgenic mice, indicating the possibility to prevent and treat the metabolic disorder in psoriasis mice by targeting gut microbial metabolites.
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Photoredox-catalyzed three-component fluorodifluoroacetylation of aromatic alkenes is reported, which features a wide substrate scope and functional group tolerance. An advantage of the reaction is the use of a nucleophilic fluoride source and a general difluoroacetylation reagent for the fluorodifluoroacetylation of alkenes.
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Alcenos , CatáliseRESUMO
Interleukin-37b (hereafter called IL-37) was identified as fundamental inhibitor of natural and acquired immunity. The molecular mechanism and function of IL-37 in colorectal cancer (CRC) has been elusive. Here, we found that IL-37 transgenic (IL-37tg) mice were highly susceptible to colitis-associated colorectal cancer (CAC) and suffered from dramatically increased tumor burdens in colon. Nevertheless, IL-37 is dispensable for intestinal mutagenesis, and CRC cell proliferation, apoptosis, and migration. Notably, IL-37 dampened protective cytotoxic T cell-mediated immunity in CAC and B16-OVA models. CD8+ T cell dysfunction is defined by reduced retention and activation as well as failure to proliferate and produce cytotoxic cytokines in IL-37tg mice, enabling tumor evasion of immune surveillance. The dysfunction led by IL-37 antagonizes IL-18-induced proliferation and effector function of CD8+ T cells, which was dependent on SIGIRR (single immunoglobulin interleukin-1 receptor-related protein). Finally, we observed that IL-37 levels were significantly increased in CRC patients, and positively correlated with serum CRC biomarker CEA levels, but negatively correlated with the CD8+ T cell infiltration in CRC patients. Our findings highlight the role of IL-37 in harnessing antitumor immunity by inactivation of cytotoxic T cells and establish a new defined inhibitory factor IL-37/SIGIRR in cancer-immunity cycle as therapeutic targets in CRC.
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Carcinogênese/imunologia , Colite/imunologia , Neoplasias Colorretais/imunologia , Interleucina-1/imunologia , Proteínas de Neoplasias/imunologia , Receptores de Interleucina-1/imunologia , Linfócitos T Citotóxicos/imunologia , Animais , Carcinogênese/genética , Colite/genética , Colite/patologia , Neoplasias Colorretais/genética , Interleucina-1/genética , Camundongos , Camundongos Transgênicos , Proteínas de Neoplasias/genética , Receptores de Interleucina-1/genéticaRESUMO
AIMS: After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils and monocytes/macrophages to myocardium, which in turn initiates inflammatory and reparative cascades, respectively. Either insufficient or excessive inflammation impairs cardiac healing. As an endogenous inhibitor of neutrophil adhesion, EDIL3 plays a crucial role in inflammatory regulation. However, the role of EDIL3 in MI remains obscure. We aimed to define the role of EDIL3 in cardiac remodelling after MI. METHODS AND RESULTS: Serum EDIL3 levels in MI patients were negatively associated with MI biomarkers. Consistently, WT mice after MI showed low levels of cardiac EDIL3. Compared with WT mice, Edil3-/- mice showed improvement of post-MI adverse remodelling, as they exhibited lower mortality, better cardiac function, shorter scar length, and smaller LV cavity. Accordingly, infarcted hearts of Edil3-/- mice contained fewer cellular debris and lower amounts of fibrosis content, with decreased collagen I/III expression and the percentage of α-smooth muscle actin myofibroblasts. Mechanistically, EDIL3 deficiency did not affect the recruitment of monocytes or T cells, but enhanced neutrophil recruitment and following expansion of pro-inflammatory Mertk-MHC-IIlo-int (myeloid-epithelial-reproductive tyrosine kinase/major histocompatibility complex II) macrophages. The injection of neutrophil-specific C-X-C motif chemokine receptor 2 antagonist eliminated the differences in macrophage polarization and cardiac function between WT and Edil3-/- mice after MI. Neutrophil extracellular traps (NETs), which were more abundant in the hearts of Edil3-/- mice, contributed to Mertk-MHC-IIlo-int polarization via Toll-like receptor 9 pathway. The inhibition of NET formation by treatment of neutrophil elastase inhibitor or DNase I impaired macrophage polarization, increased cellular debris and aggravated cardiac adverse remodelling, thus removed the differences of cardiac function between WT and Edil3-/- mice. Totally, EDIL3 plays an important role in NET-primed macrophage polarization and cardiac remodelling during MI. CONCLUSION: We not only reveal that EDIL3 deficiency ameliorates adverse cardiac healing via NET-mediated pro-inflammatory macrophage polarization but also discover a new crosstalk between neutrophil and macrophage after MI.
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Proteínas de Ligação ao Cálcio , Moléculas de Adesão Celular , Armadilhas Extracelulares , Macrófagos , Infarto do Miocárdio , Remodelação Ventricular , Animais , Biomarcadores/sangue , Proteínas de Ligação ao Cálcio/sangue , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Proteínas de Ligação ao Cálcio/metabolismo , Moléculas de Adesão Celular/sangue , Moléculas de Adesão Celular/deficiência , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Armadilhas Extracelulares/genética , Armadilhas Extracelulares/metabolismo , Humanos , Macrófagos/metabolismo , Macrófagos/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Infarto do Miocárdio/sangue , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Remodelação Ventricular/genética , Remodelação Ventricular/fisiologia , c-Mer Tirosina Quinase/metabolismoRESUMO
[This corrects the article DOI: 10.3389/fcimb.2021.701820.].
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Cleavage of dimethylsulfoniopropionate (DMSP) can deter herbivores in DMSP-producing eukaryotic algae; however, it is unclear whether a parallel defence mechanism operates in marine bacteria. Here we demonstrate that the marine bacterium Puniceibacterium antarcticum SM1211, which does not use DMSP as a carbon source, has a membrane-associated DMSP lyase, DddL. At high concentrations of DMSP, DddL causes an accumulation of acrylate around cells through the degradation of DMSP, which protects against predation by the marine ciliate Uronema marinum. The presence of acrylate can alter the grazing preference of U. marinum to other bacteria in the community, thereby influencing community structure.
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Acrilatos/metabolismo , Cilióforos/fisiologia , Rhodobacteraceae/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Liases de Carbono-Enxofre/genética , Liases de Carbono-Enxofre/metabolismo , Cilióforos/microbiologia , Rhodobacteraceae/enzimologia , Rhodobacteraceae/genética , Água do Mar/microbiologia , Compostos de Sulfônio/metabolismoRESUMO
Infection with Japanese encephalitis virus (JEV) induces high morbidity and mortality, including potentially permanent neurological sequelae. However, the mechanisms by which viruses cross the blood-brain barrier (BBB) and invade into the central nervous system (CNS) remain unclear. Here, we show that extracellular HMGB1 facilitates immune cell transmigration. Furthermore, the migration of immune cells into the CNS dramatically increases during JEV infection which may enhance viral clearance, but paradoxically expedite the onset of Japanese encephalitis (JE). In this study, brain microvascular endothelial cells (BMECs) were utilized for the detection of HMGB1 release, and leucocyte, adhesion, and the integrity of the BBB in vitro. Genetically modified JEV-expressing EGFP (EGFP-JEV) and the BBB model were established to trace JEV-infected immune cell transmigration, which mimics the process of viral neuroinfection. We find that JEV causes HMGB1 release from BMECs while increasing adhesion molecules. Recombinant HMGB1 enhances leukocyte-endothelium adhesion, facilitating JEV-infected monocyte transmigration across endothelia. Thus, JEV successfully utilizes infected monocytes to spread into the brain, expanding inside of the brain, and leading to the acceleration of JE onset, which was facilitated by HMGB1. HMGB1-promoted monocyte transmigration may represent the mechanism of JEV neuroinvasion, revealing potential therapeutic targets.
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Vírus da Encefalite Japonesa (Espécie)/patogenicidade , Encefalite Japonesa/imunologia , Proteína HMGB1 , Monócitos/citologia , Animais , Encéfalo , Adesão Celular , Movimento Celular , Modelos Animais de Doenças , Células Endoteliais , Endotélio , Feminino , Camundongos Endogâmicos C57BL , Internalização do VírusRESUMO
The MeOTf/KI-catalyzed synthesis of 2-arylnaphthalene derivatives from aryl ethylene oxides in alcohol under ambient conditions is described. The present protocol has a higher atom efficiency and wider substrate applicability with excellent yields. The reaction proceeded using the aryl ethylene oxides to give 2-arylnaphthalenes either in homo-coupling or in cross-coupling. The reaction could also be carried out at the gram scale in minutes.
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Psoriasis is an immune-mediated systemic disease with associated comorbidities, including metabolic syndrome (MetS) which contributes substantially to premature mortality in patients with psoriasis. However, the pathological mechanisms underlying this comorbidity are unclear. Studies have shown that the pathological parameters of psoriasis mediate the development of MetS. We reviewed the potential mechanisms which mediate the association between psoriasis and MetS, including endoplasmic reticulum stress, pro-inflammatory cytokine releases, excess production of reactive oxygen species, alterations in adipocytokine levels and gut microbiota dysbiosis. Here, we highlight important research questions regarding this association and offer insights into MetS research and treatment.
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Síndrome Metabólica/etiologia , Psoríase/complicações , Adipocinas/fisiologia , Citocinas/fisiologia , Estresse do Retículo Endoplasmático , Microbioma Gastrointestinal , Humanos , Síndrome Metabólica/metabolismo , Estresse Oxidativo , Psoríase/metabolismoRESUMO
BACKGROUND AND OBJECTIVE: Systematically review the current published literature on the impact of exercise training (ET) in chronic heart failure (CHF) patients who were conducted cardiac resynchronization therapy (CRT). METHODS: PubMed, EMBASE, and the Cochrane Library of Controlled Trails databases were searched for trials comparing the additional effects of ET in CHF patients after CRT implantation with no exercise or usual care control up until 2020.03.07. We independently screened the literature, extracted data, employed the tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX) to evaluate study quality and risk of bias, and performed meta-analysis with Revman 5.3 software. RESULTS: Eight trials were identified for qualitative analysis and 7 randomized controlled trails (RCTs) included 235 participants (120 ET; 115 controls) for quantitative analysis. The results showed that the maximal workload (mean difference [MD] 26.32âW, 95% CI 19.41-33.23; Pâ<â.00001, I2â=â0%) and the exercise duration (MD 68.95âseconds, 95% CI 15.41-122.48; Pâ=â.01, I2â=â76%) had significant improvement in the ET group versus control. Subgroup analysis showed that compared with control, the change in peak oxygen uptake (VO2) (MD 3.05âml/kg/minute, 95% CI 2.53-3.56; Pâ<â.00001, I2â=â0%), left ventricular ejection fraction (LVEF) (MD 4.97%, 95% CI 1.44-8.49; Pâ=â.006, I2â=â59%), and health related quality of life (HRQoL) (the change in Minnesota living with heart failure questionnaire [MLHFQ]: MD -19.96, 95% CI -21.57 to -18.34; Pâ<â.00001, I2â=â0%) were significantly improved in the light to moderate intensity training (non-HIT) group, while there seemed no statistical difference of above endpoints in the high intensity training (HIT) group. CONCLUSION: During the short term (up to 6âmonths), non-HIT could improve exercise capacity, cardiac function, and HRQoL in CHF patients with CRT. However, due to the small number of participants, a high-quality large-sample multicenter trial is demanded.
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Reabilitação Cardíaca/métodos , Terapia de Ressincronização Cardíaca/métodos , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Insuficiência Cardíaca/reabilitação , Idoso , Doença Crônica , Tolerância ao Exercício , Feminino , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Volume Sistólico/fisiologia , Resultado do Tratamento , Função Ventricular Esquerda/fisiologiaRESUMO
INTRODUCTION: Hemodynamically-instable ventricular arrhythmias (VAs) are rare in patients with pulmonary hypertension (PH). To the best of our knowledge, only 1 case has been reported so far. Moreover, the pathogenesis of this kind of arrhythmia remains obscured and its treatment is challenging. Here we report another case and presented the substrate for VAs initiation and therapeutic effect of radiofrequency ablation. PATIENT CONCERNS: This is a 57-year-old man who presented paroxysmal palpitation associated with presyncope at rest. Surface electrocardiogram (ECG) revealed frequent ventricular premature contractions and non-sustained ventricular tachycardia when symptoms occurred. He also had a history of severe PH which was secondary to atrial septal defect and partial anomalous pulmonary venous drainage and suffered from obvious dyspnea when climbing stairs World Health Organization Class III (WHO Class III). DIAGNOSIS: Hemodynamically-instable VAs associated with severe PH. INTERVENTION: Echocardiography revealed enlargement of right ventricle (right ventricle [RV]: 43âmm). Electrophysiological examination showed the origin of VAs is next to a small low-voltage zone of RV. Radiofrequency delivery at the origin successfully terminated VAs without occurrence of complication. OUTCOME: The patient was free from arrhythmias and got an improvement of exercise tolerance, just with mild dyspnea when climbing stairs World Health Organization Class II (WHO class II), during six-month follow up. LESSONS: This case suggests the low-voltage zone of remodeled RV, which may be secondary to increased pulmonary artery pressure, serves as the substrate for VAs initiation in patient with PH. Radiofrequency ablation can successfully terminate VAs and the termination of VAs can significantly improve the patient's impaired exercise tolerance.
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Hipertensão Pulmonar/complicações , Ablação por Radiofrequência/métodos , Complexos Ventriculares Prematuros/complicações , Ecocardiografia , Técnicas Eletrofisiológicas Cardíacas/métodos , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/fisiopatologia , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Complexos Ventriculares Prematuros/fisiopatologia , Complexos Ventriculares Prematuros/terapia , Remodelação VentricularRESUMO
The bulk of neutral lipids, including astaxanthin esters and triacylglycerols (TAGs), are accumulated in the green microalga Haematococcus pluvialis under high light (HL) stress. In this study, a novel bifunctional wax ester synthase (WS) gene was cloned from H. pluvialis upon HL stress. The overexpression of HpWS restored the biosynthesis of wax esters and TAGs in neutral lipid-deficient yeast mutant Saccharomyces cerevisiae H1246 fed with C18 alcohol and C18:1/C18:3 fatty acids, respectively. Under HL stress, HpWS was substantially upregulated at the transcript level, prior to that of the type I diacylglycerol:acyl-CoA acyltransferase encoding gene (HpDGAT1). HpDGAT1 is the major TAG synthase in H. pluvialis. In addition, the application of xanthohumol (a DGAT1/2 inhibitor) in the H. pluvialis cells did not completely eliminate the TAG biosynthesis under HL stress at 24 h. These results indicated that HpWS may contribute to the accumulation of TAGs in H. pluvialis at the early stage under HL stress. In addition, the overexpression of HpWS in Chlamydomonas reinhardtii bkt5, which is engineered to produce free astaxanthin, enhanced the production of TAGs and astaxanthin. Our findings broaden the understanding of TAG biosynthesis in microalgae and provide a new molecular target for genetic manipulation in biotechnological applications.
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BACKGROUND: Although outflow tract (OT) ventricular arrhythmias (VAs) are generally regarded as benign, the relationship between circulation pressure and VAs has received considerable attention in recent years. Previous studies have shown that the ratio of main pulmonary artery (MPA) to ascending aorta (AA) diameter is associated with pulmonary pressure. Here, we investigated whether an elevated MPA/AA ratio is associated with right ventricular OT (RVOT) VAs. METHODS: A total of 67 patients with OT VAs (47 patients with RVOT and 20 patients with LVOT) who underwent cardiac multidetector computed tomography and radiofrequency ablation were enrolled in this study. MPA and AA diameters were measured at the level of the bifurcation of the pulmonary artery. According to the MPA/AA ratio, patients were further divided into two groups: the MPA/AA ratio abnormal group (n = 19), which is defined as MPA/AA ratio ≥ 0.9, and the MPA/AA ratio normal group (n = 48) consisting of patients with an MPA/AA ratio < 0.9. RESULTS: Patients with RVOT VAs exhibited an elevated MPA/AA ratio (0.84 ± 0.11 vs. 0.75 ± 0.11, p = 0.006). Furthermore, this MPA/AA ratio was shown to be an independent predictor for RVOT VAs (p = 0.013, 95% confidence interval: 1.016-1.145), with an abnormal MPA/AA ratio increasing the odds of RVOT VAs 5.1-fold in patients with OT VAs. CONCLUSION: Patients with RVOT VAs exhibited significantly higher MPA/AA ratios compared with those LVOT VAs. The MPA/AA ratio was showed to be an independent predictor RVOT VAs.
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Ablação por Cateter , Taquicardia Ventricular , Aorta/diagnóstico por imagem , Eletrocardiografia , Ventrículos do Coração/diagnóstico por imagem , Ventrículos do Coração/cirurgia , Humanos , Artéria Pulmonar/diagnóstico por imagem , Taquicardia Ventricular/cirurgiaRESUMO
The precise mechanism through which macroautophagy/autophagy affects psoriasis is poorly understood. Here, we found that keratinocyte (KC) autophagy, which was positively correlated with psoriatic severity in patients and mouse models and could be inhibited by mitogen-activated protein kinase (MAPK) family inactivation. The impairment of autophagic flux alleviated psoriasisform inflammation. We also found that an autophagy-based unconventional secretory pathway (autosecretion) dependent on ATG5 (autophagy related 5) and GORASP2 (golgi reassembly stacking protein 2) promoted psoriasiform KC inflammation. Moreover, the alarmin HMGB1 (high mobility group box 1) was more effective than other autosecretory proteins in regulating psoriasiform cutaneous inflammation. HMGB1 neutralization in autophagy-efficient KCs eliminated the differences in psoriasiform inflammation between Krt14+/+-Atg5f/f KCs and Krt14Cre/+-atg5f/f KCs, and conversely, recombinant HMGB1 almost completely restored psoriasiform inflammation in Krt14Cre/+-atg5f/f KCs in vivo. These results suggest that HMGB1-associated autosecretion plays a pivotal role in cutaneous inï¬ammation. Finally, we demonstrated that Krt14Cre/+-hmgb1f/f mice displayed attenuated psoriatic inï¬ammation due to the essential crosstalk between KC-specific HMGB1-associated autosecretion and γδT cells. Thus, this study uncovered a novel autophagy mechanism in psoriasis pathogenesis, and the findings imply the clinical significance of investigating and treating psoriasis.Abbreviations: 3-MA: 3-methyladenine; ACTB: actin beta; AGER: advanced glycosylation end-product specific receptor; Anti-HMGB1: anti-HMGB1 neutralizing antibody; Anti-IL18: anti-IL18 neutralizing antibody; Anti-IL1B: anti-IL1B neutralizing antibody; ATG5: autophagy related 5; BAF: bafilomycin A1; BECN1: beclin 1; CASP1: caspase 1; CCL: C-C motif chemokine ligand; CsA: cyclosporine A; ctrl shRNA: lentivirus harboring shRNA against control; CXCL: C-X-C motif chemokine ligand; DCs: dendritic cells; DMEM: dulbecco's modified Eagle's medium; ELISA: enzyme-linked immunosorbent assay; EM: electron microscopy; FBS: fetal bovine serum; GORASP2 shRNA: lentivirus harboring shRNA against GORASP2; GORASP2/GRASP55: golgi reassembly stacking protein 2; GR1: a composite epitope between LY6 (lymphocyte antigen 6 complex) locus C1 and LY6 locus G6D antigens; H&E: hematoxylin and eosin; HMGB1: high mobility group box 1; HMGB1 shRNA: lentivirus harboring shRNA against HMGB1; IFNG/IFN-γ: interferon gamma; IL17A: interleukin 17A; IL18: interleukin 18; IL1A/IL-1α: interleukin 1 alpha; IL1B/IL-1ß: interleukin 1 beta; IL22/IL-22: interleukin 22; IL23A: interleukin 23 subunit alpha; IL23R: interleukin 23 receptor; IMQ: imiquimod; ITGAM/CD11B: integrin subunit alpha M; ITGAX/CD11C: integrin subunit alpha X; IVL: involucrin; KC: keratinocyte; KD: knockdown; KO: knockout; Krt14+/+-Atg5f/f mice: mice bearing an Atg5 flox allele, in which exon 3 of the Atg5 gene is flanked by two loxP sites; Krt14+/+-Hmgb1f/f: mice bearing an Hmgb1 flox allele, in which exon 2 to 4 of the Hmgb1 gene is flanked by two loxP sites; Krt14Cre/+-atg5f/f mice: keratinocyte-specific atg5 knockout mice generated by mating Atg5-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt4; Krt14Cre/+-hmgb1f/f mice: keratinocyte-specific hmgb1 knockout mice generated by mating Hmgb1-floxed mice with mice expressing Cre recombinase under the control of the promoter of Krt14; Krt14-Vegfa mice: mice expressing 164-amino acid Vegfa splice variant recombinase under the control of promoter of Krt14; LAMP1: lysosomal associated membrane protein 1; LDH: lactate dehydrogenase; LORICRIN: loricrin cornified envelope precursor protein; M5: TNF, IL1A, IL17A, IL22 and OSM in combination; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MKI67: marker of proliferation Ki-67; MTT: thiazolyl blue tetrazolium bromide; NFKB/NF-κB: nuclear factor kappa B; NHEKs: primary normal human epidermal keratinocytes; NS: not significant; OSM: oncostatin M; PASI: psoriasis area and severity index; PtdIns3K: class III phosphatidylinositol 3-kinase; qRT-PCR: quantitative RT-PCR; RELA/p65: RELA proto-oncogene, NF-kB subunit; rHMGB1: recombinant HMGB1; rIL18: recombinant interleukin 18; rIL1B: recombinant interleukin 1 beta; S100A: S100 calcium binding protein A; SQSTM1/p62: sequestosome 1; T17: IL17A-producing T; TCR: T-cell receptor; tcrd KO mice: tcrd (T cell receptor delta chain) knockout mice, which show deficient receptor expression in all adult lymphoid and epithelial organs; TLR: toll-like receptor; TNF/TNF-α: tumor necrosis factor; WOR: wortmannin; WT: wild-type; γδT17 cells: IL17A-producing γδ T cells.
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Autofagia/fisiologia , Proteína HMGB1/metabolismo , Inflamação/metabolismo , Queratinócitos/metabolismo , Animais , Proteína 5 Relacionada à Autofagia/metabolismo , Interleucina-1beta/metabolismo , Camundongos Transgênicos , NF-kappa B/metabolismo , Proto-Oncogene MasRESUMO
PURPOSE: In radiofrequency ablation near coronary arteries (CA), coronary angiography is traditionally recommended to estimate distance between catheter and CA. This study aimed to investigate the feasibility of an alternative approach for intuitively demonstrating spatial location of catheter and CA during ablation of ventricular arrhythmias (VAs) originating from aortic root (AR) and great cardiac vein (GCV). METHODS: During mapping and ablation, 3D-reconstructed cardiac CT and electroanatomic mapping were merged, and distance between CA and catheter was monitored. Coronary angiography, for distance verification, was used when the distance was less than 5 mm in image integration model (IIM). RESULTS: Twenty-three patients (52.26 ± 17.89 years, 12 men) with ablation originating in left cusp (LCC, n = 8), right cusp (n = 2), and left-right cusp junction (LCC-RCC, n = 12) and GCV (n = 1) were enrolled. In IIM, the distance between origin and CA was less than 5 mm in 2 VAs originating in LCC and one in GCV (3/23), whereas distance for ablation was always safe (12.3-22.3 mm) for VAs of LCC-RCC origin. IIM avoided angiography use in 20 patients, reducing radiation exposure by 80.6% (650.18 ± 624.31 vs 3356.97 ± 1529.46uGycm2, P = 0.088). VA termination failed in two cases of LCC origin due to proximity to CA, and was achieved in all other patients (91.3%). No CA damage occurred during the procedures. CONCLUSION: Mapping and ablation under IIM guidance of VAs of AR and GCV origin appears feasible and safe, while avoiding angiography use particularly in VAs of LCC-RCC origin.