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BACKGROUND: Hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs) and consequent pulmonary vascular remodeling are the crucial pathological features of pulmonary hypertension (PH). Protein methylation has been shown to be critically involved in PASMC proliferation and PH, but the underlying mechanism remains largely unknown. METHODS: PH animal models were generated by treating mice/rats with chronic hypoxia for 4 weeks. SMYD2-vTg mice (vascular smooth muscle cell-specific suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 (deformed epidural auto-regulatory factor-1) domain-containing protein 2 transgenic) or wild-type rats and mice treated with LLY-507 (3-cyano-5-{2-[4-[2-(3-methylindol-1-yl)ethyl]piperazin-1-yl]-phenyl}-N-[(3-pyrrolidin-1-yl)propyl]benzamide) were used to investigate the function of SMYD2 (suppressor of variegation, enhancer of zeste, trithorax and myeloid Nervy DEAF-1 domain-containing protein 2) on PH development in vivo. Primary cultured rat PASMCs with SMYD2 knockdown or overexpression were used to explore the effects of SMYD2 on proliferation and to decipher the underlying mechanism. RESULTS: We demonstrated that the expression of the lysine methyltransferase SMYD2 was upregulated in the smooth muscle cells of pulmonary arteries from patients with PH and hypoxia-exposed rats/mice and in the cytoplasm of hypoxia-induced rat PASMCs. More importantly, targeted inhibition of SMYD2 by LLY-507 significantly attenuated hypoxia-induced pulmonary vascular remodeling and PH development in both male and female rats in vivo and reduced rat PASMC hyperproliferation in vitro. In contrast, SMYD2-vTg mice exhibited more severe PH phenotypes and related pathological changes than nontransgenic mice after 4 weeks of chronic hypoxia treatment. Furthermore, SMYD2 overexpression promoted, while SMYD2 knockdown suppressed, the proliferation of rat PASMCs by affecting the cell cycle checkpoint between S and G2 phases. Mechanistically, we revealed that SMYD2 directly interacted with and monomethylated PPARγ (peroxisome proliferator-activated receptor gamma) to inhibit the nuclear translocation and transcriptional activity of PPARγ, which further promoted mitophagy to facilitate PASMC proliferation and PH development. Furthermore, rosiglitazone, a PPARγ agonist, largely abolished the detrimental effects of SMYD2 overexpression on PASMC proliferation and PH. CONCLUSIONS: Our results demonstrated that SMYD2 monomethylates nonhistone PPARγ and inhibits its nuclear translocation and activation to accelerate PASMC proliferation and PH by triggering mitophagy, indicating that targeting SMYD2 or activating PPARγ are potential strategies for the prevention of PH.
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Histona-Lisina N-Metiltransferase , Hipertensão Pulmonar , Hipóxia , Mitofagia , Músculo Liso Vascular , Miócitos de Músculo Liso , PPAR gama , Artéria Pulmonar , Ratos Sprague-Dawley , Animais , Humanos , Masculino , Camundongos , Ratos , Proliferação de Células , Células Cultivadas , Histona-Lisina N-Metiltransferase/metabolismo , Histona-Lisina N-Metiltransferase/genética , Hipertensão Pulmonar/metabolismo , Hipertensão Pulmonar/etiologia , Hipertensão Pulmonar/patologia , Hipertensão Pulmonar/genética , Hipóxia/complicações , Hipóxia/metabolismo , Metilação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , PPAR gama/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/metabolismo , Remodelação VascularRESUMO
BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.
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Aldeído-Desidrogenase Mitocondrial , Armadilhas Extracelulares , Leucotrieno C4 , Traumatismo por Reperfusão Miocárdica , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Aldeído-Desidrogenase Mitocondrial/genética , Aldeído-Desidrogenase Mitocondrial/metabolismo , Benzamidas , Benzodioxóis , Modelos Animais de Doenças , Armadilhas Extracelulares/metabolismo , Antagonistas de Leucotrienos/farmacologia , Antagonistas de Leucotrienos/uso terapêutico , Leucotrieno C4/antagonistas & inibidores , Leucotrieno C4/metabolismo , Camundongos Knockout , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/genética , Traumatismo por Reperfusão Miocárdica/metabolismo , Neutrófilos/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Infarto do Miocárdio com Supradesnível do Segmento ST/metabolismoRESUMO
The ALMT1 transporter aids malate secretion, chelating Al3+ ions to form nontoxic Al-malate complexes, believed to exclude Al from the roots. However, the extent to which malate secreted by ALMT1 is solely used for the exclusion of Al3+ or can be reutilized by plant roots for internal Al tolerance remains uncertain. In our investigation, we explored the impact of malate secretion on both external and internal Al resistance in Arabidopsis thaliana. Additionally, we delved into the mechanism by which the tonoplast-localized bacterial-type ATP-binding cassette (ABC) transporter complex STAR1/ALS3 promotes the degradation of the Al resistance transcription factor STOP1 to regulate ALMT1 expression. Our study demonstrates that the level of secreted malate influences whether the Al-malate complex is excluded from the roots or transported into root cells. The nodulin 26-like intrinsic protein (NIP) subfamily members NIP1;1 and NIP1;2, located in the plasma membrane, coordinate with STAR1/ALS3 to facilitate Al-malate transport from root apoplasm to the symplasm and eventually to the vacuoles for the internal Al detoxification. ALS3-dependent STAR1 interacts with and promotes the degradation of STOP1, regulating malate exudation. Our findings demonstrate the dual roles of malate exudation in external Al exclusion and Al absorption for internal Al detoxification.
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Optical coherence tomography (OCT) and its extension OCT angiography (OCTA) have become essential clinical imaging modalities due to their ability to provide depth-resolved angiographic and tissue structural information non-invasively and at high resolution. Within a field of view, the anatomic detail available is sufficient to identify several structural and vascular pathologies that are clinically relevant for multiple prevalent blinding diseases, including age-related macular degeneration (AMD), diabetic retinopathy (DR), and vein occlusions. The main limitation in contemporary OCT devices is that this field of view is limited due to a fundamental trade-off between system resolution/sensitivity, sampling density, and imaging window dimensions. Here, we describe a swept-source OCT device that can capture up to a 12 × 23-mm field of view in a single shot and show that it can identify conventional pathologic features such as non-perfusion areas outside of conventional fields of view. We also show that our approach maintains sensitivity sufficient to visualize novel features, including choriocapillaris morphology beneath the macula and macrophage-like cells at the inner limiting membrane, both of which may have implications for disease.
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Retinopatia Diabética , Vasos Retinianos , Humanos , Vasos Retinianos/patologia , Angiofluoresceinografia , Tomografia de Coerência Óptica/métodos , RetinaRESUMO
High-quality swept-source optical coherence tomography (SS-OCT) requires accurate k-sampling, which is equally vital for optical coherence tomography angiography (OCTA). Most SS-OCT systems are equipped with hardware-driven k-sampling. However, this conventional approach raises concerns over system cost, optical alignment, imaging depth, and stability in the clocking circuit. This work introduces an optimized numerical k-sampling method to replace the additional k-clock hardware. Using this method, we can realize high axial resolution (4.9-µm full-width-half-maximum, in air) and low roll-off (2.3â dB loss) over a 4-mm imaging depth. The high axial resolution and sensitivity achieved by this simple numerical method can reveal anatomic and microvascular structures with structural OCT and OCTA in both macular and deeper tissues, including the lamina cribrosa, suggesting its usefulness in imaging retinopathy and optic neuropathy.
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Angiografia , Tomografia de Coerência Óptica , Tomografia de Coerência Óptica/métodos , Angiofluoresceinografia/métodosRESUMO
BACKGROUND: To compare the difference of postoperative anastomotic leakage (AL) rate between neoadjuvant chemoradiotherapy (NCRT) with pembrolizumab and NCRT group, and investigate the risk factors of developing AL for locally advanced esophageal squamous cell cancer (ESCC). MATERIALS AND METHODS: The GF was contoured on the pretreatment planning computed tomography and dosimetric parameters were retrospectively calculated. Univariate and multivariate logistic regression analysis was performed to determine the independent risk predictors for the entire cohort. A nomogram risk prediction model for postoperative AL was established. RESULTS: A total of 160 ESCC patients were included for analysis. Of them, 112 were treated with NCRT with pembrolizumab and 44 patients with NCRT. Seventeen (10.6%) patients experienced postoperative AL with a rate of 10.7% (12/112) in NCRT with pembrolizumab and 11.4% (5/44) in NCRT group. For the entire cohort, mean, D50, Dmax, V5, V10 and V20 GF dose were statistically higher in those with AL (all p < 0.05). Multivariate logistic regression analysis indicated that tumor length (p = 0.012), volume of GF (p = 0.003) and mean dose of GF (p = 0.007) were independently predictors for postoperative AL. Using receiver operating characteristics analysis, the mean dose limit on the GF was defined as 14 Gy. CONCLUSION: Based on our prospective database, no significant difference of developing AL were observed between NCRT with pembrolizumab and NCRT group. We established an individualized nomograms based on mean GF dose combined with clinical indicators to predict AL in the early postoperative period.
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Fístula Anastomótica , Anticorpos Monoclonais Humanizados , Neoplasias Esofágicas , Carcinoma de Células Escamosas do Esôfago , Terapia Neoadjuvante , Humanos , Masculino , Feminino , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Pessoa de Meia-Idade , Terapia Neoadjuvante/efeitos adversos , Terapia Neoadjuvante/métodos , Fístula Anastomótica/etiologia , Fístula Anastomótica/epidemiologia , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Estudos Prospectivos , Idoso , Carcinoma de Células Escamosas do Esôfago/terapia , Carcinoma de Células Escamosas do Esôfago/patologia , Nomogramas , Fatores de Risco , Estudos Retrospectivos , Adulto , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/administração & dosagem , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologiaRESUMO
OBJECTIVE: This study aimed to evaluate the yield and applicability of expanded carrier screening and propose carrier rate screening thresholds suitable for the Chinese population by comparing the current screening panel with the American College of Medical Genetics and Genomics recommended panel of 113 genes. METHODS: Using targeted next-generation sequencing, a customized panel with 334 genes was performed on 2168 individuals without clinical phenotypes for expanded carrier screening purpose. Variant interpretation followed the American College of Medical Genetics and Genomics guidelines. Carrier rates were calculated for each identified variant and each gene. At-risk couple rates were also assessed. The yield of expanded carrier screening was evaluated through calculating cumulative carrier rate. RESULTS: Overall, 65.87% of the individuals were found to be carriers of at least 1 disease causing variants. The overall at-risk couple rate was 11.76%, of which the GJB2:c.109G > A related at-risk couple rate was 5.78%. The cumulative carrier rate of 334-panel was 65.53%. When screened genes with gene carrier rate ≥1/1000, the expanded carrier screening can cover over 90% of the cumulative carrier rate and at-risk couples. A total of 86 genes overlapped with American College of Medical Genetics and Genomics Tier-3 genes and were attributed to the cumulative carrier rate of 47.33%. CONCLUSION: Expanded carrier screening using the 334-gene panel showed high screening efficiency. A threshold of gene carrier rate ≥1/1000 is recommended for selecting carrier screening genes in the Chinese Han population. This study highlights the importance of customizing screening panels based on the ACMG Tier-3 genes in conjunction with population-specific carrier frequencies to improve the accuracy and effectiveness of expanded carrier screening.
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HYPOTHESIS: Our study investigates the reliability of deltoid tuberosity index (DTI) and DTI as a predictor of systemic osteoporosis. BACKGROUND: The proximal humerus is a common fragility fracture. Current literature suggests that poor local bone density is a significant predictor for surgical fixation failure. The DTI is a simple radiographical tool that is strongly correlates with local humeral BMD aiding surgical planning to consider adjuncts or arthroplasty. However, there is a lack of data in the reliability of assessment of DTI, as well as its correlation to systemic osteoporosis. METHODS: Respective cohort of patients with PHF treated at a trauma center in Singapore from August 2017 to July 2018 were recruited. Four raters at different levels of varying clinical seniority measured DTI using shoulder radiographs. The dual energy X-ray Absorptiometry (DEXA) bone mineral density (BMD) scan of the hip and lumbar spine was used to diagnose osteoporosis. Area under receiver operating characteristics (AUROC) analysis was conducted to study the diagnostic utility of DTI to predict the risk of osteoporosis. RESULTS: Our study had 87 patients consisting 18 males and 69 females, mainly of Chinese ethnicity (84%) and mean age of 69.7 years (SD 9.52, range 39-92yrs). For assessment of DTI, there was good intra-rater reliability amongst four raters (correlation coefficient range 0.805- 0.843) and excellent inter-rater reliability between al raters (intraclass correlation coefficient = 0.898; 95% CI 0.784-0.950, p-value <0.001). Based on BMD, 55.2% (n=48) were osteoporotic using T-score <-2.5. The highest correlation of DTI to BMD was with femoral neck density at 0.580. The DTI cut-off of 1.6 had the highest combined sensitivity and false positive rate, with area under curve (AUC) = 0.682 (95% CI, 0.564-0.799) for the overall population and AUC =0.706 (95% CI, 0.569-0.842) for patients <75 years. DISCUSSION: The DTI is a simple and reliable tool, strengthening its applicability in clinical practice to enhance preoperative planning in the surgical fixation of PHF. DTI with a cut off of 1.6 may be helpful tool prompting clinicians to workup and manage underlying osteoporosis.
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Recycling of carbon fiber-reinforced polymer composites (CFRCs) based on thermosetting plastics is difficult. In the present study, high-performance CFRCs are fabricated through complexation of aromatic pinacol-cross-linked polyurethane (PU-AP) thermosets with carbon fiber (CF) cloths. PU-AP thermosets exhibit a breaking strength of 95.5â MPa and toughness of 473.6â MJ m-3 and contain abundant hydrogen-bonding groups, which can have strong adhesion with CFs. Because of the high interfacial adhesion between CF cloths and PU-AP thermosets and high toughness of PU-AP thermosets, CF/PU-AP composites possess a high tensile strength of >870â MPa. Upon heating in N,N-dimethylacetamide (DMAc) at 100 °C, the aromatic pinacols in the CF/PU-AP composites can be cleaved, generating non-destructive CF cloths and linear polymers that can be converted to high-performance elastomers. The elastomers are mechanically robust, healable, reprocessable, and damage-resistant with an extremely high tensile strength of 74.2â MPa and fracture energy of 149.6â kJ m-2. As a result, dissociation of CF/PU-AP composites enables the recovery of reusable CF cloths and high-performance elastomers, thus realizing the upcycling of CF/PU-AP composites.
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Background: Some patients with hypertrophic obstructive cardiomyopathy (HOCM) still exhibit systolic anterior motion (SAM) and mitral regurgitation (MR) even after undergoing an isolated ventricular septectomy. Currently, there are disputes regarding whether to perform a mitral valve intervention and which type of operation is more effective. Methods: By searching PubMed, Cochrane, Embase, Web of Science, FDA.gov, and ClinicalTrials.gov, as well as other resource databases, we obtained all articles published before December 2022 on ventricular septal myectomy combined with mitral valve intervention for hypertrophic cardiomyopathy. Demographic information and outcome variable data were extracted from 10 screened studies on ventricular septal resection combined with mitral valve repair. The risk of bias was assessed using methodological index for non-randomized studies (MINORS). Student's t-test was used for comparisons of continuous variables, and the chi-square or Fisher's exact test was used for dichotomous variables. A total of 692 patients across 10 studies were analyzed. Results: There were 5 (0.7%) deaths in the perioperative period. The average cardiopulmonary bypass time was 64.7 ± 22.2 minutes, and the average follow-up time was 39.6 ± 36.3 months. Compared with baseline levels, the left ventricular outflow tract gradient (83.6 ± 32.2 mmHg vs. 11.0 ± 7.8 mmHg, p < 0.01), maximum interventricular septal thickness (22.5 ± 5.1 mm vs. 14.7 ± 5.5 mm, p < 0.01), III/IV mitral regurgitation (351/692 vs. 17/675, p < 0.01), anterior mitral leaflet (AML)-annulus ratio (0.49 ± 0.14 vs. 0.60 ± 0.12, p < 0.01), tenting area (2.72 ± 0.60 cm 2 vs. 1.95 ± 0.60 cm 2 , p < 0.01), and SAM (181/194 vs. 11/215, p < 0.01) were significantly improved. 14 (2.1%) patients were in New York Heart Association functional class III/IV, which was significantly improved compared with the preoperative state (541/692 vs. 14/682, p < 0.01). Conclusions: Ventricular septectomy combined with mitral valve repair can be a safe and effective treatment option for patients suffering from HOCM with SAM and severe MR.
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OBJECTIVES: A novel transapical beating-heart septal myectomy (TA-BSM) procedure was performed for patients with latent obstruction through the left intercostal incision and without cardiopulmonary bypass. This study aims to demonstrate the experience of the TA-BSM procedure for patients with latent obstruction and compare outcomes to patients with resting obstruction. METHODS: We studied 120 symptomatic hypertrophic obstructive cardiomyopathy patients (33 with latent obstruction and 87 with resting obstruction) who underwent TA-BSM. Demographic profiles, echocardiogram-derived ventricular morphology and haemodynamics and clinical outcomes were analysed. RESULTS: There were no important differences in baseline clinical characteristics between patients with latent obstruction and resting obstruction, including age, symptoms, comorbidities and medical history. Patients with latent obstruction had lower basal septum thickness, higher midventricular wall thickness, smaller left atrial chamber size and more frequency of mitral subvalvular anomalies. There was no difference in early (<30 days) deaths (0/33 vs 1/87, P > 0.999) and mid-term survival between patients with latent obstruction and resting obstruction. At 6 months after surgery, 31 (93.9%) patients with latent obstruction and 80 (92.0%) with resting obstruction achieved optimal procedural success, which was defined as a maximal gradient (after provocation) <30 mmHg and mitral regurgitation ≤ grade 1+ without mortality. Maximal left ventricular outflow tract gradient, basal septum thickness, midventricular wall thickness, mitral regurgitation grade and left atrial chamber size were significantly decreased after TA-BSM. In the follow-up, the New York Heart Association class was significantly improved following surgery. CONCLUSIONS: TA-BSM preserved favourable gold-standard guideline desired outcomes through real-time echocardiographic-guided resection. Equipoise of outcomes for this procedure regardless of degree of resting left ventricular outflow tract gradients supports operative management with this approach in symptomatic patients with latent obstruction.
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Procedimentos Cirúrgicos Cardíacos , Cardiomiopatia Hipertrófica , Doenças das Valvas Cardíacas , Insuficiência da Valva Mitral , Obstrução do Fluxo Ventricular Externo , Humanos , Insuficiência da Valva Mitral/cirurgia , Procedimentos Cirúrgicos Cardíacos/métodos , Septos Cardíacos/diagnóstico por imagem , Septos Cardíacos/cirurgia , Resultado do Tratamento , Obstrução do Fluxo Ventricular Externo/diagnóstico por imagem , Obstrução do Fluxo Ventricular Externo/cirurgia , Obstrução do Fluxo Ventricular Externo/etiologia , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/diagnóstico por imagem , Cardiomiopatia Hipertrófica/cirurgiaRESUMO
Background: We developed a novel minimally invasive transapical beating-heart septal myectomy (TA-BSM) procedure for patients with midventricular obstruction (MVO), without the aid of cardiopulmonary bypass. This study aims to describe the TA-BSM procedure for the relief of MVO and to detail the clinical outcomes in these patients. Methods: Sixty-one patients receiving TA-BSM for MVO were included: isolated MVO (n = 12) and combined MVO and subaortic obstruction (n = 49). We reviewed the electronic medical record to collect information on preoperative, intraoperative, and postoperative parameters. Results: The intraventricular pressure gradient after the resection was largely attenuated. On the catheter measurement, the median resting and provoked gradient decreased by 29.0 and 71.0 mm Hg, respectively. Likewise, the resting intraventricular gradient was successfully reduced from 58.0 to 11.0 mm Hg, and the maximal intraventricular gradient was reduced from 88.0 to 20.0 mm Hg at 6 months follow-up. In addition, all patients showed significantly improved MR and 37 of 42 patients with preoperative MR grade ≥2+ showed MR grade ≤1+ after TA-BSM. During the follow-up, no death was observed and no one had HCM-related rehospitalization. All patients reported improvement in symptoms and the mean New York Heart Association class improved from 3.0 (IQR, 3.0-3.0) preoperatively to 1.0 (IQR, 1.0-1.0) at 6 months follow-up. Conclusions: The TA-BSM procedure is a valuable therapy to relieve MVO, improving hemodynamics and providing satisfactory clinical outcomes. The procedure can also preserve favorable outcomes for patients with MVO and concomitant subaortic obstruction.
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DNA double-strand break (DSB) sites that prevent the disjunction of broken DNA ends are formed through poly (ADP-ribose) (PAR) polymerase 1 (PARP1)-DNA co-condensation. The co-condensates apply mechanical forces to hold the DNA ends together and generate enzymatic activity for the synthesis of PAR. PARylation can promote the release of PARP1 from DNA ends and recruit various proteins, such as Fused in sarcoma (FUS) proteins, thereby stabilizing broken DNA ends and preventing their separation.
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Quebras de DNA de Cadeia Dupla , Reparo do DNA , DNA , Poli(ADP-Ribose) Polimerase-1 , Humanos , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/metabolismo , Reparo do DNA/genética , DNA/genética , DNA/metabolismoRESUMO
A highly homogeneous microwave zero-index metamaterial based on high-permittivity SrTiO3 ceramics is demonstrated to realize the small-aperture high-directivity antenna. Such a novel technique is a remarkable step forward to develop compact devices with better performance.
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During oxidative phosphorylation, mitochondria continuously produce reactive oxygen species (ROS), and untimely ROS clearance can subject mitochondria to oxidative stress, ultimately resulting in mitochondrial damage. Mitophagy is essential for maintaining cellular mitochondrial quality control and homeostasis, with activation involving both ubiquitin-dependent and ubiquitin-independent pathways. Over the past decade, numerous studies have indicated that different forms of regulated cell death (RCD) are connected with mitophagy. These diverse forms of RCD have been shown to be regulated by mitophagy and are implicated in the pathogenesis of a variety of diseases, such as tumors, degenerative diseases, and ischemiaâreperfusion injury (IRI). Importantly, targeting mitophagy to regulate RCD has shown excellent therapeutic potential in preclinical trials, and is expected to be an effective strategy for the treatment of related diseases. Here, we present a summary of the role of mitophagy in different forms of RCD, with a focus on potential molecular mechanisms by which mitophagy regulates RCD. We also discuss the implications of mitophagy-related RCD in the context of various diseases.
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Mitofagia , Humanos , Animais , Morte Celular Regulada , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genéticaRESUMO
AIMS: We aim to investigate the causal effect of blood lipids mediating sodium-glucose cotransporter 2 (SGLT2) inhibition in cardiovascular disease (CVD) using Mendelian randomization (MR). METHODS AND RESULTS: A two-sample two-step MR study was conducted to evaluate the association of SGLT2 inhibition with CVDs and the mediation effects of blood lipids linking SGLT2 inhibition with CVDs. Genetic instruments for SGLT2 inhibition were identified as genetic variants, which were associated with the expression of the SLC5A2 gene and glycated haemoglobin level (HbA1c). SGLT2 inhibition was associated with reduced risk of heart failure (HF) (OR 0.44 [95% CI 0.32-0.61]; P = 6.0 × 10-7), atrial fibrillation (AF) (0.47 [0.37-0.61]; P = 1.81 × 10-8), coronary artery disease (CAD) (0.47 [0.30-0.73]; P = 7.46 × 10-4), myocardial infarction (MI) (0.30 [0.15-0.61]; P = 7.44 × 10-4), any stroke (AS) (0.28 [0.18-0.42]; P = 1.14 × 10-9), and ischaemic stroke (IS) (0.27 [0.17-0.44]; P = 1.97 × 10-7). Our results indicated that the proportion mediated of the mediating effect of total cholesterol was 1.7% (OR 0.99 [95% CI 0.98, 0.99], P = 0.004), 4.7% (0.96 [0.95, 0.98], P = 0.002), and 2.7% (0.97 [0.95, 0.98], P = 0.002) in the association between SGLT2 inhibition and the risk of HF, CAD, and MI, respectively. For low-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 2.2% for HF (OR 0.98 [95% CI 0.98, 0.99], P = 0.003), 8.6% for CAD (0.93 [0.91, 0.95], P = 5.74 × 10-4), and 5.0% for MI (0.95 [0.94, 0.96], P = 6.97 × 10-4). For non-high-density lipoprotein cholesterol, the proportion mediated of the mediating effect was 3.4% for HF (OR 0.98 [95% CI 0.97, 0.98], P = 4.42 × 10-6), 11.8% for CAD (0.92 [0.90, 0.93], P = 7.23 × 10-8), 5.7% for MI (0.94 [0.92, 0.95], P = 8.17 × 10-7), 1.5% for AS (0.98 [0.98, 0.99], P = 0.001), and 1.4% for IS (0.98 [0.98, 0.99], P = 0.004). CONCLUSIONS: Our study showed the association of SGLT2 inhibition with the reduced risk of CVDs and blood lipids might mediate this association.
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Diabetic retinopathy disease contains lesions (e.g., exudates, hemorrhages, and microaneurysms) that are minute to the naked eye. Determining the lesions at pixel level poses a challenge as each pixel does not reflect any semantic entities. Furthermore, the computational cost of inspecting each pixel is expensive because the number of pixels is high even at low resolution. In this work, we propose a hybrid image processing method. Simple Linear Iterative Clustering with Gaussian Filter (SLIC-G) for the purpose of overcoming pixel constraints. The SLIC-G image processing method is divided into two stages: (1) simple linear iterative clustering superpixel segmentation and (2) Gaussian smoothing operation. In such a way, a large number of new transformed datasets are generated and then used for model training. Finally, two performance evaluation metrics that are suitable for imbalanced diabetic retinopathy datasets were used to validate the effectiveness of the proposed SLIC-G. The results indicate that, in comparison to prior published works' results, the proposed SLIC-G shows better performance on image classification of class imbalanced diabetic retinopathy datasets. This research reveals the importance of image processing and how it influences the performance of deep learning networks. The proposed SLIC-G enhances pre-trained network performance by eliminating the local redundancy of an image, which preserves local structures, but avoids over-segmented, noisy clips. It closes the research gap by introducing the use of superpixel segmentation and Gaussian smoothing operation as image processing methods in diabetic retinopathy-related tasks.
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Aprendizado Profundo , Retinopatia Diabética , Fundo de Olho , Processamento de Imagem Assistida por Computador , Retinopatia Diabética/diagnóstico por imagem , Retinopatia Diabética/patologia , Humanos , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Redes Neurais de Computação , Fotografação/métodos , Interpretação de Imagem Assistida por Computador/métodos , Distribuição NormalRESUMO
Background: Acute pulmonary embolism (APE) is classified as a subset of diseases that are characterized by lung obstruction due to various types of emboli. Current clinical APE treatment using anticoagulants is frequently accompanied by high risk of bleeding complications. Recombinant hirudin (R-hirudin) has been found to have antithrombotic properties. However, the specific impact of R-hirudin on APE remains unknown. Methods: Sprague-Dawley (SD) rats were randomly assigned to five groups, with thrombi injections to establish APE models. Control and APE group rats were subcutaneously injected with equal amounts of dimethyl sulfoxide (DMSO). The APE+R-hirudin low-dose, middle-dose, and high-dose groups received subcutaneous injections of hirudin at doses of 0.25 mg/kg, 0.5 mg/kg, and 1.0 mg/kg, respectively. Each group was subdivided into time points of 2 h, 6 h, 1 d, and 4 d, with five animals per point. Subsequently, all rats were euthanized, and serum and lung tissues were collected. Following the assessment of right ventricular pressure (RVP) and mean pulmonary artery pressure (mPAP), blood gas analysis, enzyme-linked immunosorbnent assay (ELISA), pulmonary artery vascular testing, hematoxylin-eosin (HE) staining, Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) staining, immunohistochemistry, and Western blot experiments were conducted. Results: R-hirudin treatment caused a significant reduction of mPAP, RVP, and Malondialdehyde (MDA) content, as well as H2O2 and myeloperoxidase (MPO) activity, while increasing pressure of oxygen (PaO2) and Superoxide Dismutase (SOD) activity. R-hirudin also decreased wall area ratio and wall thickness to diameter ratio in APE rat pulmonary arteries. Serum levels of endothelin-1 (ET-1) and thromboxaneB2 (TXB2) decreased, while prostaglandin (6-K-PGF1α) and NO levels increased. Moreover, R-hirudin ameliorated histopathological injuries and reduced apoptotic cells and Matrix metalloproteinase-9 (MMP9), vascular cell adhesion molecule-1 (VCAM-1), p-Extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P65/P65 expression in lung tissues. Conclusion: R-hirudin attenuated pulmonary hypertension and thrombosis in APE rats, suggesting its potential as a novel treatment strategy for APE.
Assuntos
Hominidae , Hipertensão Pulmonar , Embolia Pulmonar , Trombose , Ratos , Animais , Hipertensão Pulmonar/tratamento farmacológico , Ratos Sprague-Dawley , Hirudinas/farmacologia , Peróxido de Hidrogênio/uso terapêutico , Embolia Pulmonar/complicações , Trombose/tratamento farmacológicoRESUMO
BACKGROUND: Postherpetic neuralgia (PHN) is the most common complication of varicella-zoster infection and tends to occur in older people. All patients treated with a single regimen have not achieved consistent success across all current study protocols, and multimodal combination regimens still need to be explored. METHODS: A total of 111 patients with PHN were randomly divided into drug group (group A), thoracic paravertebral nerve block group (group B), thoracic paravertebral nerve block combined with acupuncture group (group C), with 37 cases in each group. Group A: received oral gabapentin capsules and external lidocaine gel plaster; group B: combined with thoracic paravertebral nerve block based on group A; group C: combined with acupuncture based on group B. The primary outcome was effective rate, and secondary outcomes included pain sensation score (numerical rating scale), SF-36 quality of life score, and sleep quality. RESULTS: Before treatment, there were no significant differences in numerical rating scale value, SF-36 quality of life score, and sleep quality level among the 3 groups (Pâ >â .05). After 12 weeks of treatment, the total effective rate of treatment of patients in group C (91.43%) was higher than that in group B (77.14%), and significantly higher than that in group A (51.43%) (Pâ <â .05). CONCLUSION: Based on drug treatment combined with thoracic paravertebral nerve block and acupuncture, the treatment of PHN in the elderly can quickly and effectively relieve pain, improve the quality of life of patients, and improve the quality of sleep.
Assuntos
Terapia por Acupuntura , Bloqueio Nervoso , Neuralgia Pós-Herpética , Humanos , Idoso , Neuralgia Pós-Herpética/tratamento farmacológico , Qualidade de Vida , Estudos Prospectivos , Bloqueio Nervoso/métodos , AbdomeRESUMO
BACKGROUND: The cancer-associated biological mechanisms and the implementation of immunotherapy are heavily impacted by the activities of T cells, consequently influencing the effectiveness of therapeutic interventions. Nevertheless, the mechanistic actions of T-cell proliferation in response to immunotherapy and the overall prognosis of individuals diagnosed with hepatocellular carcinoma (HCC) remains insufficiently understood. The present work seeks to present a comprehensive analysis immune landscape in the context of HCC. METHODS: To achieve this objective, both clinical data and RNA sequencing data were acquired from authoritative databases such as The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). RESULTS: Through the utilization of consensus clustering techniques, distinct molecular subtypes associated with T-cell proliferation were delineated. Following this, seven genes of prognostic significance were identified via a combination of Cox and Lasso regression analyses. By integrating these genes into a prognostic signature, the predictive capability of the model was verified through an examination of internal and external datasets. Moreover, immunohistochemistry and qRT-PCR tests have verified the reliability of prognostic markers. Notably, the high-risk group exhibited elevated expression of immune checkpoint genes as well as higher benefit in terms of drug sensitivity testing, as determined by the Chi-square test (P < 0.001). The risk score derived from the prognostic signature depicted considerable efficacy in predicting the survival outcomes of HCC cases. CONCLUSIONS: Overall, prognostic markers may become valuable predictive tool for individuals diagnosed with HCC, allowing for the prediction of their prognosis as well as the assessment of their immunological condition and response to immunotherapy.