RESUMEN
Self-supervised learning plays an important role in molecular representation learning because labeled molecular data are usually limited in many tasks, such as chemical property prediction and virtual screening. However, most existing molecular pre-training methods focus on one modality of molecular data, and the complementary information of two important modalities, SMILES and graph, is not fully explored. In this study, we propose an effective multi-modality self-supervised learning framework for molecular SMILES and graph. Specifically, SMILES data and graph data are first tokenized so that they can be processed by a unified Transformer-based backbone network, which is trained by a masked reconstruction strategy. In addition, we introduce a specialized non-overlapping masking strategy to encourage fine-grained interaction between these two modalities. Experimental results show that our framework achieves state-of-the-art performance in a series of molecular property prediction tasks, and a detailed ablation study demonstrates efficacy of the multi-modality framework and the masking strategy.
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Aprendizaje Automático Supervisado , Algoritmos , Biología Computacional/métodosRESUMEN
Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and ß-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both ß-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs, and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.
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Aneurisma de la Aorta Torácica , Disección de la Aorta Torácica , Factores de Transcripción de Tipo Kruppel , Miocitos del Músculo Liso , Factores de Transcripción , Animales , Humanos , Masculino , Ratones , Angiotensina II/metabolismo , Angiotensina II/farmacología , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/patología , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Muscular/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Músculo Liso Vascular/citología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Fenotipo , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: Abdominal aortic aneurysm (AAA) is a potentially life-threatening vascular condition, but approved medical therapies to prevent AAA progression and rupture are currently lacking. Sphingolipid metabolism disorders are associated with the occurrence and development of AAA. It has been discovered that ganglioside GM3, a sialic acid-containing type of glycosphingolipid, plays a protective role in atherosclerosis, which is an important risk factor for AAA; however, the potential contribution of GM3 to AAA development has not been investigated. METHODS: We performed a metabolomics study to evaluated GM3 level in plasma of human patients with AAA. We profiled GM3 synthase (ST3GAL5) expression in the mouse model of aneurysm and human AAA tissues through Western blotting and immunofluorescence staining. RNA sequencing, affinity purification and mass spectrometry, proteomic analysis, surface plasmon resonance analysis, and functional studies were used to dissect the molecular mechanism of GM3-regulating ferroptosis. We conditionally deleted and overexpressed St3gal5 in smooth muscle cells (SMCs) in vivo to investigate its role in AAA. RESULTS: We found significantly reduced plasma levels of GM3 in human patients with AAA. GM3 content and ST3GAL5 expression were decreased in abdominal aortic vascular SMCs in patients with AAA and an AAA mouse model. RNA sequencing analysis showed that ST3GAL5 silencing in human aortic SMCs induced ferroptosis. We showed that GM3 interacted directly with the extracellular domain of TFR1 (transferrin receptor 1), a cell membrane protein critical for cellular iron uptake, and disrupted its interaction with holo-transferrin. SMC-specific St3gal5 knockout exacerbated iron accumulation at lesion sites and significantly promoted AAA development in mice, whereas GM3 supplementation suppressed lipid peroxidation, reduced iron deposition in aortic vascular SMCs, and markedly decreased AAA incidence. CONCLUSIONS: Together, these results suggest that GM3 dysregulation promotes ferroptosis of vascular SMCs in AAA. Furthermore, GM3 may constitute a new therapeutic target for AAA.
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Aneurisma de la Aorta Abdominal , Ferroptosis , Humanos , Ratones , Animales , Gangliósido G(M3)/metabolismo , Proteómica , Músculo Liso Vascular/metabolismo , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/prevención & control , Aneurisma de la Aorta Abdominal/metabolismo , Hierro , Miocitos del Músculo Liso/metabolismo , Modelos Animales de EnfermedadRESUMEN
Mosquitoes bring global health problems by transmitting parasites and viruses such as malaria and dengue. Unfortunately, current insecticide-based control strategies are only moderately effective because of high cost and resistance. Thus, scalable, sustainable, and cost-effective strategies are needed for mosquito-borne disease control. Symbiont-based and genome engineering-based approaches provide new tools that show promise for meeting these criteria, enabling modification or suppression approaches. Symbiotic bacteria like Wolbachia are maternally inherited and manipulate mosquito host reproduction to enhance their vertical transmission. Genome engineering-based gene drive methods, in which mosquitoes are genetically altered to spread drive alleles throughout wild populations, are also proving to be a potentially powerful approach in the laboratory. Here, we review the latest developments in both symbionts and gene drive-based methods. We describe some notable similarities, as well as distinctions and obstacles, relating to these promising technologies.
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Culicidae , Tecnología de Genética Dirigida , Malaria , Wolbachia , Animales , Culicidae/genética , Malaria/genética , Malaria/prevención & control , Mosquitos Vectores/genética , Wolbachia/genéticaRESUMEN
Excessive deposition of extracellular matrix, mainly collagen protein, is the hallmark of organ fibrosis. The molecular mechanisms regulating fibrotic protein biosynthesis are unclear. Here, we find that chemoattractant receptor homologous molecule expressed on TH2 cells (CRTH2), a plasma membrane receptor for prostaglandin D2, is trafficked to the endoplasmic reticulum (ER) membrane in fibroblasts in a caveolin-1-dependent manner. ER-anchored CRTH2 binds the collagen mRNA recognition motif of La ribonucleoprotein domain family member 6 (LARP6) and promotes the degradation of collagen mRNA in these cells. In line, CRTH2 deficiency increases collagen biosynthesis in fibroblasts and exacerbates injury-induced organ fibrosis in mice, which can be rescued by LARP6 depletion. Administration of CRTH2 N-terminal peptide reduces collagen production by binding to LARP6. Similar to CRTH2, bumetanide binds the LARP6 mRNA recognition motif, suppresses collagen biosynthesis, and alleviates bleomycin-triggered pulmonary fibrosis in vivo. These findings reveal a novel anti-fibrotic function of CRTH2 in the ER membrane via the interaction with LARP6, which may represent a therapeutic target for fibrotic diseases.
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Autoantígenos/metabolismo , Colágeno/antagonistas & inhibidores , Cirrosis Hepática/prevención & control , Fibrosis Pulmonar/prevención & control , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Ribonucleoproteínas/metabolismo , Animales , Bleomicina , Tetracloruro de Carbono , Células Cultivadas , Colágeno/biosíntesis , Colágeno/genética , Retículo Endoplásmico/metabolismo , Fibroblastos/metabolismo , Membranas Intracelulares/metabolismo , Isoproterenol , Hígado/metabolismo , Hígado/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones Transgénicos , Miocardio/metabolismo , Miocardio/patología , Unión Proteica , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Receptores Inmunológicos/genética , Receptores de Prostaglandina/genética , Antígeno SS-BRESUMEN
Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra-tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single-cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease-free survival. Further analysis identified that APP-CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra-tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
RESUMEN
High CXCL16 levels during acute cardiovascular events increase long-term mortality. However, the mechanistic role of CXCL16 in myocardial infarction (MI) is unknown. Here we investigated the role of CXCL16 in mice with MI injury. CXCL16 deficiency increased the survival of mice after MI injury, and inactivation of CXCL16 resulted in improved cardiac function and decreased infarct size. Hearts from CXCL16 inactive mice exhibited decreased infiltration of Ly6Chigh monocytes. In addition, CXCL16 promoted the macrophage expression of CCL4 and CCL5. Both CCL4 and CCL5 stimulated Ly6Chigh monocyte migration, and CXCL16 inactive mice had a reduced expression of CCL4 and CCL5 in the heart after MI. Mechanistically, CXCL16 promoted CCL4 and CCL5 expression by activating the NF-κB and p38 MAPK signaling pathways. Anti-CXCL16 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Additionally, anti-CCL4 and anti-CCL5 neutralizing Ab administration inhibited Ly6Chigh monocyte infiltration and improved cardiac function after MI. Thus, CXCL16 aggravated cardiac injury in MI mice by facilitating Ly6Chigh monocyte infiltration.
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Monocitos , Infarto del Miocardio , Animales , Ratones , Macrófagos , Sistema de Señalización de MAP Quinasas , FN-kappa B , Quimiocina CXCL16RESUMEN
Human leukocyte antigen (HLA) molecules play critically significant role within the realm of immunotherapy due to their capacities to recognize and bind exogenous antigens such as peptides, subsequently delivering them to immune cells. Predicting the binding between peptides and HLA molecules (pHLA) can expedite the screening of immunogenic peptides and facilitate vaccine design. However, traditional experimental methods are time-consuming and inefficient. In this study, an efficient method based on deep learning was developed for predicting peptide-HLA binding, which treated peptide sequences as linguistic entities. It combined the architectures of textCNN and BiLSTM to create a deep neural network model called APEX-pHLA. This model operated without limitations related to HLA class I allele variants and peptide segment lengths, enabling efficient encoding of sequence features for both HLA and peptide segments. On the independent test set, the model achieved Accuracy, ROC_AUC, F1, and MCC is 0.9449, 0.9850, 0.9453, and 0.8899, respectively. Similarly, on an external test set, the results were 0.9803, 0.9574, 0.8835, and 0.7863, respectively. These findings outperformed fifteen methods previously reported in the literature. The accurate prediction capability of the APEX-pHLA model in peptide-HLA binding might provide valuable insights for future HLA vaccine design.
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Antígenos de Histocompatibilidad Clase I , Péptidos , Unión Proteica , Humanos , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Péptidos/química , Péptidos/inmunología , Aprendizaje Profundo , Antígenos HLA/inmunología , Antígenos HLA/genética , Redes Neurales de la Computación , Biología Computacional/métodosRESUMEN
Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection.
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Disección Aórtica , Matriz Extracelular , MicroARNs , Músculo Liso Vascular , Miocitos del Músculo Liso , Fenotipo , MicroARNs/genética , MicroARNs/metabolismo , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Disección Aórtica/genética , Disección Aórtica/metabolismo , Disección Aórtica/patología , Animales , Matriz Extracelular/metabolismo , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Humanos , Ratones , Masculino , Regulación hacia Abajo/genética , Factores de Transcripción de Dominio TEA , Transducción de Señal , Proteínas Proto-Oncogénicas c-akt/metabolismo , Regulación de la Expresión Génica , Femenino , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
Aortic dissection (AD) is the most catastrophic vascular disease with a high mortality rate. Trimethylamine N-oxide (TMAO), a gut microbial metabolite, has been implicated in the pathogenesis of cardiovascular diseases. However, the role of TMAO in AD and the underlying mechanisms remain unclear. This study aimed to explore the effects of TMAO on AD. Plasma and fecal samples from patients with AD and healthy individuals were collected to analyze TMAO levels and gut microbial species, respectively. The plasma levels of TMAO were significantly higher in 253 AD patients compared with those in 98 healthy subjects (3.47, interquartile range (IQR): 2.33 to 5.18 µM vs. 1.85, IQR: 1.40 to 3.35 µM; p < 0.001). High plasma TMAO levels were positively associated with AD severity. An increase in the relative abundance of TMA-producing genera in patients with AD was revealed using 16S rRNA sequencing. In the angiotensin II or ß-aminopropionitrile-induced rodent model of AD, mice fed a TMAO-supplemented diet were more likely to develop AD compared to mice fed a normal diet. Conversely, TMAO depletion mitigated AD formation in the BAPN model. RNA sequencing of aortic endothelial cells isolated from mice administered TMAO revealed significant upregulation of genes involved in inflammatory pathways. The in vitro experiments verified that TMAO promotes endothelial dysfunction and activates nuclear factor (NF)-κB signaling. The in vivo BAPN-induced AD model confirmed that TMAO increased aortic inflammation. Our study demonstrates that the gut microbial metabolite TMAO aggravates the development of AD at least in part by inducing endothelial dysfunction and inflammation. This study provides new insights into the etiology of AD and ideas for its management.
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Disección Aórtica , Microbioma Gastrointestinal , Metilaminas , Humanos , Ratones , Animales , Microbioma Gastrointestinal/fisiología , ARN Ribosómico 16S , Aminopropionitrilo , Células Endoteliales , Inflamación , Disección Aórtica/etiologíaRESUMEN
Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.
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Aneurisma de la Aorta Torácica , Disección Aórtica , Azidas , Desoxiglucosa/análogos & derivados , Humanos , Ratones , Animales , Vía Alternativa del Complemento , Metaloproteinasa 2 de la Matriz , Aneurisma de la Aorta Torácica/genética , Aneurisma de la Aorta Torácica/metabolismo , Aneurisma de la Aorta Torácica/patología , Disección Aórtica/genética , InflamaciónRESUMEN
Successful muscle regeneration following injury is essential for functional homeostasis of skeletal muscles. Krüppel-like factor 15 (KLF15) is a metabolic transcriptional regulator in the muscles. However, little is known regarding its function in muscle regeneration. Here, we examined microarray datasets from the Gene Expression Omnibus database, which indicated downregulated KLF15 in muscles from patients with various muscle diseases. Additionally, we found that Klf15 knockout (Klf15KO) impaired muscle regeneration following injury in mice. Furthermore, KLF15 expression was robustly induced during myoblast differentiation. Myoblasts with KLF15 deficiency showed a marked reduction in their fusion capacity. Unbiased transcriptome analysis of muscles on day 7 postinjury revealed downregulated genes involved in cell differentiation and metabolic processes in Klf15KO muscles. The FK506-binding protein 51 (FKBP5), a positive regulator of myoblast differentiation, was ranked as one of the most strongly downregulated genes in the Klf15KO group. A mechanistic search revealed that KLF15 binds directly to the promoter region of FKBP5 and activates FKBP5 expression. Local delivery of FKBP5 rescued the impaired muscle regeneration in Klf15KO mice. Our findings reveal a positive regulatory role of KLF15 in myoblast differentiation and muscle regeneration by activating FKBP5 expression. KLF15 signaling may be a novel therapeutic target for muscle disorders associated with injuries or diseases.
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Mioblastos , Proteínas de Unión a Tacrolimus , Animales , Humanos , Ratones , Diferenciación Celular/genética , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Ratones Noqueados , Músculo Esquelético/metabolismo , Mioblastos/metabolismo , Regeneración/genética , Proteínas de Unión a Tacrolimus/metabolismo , Masculino , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The present study aimed to evaluate the efficacy and safety of intravenous tirofiban versus alteplase before endovascular treatment (EVT) in acute ischemic stroke patients with intracranial large vessel occlusion. METHODS: This was a post hoc analysis using data from 2 multicenter, randomized trials: the DEVT trial (Direct Endovascular Treatment for Large Vessel Occlusion Stroke) from May 2018 to May 2020 and the RESCUE BT trial (Intravenous Tirofiban Before Endovascular Thrombectomy for Acute Ischemic Stroke) from October 2018 to October 2021. Patients with acute intracranial large vessel occlusion within 4.5 hours from last known well were dichotomized into 2 groups: tirofiban plus EVT versus alteplase bridging with EVT. The primary outcome was functional independence (modified Rankin Scale score of 0-2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and 3-month mortality. Multivariable logistic regression (adjusting for baseline systolic blood pressure, occlusion site, onset-to-puncture time, anesthesia, and first choice of EVT) and propensity score overlap weighting (balance in demographic covariates, stroke characteristics, and initial management between groups) were performed. RESULTS: One-hundred and eighteen alteplase-treated patients in the DEVT trial and 98 tirofiban-treated patients in the RESCUE BT trial were included (median age, 70 years; 115 [53.2%] men). The rate of functional independence was 60.2% in the tirofiban group compared with 46.6% in the alteplase group (adjusted odds ratio, 1.25 [95% CI, 0.60-2.63]). Compared with alteplase, tirofiban was not associated with increased risk of symptomatic intracranial hemorrhage (6.8% versus 9.2%; P=0.51) and mortality (17.8% versus 19.4%; P=0.76). The propensity score overlap weighting analyses showed consistent outcomes. CONCLUSIONS: Among patients with intracranial large vessel occlusion within 4.5 hours of onset, tirofiban plus EVT was comparable to alteplase bridging with EVT regarding the efficacy and safety outcomes. These findings should be interpreted as preliminary and require confirmation in a randomized trial. REGISTRATION: URL: https://www.chictr.org.cn; Unique identifiers: ChiCTR-IOR-17013568 and ChiCTR-INR-17014167.
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Isquemia Encefálica , Procedimientos Endovasculares , Accidente Cerebrovascular Isquémico , Accidente Cerebrovascular , Masculino , Humanos , Anciano , Femenino , Activador de Tejido Plasminógeno/uso terapéutico , Tirofibán/uso terapéutico , Fibrinolíticos , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/cirugía , Terapia Trombolítica/efectos adversos , Resultado del Tratamiento , Procedimientos Endovasculares/efectos adversos , Accidente Cerebrovascular/tratamiento farmacológico , Accidente Cerebrovascular/cirugía , Trombectomía/efectos adversos , Hemorragias Intracraneales/etiología , Hemorragias Intracraneales/inducido químicamente , Estudios Multicéntricos como AsuntoRESUMEN
Isolated thoracic aortic aneurysms (TAAs) are asymptomatic before dissection or rupture and heterogeneous in clinical phenotype. It is urgent need but difficult to identify individuals at high risk to enable enhanced screening or preventive therapies. Because TAAs have a genetic component, one possible approach is to stratify individuals based on inherited DNA variations. Here, we constructed an integrated exome risk score (ERS) based on both common and rare variants found in whole-exome sequencing through a machine-learning framework in discovery population consisting of 551 cases and 1071 controls. We evaluated the performance of the ERS in an independent population including 151 cases and 779 controls with a raw odds ratio (OR) per 1 standard deviation (SD) = 1.95 and area under the receiver operating characteristic curve (AUC) = 0.680. When adjusted by gender and the first four principal components, OR per SD = 1.68 and AUC reached 0.783. Individuals in the top 20% of ERS distribution had an OR of 3.20 compared with others. Finally, we found that individuals with top 20% ERS developed TAA at a younger age (P = 0.002) and with a larger diameter (P = 0.016) compared with lower ERS, and were more likely to suffer from aortic root aneurysms (P = 0.009). Our analysis provides a global view of the genetic components of isolated TAA. The exome score developed and evaluated here is the first polygenic risk score for TAA and is a promising predictor of disease risk and severity, which will facilitate the implementation of the risk-reduction strategies.
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Aneurisma de la Aorta Torácica , Humanos , Aneurisma de la Aorta Torácica/genética , Secuenciación del Exoma , Exoma/genética , Factores de Riesgo , Oportunidad RelativaRESUMEN
BACKGROUND: Bleomycin, a potent antitumor agent, is limited in clinical use due to the potential for fatal pulmonary toxicity. The accelerated DNA damage and senescence in alveolar epithelial cells (AECs) is considered a key factor in the development of lung pathology. Understanding the mechanisms for bleomycin-induced lung injury is crucial for mitigating its adverse effects. METHODS: Human lung epithelial (A549) cells were exposed to bleomycin and subsequently assessed for cellular senescence, DNA damage, and double-strand break (DSB) repair. The impact of Rad51 overexpression on DSB repair and senescence in AECs was evaluated in vitro. Additionally, bleomycin was intratracheally administered in C57BL/6 mice to establish a pulmonary fibrosis model. RESULTS: Bleomycin exposure induced dose- and time-dependent accumulation of senescence hallmarks and DNA lesions in AECs. These effects are probably due to the inhibition of Rad51 expression, consequently suppressing homologous recombination (HR) repair. Mechanistic studies revealed that bleomycin-mediated transcriptional inhibition of Rad51 might primarily result from E2F1 depletion. Furthermore, the genetic supplement of Rad51 substantially mitigated bleomycin-mediated effects on DSB repair and senescence in AECs. Notably, decreased Rad51 expression was also observed in the bleomycin-induced mouse pulmonary fibrosis model. CONCLUSIONS: Our works suggest that the inhibition of Rad51 plays a pivotal role in bleomycin-induced AECs senescence and lung injury, offering potential strategies to alleviate the pulmonary toxicity of bleomycin.
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Bleomicina , Senescencia Celular , Reparación del ADN , Recombinasa Rad51 , Bleomicina/efectos adversos , Recombinasa Rad51/metabolismo , Recombinasa Rad51/genética , Animales , Senescencia Celular/efectos de los fármacos , Senescencia Celular/genética , Humanos , Ratones , Reparación del ADN/efectos de los fármacos , Ratones Endogámicos C57BL , Fibrosis Pulmonar/inducido químicamente , Fibrosis Pulmonar/genética , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Células A549 , Daño del ADN/efectos de los fármacos , Roturas del ADN de Doble Cadena/efectos de los fármacos , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/efectos de los fármacosRESUMEN
The aim of this study was to evaluate the role of angiotensin-converting enzyme 1 (ACE1) in H2O2-induced trophoblast cell injury and the potential molecular mechanisms. Oxidative stress was modeled by exposing HTR-8/SVneo cells to 200 µM H2O2. Western blot and real-time quantitative PCR methods were used to detect protein and mRNA expression level of ACE1 in chorionic villus tissue and trophoblast HTR-8/SVneo cell. Inhibition of ACE1 expression was achieved by transfection with small interfering RNA. Then flow cytometry, Cell Counting Kit-8, and Transwell assay was used to assess apoptosis, viability, and migration ability of the cells. Reactive oxygen species (ROS) were detected by fluorescent probes, and malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) activities were determined by corresponding detection kits. Angiotensin-converting enzyme 1 expression was upregulated in chorionic villus tissue of patients with missed abortion (MA) compared with individuals with normal early pregnancy abortion. H2O2 induced elevated ACE1 expression in HTR-8/SVneo cells, promoted apoptosis, and inhibited cell viability and migration. Knockdown of ACE1 expression inhibited H2O2-induced effects to enhance cell viability and migration and suppress apoptosis. Additionally, H2O2 stimulation caused increased levels of ROS and MDA and decreased SOD and GSH activity in the cells, whereas knockdown of ACE1 expression led to opposite changes of these oxidative stress indicators. Moreover, knockdown of ACE1 attenuated the inhibitory effect of H2O2 on the Nrf2/HO-1 pathway. Angiotensin-converting enzyme 1 was associated with MA, and it promoted H2O2-induced injury of trophoblast cells through inhibiting the Nrf2 pathway. Therefore, ACE1 may serve as a potential therapeutic target for MA.
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Aborto Retenido , Peróxido de Hidrógeno , Peptidil-Dipeptidasa A , Trofoblastos , Humanos , Trofoblastos/metabolismo , Trofoblastos/efectos de los fármacos , Peróxido de Hidrógeno/farmacología , Peptidil-Dipeptidasa A/genética , Peptidil-Dipeptidasa A/metabolismo , Femenino , Embarazo , Aborto Retenido/genética , Aborto Retenido/metabolismo , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Línea Celular , Especies Reactivas de Oxígeno/metabolismo , Supervivencia Celular/efectos de los fármacos , Adulto , Movimiento Celular/efectos de los fármacosRESUMEN
BACKGROUND: Patients with ischemic heart disease (IHD) experience a high incidence of progression to heart failure (HF) despite current therapies. We speculated that steroid hormone metabolic disorders distinct adverse phenotypes and contribute to HF. METHODS: We measured 18 steroids using liquid chromatography with tandem mass spectrometry in 2023 patients from the Registry Study of Biomarkers in Ischemic Heart Disease (BIOMS-IHD), including 1091 patients with IHD in a retrospective discovery set and 932 patients with IHD in a multicentre validation set. Our outcomes included incident HF after a median follow-up of 4 years. RESULTS: We demonstrated steroid-based signatures of inflammation, coronary microvascular dysfunction and left ventricular hypertrophy that were associated with subsequent HF events in patients with IHD. In both cohorts, patients with a high steroid-heart failure score (SHFS) (>1) exhibited a greater risk of incident HF than patients with a low SHFS (≤1). The SHFS further improved the prognostic accuracy beyond clinical variables (net reclassification improvement of 0.628 in the discovery set and 0.299 in the validation set) and demonstrated the maximal effect of steroid signatures in patients with IHD who had lower B-type natriuretic peptide levels (pinteraction = 0.038). CONCLUSIONS: A steroid-based strategy can simply and effectively identify individuals at higher HF risk who may derive benefit from more intensive follow-ups.
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Insuficiencia Cardíaca , Isquemia Miocárdica , Humanos , Estudios Retrospectivos , Factores de Riesgo , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/complicaciones , Isquemia Miocárdica/epidemiología , Isquemia Miocárdica/complicaciones , Biomarcadores , EsteroidesRESUMEN
BACKGROUND: As a key enzyme in ceramide synthesis, longevity assurance homologue 2 (LASS2) has been indicated to act as a tumour suppressor in a variety of cancers. Ferroptosis is involved in a variety of tumour processes; however, the role of LASS2 in regulating ferroptosis has yet to be explored. This article explores the potential underlying mechanisms involved. METHODS: Bioinformatics tools and immunohistochemical staining were used to evaluate LASS2 expression, and the results were analysed in relation to overall survival and clinical association in multiple cancers. Coimmunoprecipitation-coupled liquid chromatography-mass spectrometry (co-IP LC-MS) was performed to identify potential LASS2-interacting proteins in thyroid, breast, and liver cancer cell lines. Transcriptomics, proteomics and metabolomics analyses of multiple cancer cell types were performed using MS or LC-MS to further explore the underlying mechanisms involved. Among these tumour cells, the common LASS2 interaction partner transferrin receptor (TFRC) was analysed by protein-protein docking and validated by coimmunoprecipitation western blot, immunofluorescence, and proximity ligation assays. Then, we performed experiments in which tumour cells were treated with Fer-1 or erastin or left untreated, with or without inducing LASS2 overexpression, and assessed the molecular biological and cellular functions by corresponding analyses. RESULTS: Low LASS2 expression is correlated with adverse clinical characteristic and poor prognosis in patients with thyroid cancer, breast cancer or HCC. Multiomics analyses revealed significant changes in the ferroptosis signalling pathway, iron ion transport and iron homeostasis. Our in vitro experiments revealed that LASS2 overexpression regulated ferroptosis status in these tumour cells by affecting iron homeostasis, which in turn inhibited tumour migration, invasion and EMT. In addition, LASS2 overexpression reversed the changes in tumour cell metastasis induced by either Fer-1 or erastin. Mechanistically, LASS2 interacts directly with TFRC to regulate iron homeostasis in these tumour cells. CONCLUSIONS: In summary, our study reveals for the first time that LASS2 can inhibit tumour cell metastasis by interacting with TFRC to regulate iron metabolism and influence ferroptosis status in thyroid, breast, and liver cancer cells, these results suggest potential universal therapeutic targets for the treatment of these cancers.
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BACKGROUND: Accurate prediction of death is an unmet need in patients with acute decompensated heart failure (HF). Arachidonic acid (AA) metabolites play an important role in the multiple pathophysiological processes. We aimed to develop an AA score to accurately predict mortality in patients with acute decompensated HF and explore the causal relationship between the AA predictors and HF. METHODS: The serum AA metabolites was measured in patients with acute decompensated HF (discovery cohort n=419; validation cohort n=386) by mass spectroscopy. We assessed the prognostic importance of AA metabolites for 1-year death using Cox regression and machine learning approaches. A machine learning-based AA score for predicting 1-year death was created and validated. We explored the mechanisms using transcriptome and functional experiments in a mouse model of early ischemic cardiomyopathy. RESULTS: Among the 27 AA metabolites, elevated 14,15-DHET/14,15-EET ratio was the strongest predictor of 1-year death (hazard ratio, 2.10, P=3.1×10-6). Machine learning-based AA score using a combination of the 14,15-DHET/14,15-EET ratio, 14,15-DHET, PGD2, and 9-HETE performed best (area under the curve [AUC]: 0.85). The machine learning-based AA score provided incremental information to predict mortality beyond BNP (B-type natriuretic peptide; ΔAUC: 0.19), clinical score (ΔAUC: 0.09), and preexisting Acute Decompensated Heart Failure National Registry, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure, and Get With The Guidelines Heart Failure scores (ΔAUC: 0.17, 0.17, 0.15, respectively). In the validation cohort, the AA score accurately predicted mortality (AUC:0.81). False-negative and false-positive findings, as classified by the BNP threshold, were correctly reclassified by the AA score (46.2% of false-negative and 84.5% of false-positive). In a murine model, the expression and enzymatic activity of sEH (soluble epoxide hydrolase) increased after myocardial infarction. Genetic deletion of sEH improved HF and the blockade of 14,15-EET abolished this cardioprotection. We mechanistically revealed the beneficial effect of 14,15-EET by impairing the activation of monocytes/macrophages. CONCLUSIONS: Our studies propose that the AA score predicts death in patients with acute decompensated HF and inhibiting sEH serves as a therapeutic target for treating HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04108182.
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Insuficiencia Cardíaca , Péptido Natriurético Encefálico , Animales , Ácido Araquidónico , Insuficiencia Cardíaca/diagnóstico , Insuficiencia Cardíaca/terapia , Humanos , Ratones , Pronóstico , Sistema de RegistrosRESUMEN
A bacterial strain, designated S6T, was isolated from the sandy soil on a rocky mountain in South China. Cells of S6T were Gram-stain-negative, aerobic, non-spore-forming, non-motile and non-prosthecae-producing. 16S rRNA gene sequence analysis revealed the highest similarities to 12 uncultured bacteria, followed by Phenylobacterium sp. B6.10-61 (97.14â%). The closest related validly published strains are Caulobacter henricii ATCC 15253T (96.15â%), Phenylobacterium conjunctum FWC 21T (96.08â%) and Caulobacter mirabilis FWC 38T (96.08â%). Phylogenetic analysis based on 16S rRNA gene, genome and proteome sequences demonstrated that S6T formed a separated lineage in the genus Phenylobacterium. Strain S6T contained Q-10 (97.5â%) as the major ubiquinone and C18â:â1 ω7c and C16â:â0 as the major fatty acids. The polar lipid profile consisted of phosphatidylglycerol, an unknown phosphoglycolipid and three unknown glycolipids. The assembled genome comprises a chromosome with a length of 5.5 Mb and a plasmid of 96â014 bp. The G+C content was 67.6 mol%. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus it is proposed that strain S6T represents a novel species in the genus Phenylobacterium, for which the name Phenylobacterium montanum sp. nov. is proposed. The type strain is S6T (=NBRC 115419T=GCMCC 1.18594T).