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BACKGROUND: Colorectal polyps, which are characterized by a high recurrence rate, represent preneoplastic conditions of the intestine. Due to unclear mechanisms of pathogenesis, first-line therapies for non-hereditary recurrent colorectal polyps are limited to endoscopic resection. Although recent studies suggest a mechanistic link between intestinal dysbiosis and polyps, the exact compositions and roles of bacteria in the mucosa around the lesions, rather than feces, remain unsettled. AIM: To clarify the composition and diversity of bacteria in the mucosa surrounding or 10 cm distal to recurrent intestinal polyps. METHODS: Mucosal samples were collected from four patients consistently with adenomatous polyps (Ade), seven consistently with non-Ade (Pol), ten with current Pol but previous Ade, and six healthy individuals, and bacterial patterns were evaluated by 16S rDNA sequencing. Linear discriminant analysis and Student's t-tests were used to identify the genus-level bacteria differences between groups with different colorectal polyp phenotypes. Pearson's correlation coefficients were used to evaluate the correlation between intestinal bacteria at the genus level and clinical indicators. RESULTS: The results confirmed a decreased level of probiotics and an enrichment of pathogenic bacteria in patients with all types of polyps compared to healthy individuals. These changes were not restricted to the mucosa within 0.5 cm adjacent to the polyps, but also existed in histologically normal tissue 10 cm distal from the lesions. Significant differences in bacterial diversity were observed in the mucosa from individuals with normal conditions, Pol, and Ade. Increased abundance of Gram-negative bacteria, including Klebsiella, Plesiomonas, and Cronobacter, was observed in Pol group and Ade group, suggesting that resistance to antibiotics may be one risk factor for bacterium-related harmful environment. Meanwhile, age and gender were linked to bacteria changes, indicating the potential involvement of sex hormones. CONCLUSION: These preliminary results support intestinal dysbiosis as an important risk factor for recurrent polyps, especially adenoma. Targeting specific pathogenic bacteria may attenuate the recurrence of polyps.
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BACKGROUND: Mung bean (Vigna radiata L.) is an important warm-season grain legume. Adaptation to extreme environmental conditions, supported by evolution, makes mung bean a rich gene pool for stress tolerance traits. The exploration of resistance genes will provide important genetic resources and a theoretical basis for strengthening mung bean breeding. B-box (BBX) proteins play a major role in developmental processes and stress responses. However, the identification and analysis of the mung bean BBX gene family are still lacking. RESULTS: In this study, 23 VrBBX genes were identified through comprehensive bioinformatics analysis and named based on their physical locations on chromosomes. All the VrBBXs were divided into five groups based on their phylogenetic relationships, the number of B-box they contained and whether there was an additional CONSTANS, CO-like and TOC1 (CCT) domain. Homology and collinearity analysis indicated that the BBX genes in mung bean and other species had undergone a relatively conservative evolution. Gene duplication analysis showed that only chromosomal segmental duplication contributed to the expansion of VrBBX genes and that most of the duplicated gene pairs experienced purifying selection pressure during evolution. Gene structure and motif analysis revealed that VrBBX genes clustered in the same group shared similar structural characteristics. An analysis of cis-acting elements indicated that elements related to stress and hormone responses were prevalent in the promoters of most VrBBXs. The RNA-seq data analysis and qRT-PCR of nine VrBBX genes demonstrated that VrBBX genes may play a role in response to environmental stress. Moreover, VrBBX5, VrBBX10 and VrBBX12 are important candidate genes for plant stress response. CONCLUSIONS: In this study, we systematically analyzed the genomic characteristics and expression patterns of the BBX gene family under ABA, PEG and NaCl treatments. The results will help us better understand the complexity of the BBX gene family and provide valuable information for future functional characteristics of specific genes in this family.
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Evolución Molecular , Familia de Multigenes , Filogenia , Proteínas de Plantas , Vigna , Vigna/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Regulación de la Expresión Génica de las Plantas , Genes de Plantas , Genoma de Planta , Duplicación de Gen , Estrés Fisiológico/genéticaRESUMEN
BACKGROUND: Chlorogenic acid (CA, United States Patent No. 10772340), a natural biologically active food ingredient, displays potent antitumor activity against a variety of cancer cells. However, the mechanism underlying its anticancer effect is not well elucidated. OBJECTIVE: In the present study, we hope to dissect the mechanism underlying the anticancer effects of CA in pancreatic cancer cells. METHODS: The cytotoxicity of CA in pancreatic cancer cells was determined by MTT assay. Flow cytometry was performed to evaluate the cells apoptosis, while a clonogenic assay was carried out to check the colony formation of cancer cells. Transwell assay was performed to assess the cells migration and invasion. The protein expression of AKT/GSK-3ß/ß-catenin signaling pathway was detected by Western Blot. RESULTS: Our data indicated that CA inhibited the proliferation of PANC-28 and PANC-1 cells in a dose and time-dependent manner. CA was able to inhibit colony formation, migration, and invasion ability and trigger apoptosis in PANC-28 and PANC-1 cells. Further study showed that CA down-regulated the expression of AKT, p-AKT(Thr308), p-GSK-3ß(Ser9), ß-catenin, N-cadherin, and vimentin while enhancing the expression of cleaved-caspase 3 and cleaved-caspase 7 in PANC-28 and PANC-1 cells. CONCLUSION: Our study provides significant evidence that CA is able to inhibit the growth of pancreatic cancer via the AKT/GSK-3ß/ß-catenin signaling pathway.
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Neoplasias Pancreáticas , Proteínas Proto-Oncogénicas c-akt , Humanos , Apoptosis , beta Catenina/metabolismo , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Ácido Clorogénico/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Neoplasias Pancreáticas/tratamiento farmacológico , Patentes como Asunto , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
BACKGROUND: Major depressive disorder (MDD) is a major and common cause of suicide. The purpose of this article is to report the clinical characteristics and patterns of co-morbid suicidal behavior (SB) in first hospitalized and drug-naïve MDD patients. METHODS: A total of 345 patients with first hospitalization and drug-naïve MDD with SB were included in this study, while 183 patients without SB were included as a control group. We collected socio-demographic, general clinical data and common biochemical indicators of all participants and assessed their clinical symptoms. RESULTS: Compared to patients without SB, MDD with SB had more severe clinical symptoms and worse metabolic indicators. Duration of disease, depressive symptom scores, and thyroid stimulating hormone (TSH) levels was risk factors for SB and its number. CONCLUSIONS: MDD patients with SB suffered more severe clinical symptoms and worse metabolic indicators, and risk factors for SB in this population were identified, which may provide beneficial insight and reference for clinical prevention and intervention of SB in MDD patients.
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Obesity is a recognized risk factor for heart failure. People with similar weights may have different metabolic health. Notably, insulin resistance is a hallmark of obesity and a feature of heart failure. We aimed to evaluate the effects of obesity and metabolic health status on subclinical left cardiac function. We also investigated whether insulin resistance (TyG index) plays a role in BMI-linked subclinical left cardiac dysfunction. The study involved 403 volunteers. Hierarchical multiple regression models were used to assess associations between obesity, metabolic health, and overall subclinical left cardiac function. Mediating analysis was used to explore the role of the TyG index in the association between BMI and left cardiac function. Finally, ROC analysis was performed to explore the predictive value of the TyG index in subclinical left cardiac dysfunction. The correlation analysis showed that metabolic unhealth increased the risk of subclinical left ventricular (LV) dysfunction; obesity was associated with an increased risk of global left cardiac dysfunction regardless of metabolic health status. The TyG index mediated 25% of the associations between BMI and Left atrial (LA) functional parameters. ROC analysis exhibited that the TyG index can be used as a predictor of LA dysfunction (AUC = 0.63), and the optimal cut-off point for the TyG index is 9.33. Even a "non-obese metabolically unhealthy" is a detrimental state of early LV function; obesity remains a major risk factor for global subclinical left cardiac dysfunction. Using the TyG index could allow early identification of individuals at high risk of subclinical left cardiac dysfunction.Registration number: ChiCTR2200057991; Date of registration: 2022-03-25. URL: http://www.chictr.org.cn/showproj.aspx?proj=162316 .
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Insuficiencia Cardíaca , Resistencia a la Insulina , Disfunción Ventricular Izquierda , Humanos , Obesidad/complicaciones , Corazón/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico por imagen , Factores de Riesgo , TriglicéridosRESUMEN
OBJECTIVE: This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the deacetylation of FoxO3a and inhibiting pyroptosis. METHODS: SIRT3-overexpressing and silenced BEAS-2B cells were used to evaluate the effect of SIRT3 on apoptosis in LPS-treated lung epithelial cells. FoxO3a-silenced BEAS-2B cells were also used to verify the mechanism by which SIRT3 inhibited oxidative stress and pyroptosis in vitro in ALI. 3-TYP was used to inhibit the deacetylation function of SIRT3 in vivo. Pyroptosis was assessed by detecting GSDMD-N and LDH efflux. RESULTS: In CLP-induced ALI mice, GSDMD-N and LDH levels were elevated, pyroptosis was induced. Silencing of SIRT3 exacerbated oxidative stress, NLRP3 activation and pyroptosis, and inhibited the deacetylation of FoxO3a. Overexpression of SIRT3 attenuated pyroptosis, induced deacetylation and restored the expression of FoxO3a and MnSOD. Silencing FoxO3a aggravated pyroptosis. Overexpression of SIRT3 restored the reduced FoxO3a expression and suppressed pyroptosis. 3-TYP blocked the promotion of FoxO3a by SIRT3 and the inhibitory effect of SIRT3 on pyroptosis. CONCLUSION: The reduction of SIRT3 in sepsis caused hyperacetylation of FoxO3a, which in turn exacerbates oxidative stress and induces pyroptosis of ALI. Increasing the level of SIRT3 promotes FoxO3a through deacetylation, thereby inhibiting pyroptosis and relieving ALI.
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Lesión Pulmonar Aguda , Sepsis , Sirtuina 3 , Animales , Ratones , Lesión Pulmonar Aguda/etiología , Apoptosis , Lipopolisacáridos , Piroptosis , Sepsis/complicaciones , Sirtuina 3/genéticaRESUMEN
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive and extremely rare hematologic disease with a poor prognosis, involving mainly the skin and bone marrow. The immunophenotype of these tumor cells is characterized by the expression of CD4, CD56, CD123, TCL-1, and CD303. To date, no consensus has been reached on the standard of care for BPDCN. Currently, clinical treatment is mainly based on high-dose chemotherapy combined with hematopoietic stem cell transplantation. However, this treatment method has limitations for elderly, frail, and relapsed/refractory patients. In recent years, breakthroughs in molecular biology and genetics have not only provided new ideas for the diagnosis of BPDCN but also helped develop targeted treatment strategies for this disease. The emergence of targeted drugs has filled the gap left by traditional therapies and shown great clinical promise. This article focuses on the latest advances in genetics and targeted therapies for BPDCN, especially the emerging therapies that may provide new ideas for the clinical treatment of BPDCN.
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Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Células Dendríticas/patología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Trastornos Mieloproliferativos/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/terapiaRESUMEN
In this study, banana cellulose nanofibres (BNCFs) were prepared using waste banana stems. A novel two-dimensional (2D) Zn-MOF was synthesized using 5-(1-hydro-imidazolyl) isophthalic acid as the ligand. The results of the X-ray diffraction, thermogravimetry, and scanning electron microscopy analyses confirmed the stability of Zn-MOF. Thus, Zn-MOF was used to catalyze BNCFs grafted with poly(ε-caprolactone) (ε-CL) (BGCL) by homogeneous ring-opening polymerization in ionic liquid. The grafting ratio of the BGCL prepared by Zn-MOF reached 84.12 %, which was 10.03% higher than that catalyzed by 4-dimethylamino pyridine which was the state-of-the-art catalyst for this reaction. The banana cellulose nanofibres grafted with ε-CL reactions followed the coordination-insertion mechanism, which was confirmed by the theoretical calculations using the Materials Studio software. The cytotoxicity results indicated that BGCL was not only non-toxic to Hela cells but also promoted Hela cell growth within a certain concentration range. Therefore, this study demonstrated the promising potential of BGCL for biomedical applications, and the high efficiency, non-toxicity, and stability of Zn-MOF as the catalyst. Further, this will provide a theoretical basis for the application of MOFs as catalysts in polymerization reactions.
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Estructuras Metalorgánicas , Musa , Nanofibras , Humanos , Celulosa , Células HeLa , Zinc , CatálisisRESUMEN
BACKGROUND: The Lingqihuangban Granule (LQHBG), a remarkable Chinese herbal compound, has been used for decades to treat diabetic retinopathy (DR) in the Department of Ophthalmology, Shanghai General Hospital (National Clinical Research Center for Eye Diseases) with obvious effects. Through the method of network pharmacology, the present study constructed bioactive component-relative targets and protein-protein interaction network of the LQHBG and implemented gene function analysis and pathway enrichment of targets, discussing the mechanisms of traditional Chinese medicine LQHBG in treating DR. MATERIALS AND METHODS: The bioactive ingredients of LQHBG were screened and obtained using TCMSP and ETCM databases, while the potential targets of bioactive ingredients were predicted by SwissTargetPrediction and ETCM databases. Compared with the disease target databases of TTD, Drugbank, OMIM and DisGeNET, the therapeutic targets of LQHBG for DR were extracted. Based on the DAVID platform, GO annotation and KEGG pathway analyses of key targets were explored, combined with the screening of core pathways on the Omicshare database and pathway annotation on the Reactome database. RESULTS: A total of 357 bioactive components were screened from LQHBG, involving 86 possible targets of LQHBG treating DR. In the PPI network, INS and ALB were identified as key genes. The effective targets were enriched in multiple signaling pathways, such as PI3K/Akt and MAPK pathways. CONCLUSION: This study revealed the possible targets and pathways of LQHBG treating DR, reflecting the characteristics of multicomponent, multitarget and multipathway treatment of a Chinese herbal compound, and provided new ideas for further discussion.
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Diabetes Mellitus , Retinopatía Diabética , Humanos , Retinopatía Diabética/tratamiento farmacológico , Farmacología en Red , Fosfatidilinositol 3-Quinasas , China , Bases de Datos FactualesRESUMEN
BACKGROUND: Enzalutamide has been approved clinically for the treatment of castrationresistant prostate cancer (CRPC) but is limited by the emergence of resistance. RhoA has been shown to play a vital role in carcinogenesis, invasion, and metastasis. However, the role of RhoA in enzalutamide-resistant prostate cancer (PCa) remains unclear. OBJECTIVES: This study investigated the role of RhoA and the associated mechanisms of RhoA depletion in enzalutamide resistance in CRPC. METHODS: Western blotting, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and colony formation assays were used to assess protein expression, survival, and proliferation of PCa cells, respectively. Xenograft experiments and hematoxylin and eosin (H&E) staining were used to detect further effects of RhoA on enzalutamide resistance in vivo. RESULTS: In the present study, the expression of RhoA, ROCK2, p38, p-p38, and AR was upregulated in enzalutamide-resistant PCa cells treated with enzalutamide, and silencing of RhoA or ROCK2 attenuated enzalutamide-resistant cell proliferation and colony formation. Furthermore, the deletion of RhoA dramatically increased the efficacy of enzalutamide in inhibiting 22RV1-derived xenograft tumor growth. Additionally, there was no significant change in ROCK1 expression in C4-2R cells treated with or without enzalutamide. Mechanistically, the knockdown of RhoA expression reverted the resistance to enzalutamide via RhoA/ROCK2/p38 rather than RhoA/ROCK1/p38. CONCLUSION: Our results suggested that RhoA is a promising therapeutic target. As the inhibition of RhoA reverted enzalutamide resistance, it may increase its effectiveness in CRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Proteínas Quinasas p38 Activadas por Mitógenos , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Proteína de Unión al GTP rhoA/genética , Quinasas Asociadas a rhoRESUMEN
OBJECTIVES: High sodium intake is strongly associated with hypertension and obesity. This study aims to investigate the relationship between 24-h urinary sodium (a surrogate measure of sodium intake), ambulatory blood pressure parameters, left atrial function, and left atrioventricular coupling. Further, we intend to examine whether blood pressure and BMI might be mediators of the relationship between 24-h urinary sodium and subclinical cardiac function. METHODS: Our study had 398 participants, all of whom were subjected to 24-h urine collection, 24-h ambulatory blood pressure measurement, and cardiac magnetic resonance imaging. RESULTS: The average age of the participants was 55.70â±â11.30âyears old. The mean urinary sodium of the participants was 172.01â±â80.24âmmol/24âh. After adjusting for age, sex, history of diabetes, smoking status, alcohol consumption, and use of diuretics, 24-h urinary sodium was correlated with multiple ambulatory blood pressure parameters, BMI, left atrial function, and the left atrioventricular coupling index (LACI) (Pâ<â0.05). Mediation analysis showed that BMI explained 16% of the indirect effect of 24-h urinary sodium and left atrial function and 30% of the indirect effect of LACI. Independent of the mediator, 24-h urinary sodium had a significant direct effect on left atrial function and left atrioventricular coupling. CONCLUSIONS: Higher 24-h urinary sodium was associated with a greater BMI as well as poor left atrial function and left atrioventricular coupling, and the BMI mediated the relationship between 24-h urinary sodium and subclinical left cardiac function. Furthermore, and more importantly, 24-h urinary sodium may have directly affected the left atrial function and left atrioventricular coupling independent of intermediary factors.
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Función del Atrio Izquierdo , Sodio en la Dieta , Humanos , Adulto , Persona de Mediana Edad , Anciano , Monitoreo Ambulatorio de la Presión Arterial , Radioisótopos de Sodio , ChinaRESUMEN
INTRODUCTION: The maculopathy in highly myopic eyes is complex. Its clinical diagnosis is a huge workload and subjective. To simply and quickly classify pathologic myopia (PM), a deep learning algorithm was developed and assessed to screen myopic maculopathy lesions based on color fundus photographs. METHODS: This study included 10,347 ocular fundus photographs from 7606 participants. Of these photographs, 8210 were used for training and validation, and 2137 for external testing. A deep learning algorithm was trained, validated, and externally tested to screen myopic maculopathy which was classified into four categories: normal or mild tessellated fundus, severe tessellated fundus, early-stage PM, and advanced-stage PM. The area under the precision-recall curve, the area under the receiver operating characteristic curve (AUC), sensitivity, specificity, accuracy, and Cohen's kappa were calculated and compared with those of retina specialists. RESULTS: In the validation data set, the model detected normal or mild tessellated fundus, severe tessellated fundus, early-stage PM, and advanced-stage PM with AUCs of 0.98, 0.95, 0.99, and 1.00, respectively; while in the external-testing data set of 2137 photographs, the model had AUCs of 0.99, 0.96, 0.98, and 1.00, respectively. CONCLUSIONS: We developed a deep learning model for detection and classification of myopic maculopathy based on fundus photographs. Our model achieved high sensitivities, specificities, and reliable Cohen's kappa, compared with those of attending ophthalmologists.
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Evidence has been presented demonstrating that CD8+ T cells confer anti-cancer effects, which offers a promising approach to enhance immunotherapy. M2-polarized tumor-associated macrophages (TAMs) could transfer RNA to cancer cells by secreting extracellular vesicles (EVs) and stimulate immune escape of cancer cells. Thus, the current study aimed at exploring how EVs derived from M2-polarized TAMs (M2-TAMs) affected the proliferation of ovarian cancer (OC) cells and apoptosis of CD8+ T cells. M2-TAMs were observed in OC tissues, which promoted proliferation of OC cells and CD8+ T cell apoptosis by secreting EVs. OC-associated differentially expressed gene NEAT1 was screened by bioinformatics analysis. The in vitro and in vivo effects of TAM-EVs-NEAT1 and its regulatory mechanism were assessed using gain- and loss-of-function assays in co-culture systems of TAMs-derived EVs, OC cells, and CD8+ T cells and in tumor-bearing mice. NEAT1 was highly expressed in M2-derived EVs and OC cells co-cultured with M2-derived EVs. NEAT1 sponged miR-101-3p to increase ZEB1 and PD-L1 expression. In vitro and in vivo assays confirmed the tumor-supporting effects of NEAT1 delivered by M2-derived EVs on OC cell proliferation and CD8+ T cell apoptosis as well as tumor growth. Collectively, M2-derived EVs containing NEAT1 exerted a tumor-promoting role in OC via the miR-101-3p/ZEB1/PD-L1 axis.
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Vesículas Extracelulares , MicroARNs , Neoplasias Ováricas , Humanos , Femenino , Animales , Ratones , Macrófagos Asociados a Tumores/metabolismo , Linfocitos T CD8-positivos/metabolismo , Antígeno B7-H1/metabolismo , Línea Celular Tumoral , Neoplasias Ováricas/patología , Vesículas Extracelulares/patología , MicroARNs/genética , Homeobox 1 de Unión a la E-Box con Dedos de Zinc/genéticaRESUMEN
Background: ß-blockers have been used in the treatment of end-stage renal disease (ESRD) patients and cardiovascular disease (CVD) patients, separately. However, the effects of ß-blockers on ESRD patients with CVD have not been fully investigated. This study sought to investigate the effects of ß-blockers therapy on the 28-day and 3-year survival rates of ESRD patients with pre-existing CVD who were admitted to the intensive care unit (ICU). Methods: After excluding patients without CVD, receiving a kidney transplant, not admitted to the ICU, and with missing baseline data, this cohort study included 1081 ESRD participants with CVD from the Medical Information Mark for Intensive Care III database. Baseline characteristics, including demographic data and clinical data, were collected. The outcomes were 28-day and 3-year survival rates of the patients. At the 28-day of ICU hospitalization, patients had a mean inpatient hospital stay of 24.7 days. At 3-year, the patients had a median survival time of 489.2 days. Univariate and multivariate Cox regression analyses were used to evaluate the effects of ß-blockers therapy on the 28-day and 3-year survival outcomes of ESRD patients with CVD. Results: The 28-day and 3-year survival rates were 82.8% and 37.9%, respectively. The mean age of the all patients was 68 years, and 642 were male. After adjusting for age, race, hyperlipidemia, dialysis, simplified acute physiological score (SAPS) II, sequential organ failure assessment (SOFA) score, glucocorticoid, hemoglobin, diabetes, hypertension, the 28-day survival rate of the ESRD patients with CVD requiring intensive care who received ß-blockers therapy was higher than that of the patients who did not receive the treatment. Similarly, after adjusting for age, race, hyperlipidemia, dialysis, SAPS II, SOFA score, glucocorticoid, hemoglobin, diabetes, hypertension, creatinine, the long-term survival rate of the patients who received ß-blockers therapy was also higher than that of those who did not. Conclusions: ß-blockers therapy was associated with increased 28-day and 3-year survival rates in ESRD patients with CVD requiring intensive care. Our findings may provide a theoretical basis for the prognostic impact of ß-blockers therapy among patients with ESRD and CVD who were admitted to the ICU.
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Objective: We aim to investigate the protective effect and underlying mechanisms of BMSCs-exo on human endometrial stromal cells (HESCs) induced by mifepristone in this study. Methods: BMSCs-exo were extracted and then identified by transmission electron microscopy and western-blot assay. RT-PCR assay was used to determine the level of miR-941. MiR-941 mimics or inhibitor were transfected into BMSCs and the exosomes were extracted. Then, Cell activity, apoptosis rate, cell migration and invasion, as well as the expression of angiogenic proteins were determined in HESCs stimulated by mifepristone and BMSCs-exo. Next, Dual-luciferase reporting assay was used to verify the targeted binding of miR-941 to TLR3, and the TLR3 expression in HESCs was detected by RT-PCR and western-blot. Finally, TLR3 was overexpressed to evaluate the effects of miR-941 from BMSCs-exo on cell apoptosis, cell invasion and angiogenesis in HESCs induced by mifepristone. Results: miR-941 was highly expressed in BMSCs-exo. Exosome miR-941 in BMSCs-exo inhibited the cell apoptosis, and promoted cell activity, cell migration, invasion as well as angiogenesis were also improved in HESCs induced by mifepristone. TLR3 was a target of miR-941, which was up-regulated in mifepristonetreated HESCs. We further found that miR-941 derived from BMSCs-exo down-regulated the expression of TLR3 in HESCs treated by mifepristone. In addition, TLR3 overexpression blocked the inhibition of miR-941 on mifepristone-induced cell apoptosis, as well as cell migration and angiogenesis in HESCs. Conclusions: Thus, we concluded that BMSCs-exo has protective effect on mifepristone-induced cell damage by delivering miR-941 which targeted TLR3 and regulated cell activity, migration, and angiogenesis in HESCs.
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Exosomas , Células Madre Mesenquimatosas , MicroARNs , Humanos , Exosomas/metabolismo , Mifepristona/farmacología , Mifepristona/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/metabolismo , MicroARNs/genética , MicroARNs/metabolismo , Células Madre Mesenquimatosas/metabolismoRESUMEN
Large dense-core vesicles (LDCVs) are larger in volume than synaptic vesicles, and are filled with multiple neuropeptides, hormones, and neurotransmitters that participate in various physiological processes. However, little is known about the mechanism determining the size of LDCVs. Here, it is reported that secretogranin II (SgII), a vesicle matrix protein, contributes to LDCV size regulation through its liquid-liquid phase separation in neuroendocrine cells. First, SgII undergoes pH-dependent polymerization and the polymerized SgII forms phase droplets with Ca2+ in vitro and in vivo. Further, the Ca2+ -induced SgII droplets recruit reconstituted bio-lipids, mimicking the LDCVs biogenesis. In addition, SgII knockdown leads to significant decrease of the quantal neurotransmitter release by affecting LDCV size, which is differently rescued by SgII truncations with different degrees of phase separation. In conclusion, it is shown that SgII is a unique intravesicular matrix protein undergoing liquid-liquid phase separation, and present novel insights into how SgII determines LDCV size and the quantal neurotransmitter release.
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Neuropéptidos , Secretogranina II , Vesículas de Núcleo Denso , Hormonas , Lípidos , Neurotransmisores/metabolismo , Secretogranina II/metabolismoRESUMEN
Background: TP53 mutations are associated with poor outcome for patients with endometrial carcinoma (EC). However, to date, there have been no studies focused on the construction of TP53 mutational status-associated signature in EC. In this study, we aim to conduct a TP53 mutation-associated prognostic gene signature for EC. Methods: Hence, we explored the mutational landscape of TP53 in patients with EC based on the simple nucleotide variation data downloaded from The Cancer Genome Atlas (TCGA) database. Differential expression analysis and least absolute shrinkage and selection operator (LASSO)-Cox analysis was used to establish TP53 mutation-associated prognostic gene signature. The overall survival rate between the high-risk and low-risk groups was compared by the Kaplan-Meier (K-M) method. Results: We found that the TP53 mutation was associated with poor outcome, older age, lower BMI, and higher grade and stage of EC in patients. A TP53 mutational status-associated signature was established based on transcriptome profiling data. Moreover, the patients in TCGA database were categorized into high- and low-risk groups. Kaplan-Meier (K-M) analysis indicated that the patients in the high-risk group have poor survival outcome. Furthermore, receiver operating characteristic (ROC) curves confirmed the robust prognostic prediction efficiency of the TP53 mutational status-associated signature. Finally, the prognostic ability was successfully verified in the other two datasets from cBioPortal database as well as in 60 clinical specimens. Univariate (hazard ratio (HR) = 1.041, 95%CI = 1.031-1.051, p < 0.001) and multivariate (hazard ratio (HR) = 1.029, 95%CI = 1.018-1.040, p < 0.001) Cox regression analyses indicated that the TP53 mutational status-associated signature could be used as an independent prognostic factor for EC patients. Conclusion: In summary, our research constructed a powerful TP53 mutational status-associated signature that could be a potential novel prognostic biomarker and therapeutic target for EC.
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Biomarcadores de Tumor , Neoplasias Endometriales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias Endometriales/genética , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Estimación de Kaplan-Meier , Modelos de Riesgos Proporcionales , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Effective treatments for age-related macular degeneration (AMD), the most prevalent neurodegenerative form of blindness in older adults, are lacking. Genome-wide association studies have identified lipid metabolism and inflammation as AMD-associated pathogenic changes. Liver X receptors (LXRs) play a critical role in intracellular homeostases, such as lipid metabolism, glucose homeostasis, inflammation, and mitochondrial function. However, its specific role in AMD and its underlying molecular mechanisms remain unknown. In this study, we investigated the effects of lipotoxicity in human retinal pigmental epithelial (ARPE-19) cells and evaluated how LXRs reduce 7-ketocholesterol (7KCh) lipotoxicity in RPE cells using models, both in vivo and in vitro. A decrease in oxidative lipid accumulation was observed in mouse retinas following the activation of the LXRs; this result was also confirmed in cell experiments. At the same time, LXRs activation reduced RPE cell apoptosis induced by oxysterols. We found that oxysterols decreased the mitochondrial membrane potential in ARPE-19 cells, while LXR agonists counteracted these effects. In cultured ARPE-19 cells, activating LXRs reduced p62, mTOR, and LC3I/II levels, and the knockdown of LXRs elevated the expression of these proteins, indicating that activating LXRs could boost mitophagy. The findings of this study suggest LXR-active pharmaceuticals as a potential therapeutic target for dry AMD.
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Degeneración Macular , Oxiesteroles , Animales , Estudio de Asociación del Genoma Completo , Inflamación/metabolismo , Receptores X del Hígado/genética , Receptores X del Hígado/metabolismo , Degeneración Macular/metabolismo , Ratones , Mitocondrias/metabolismo , Oxiesteroles/metabolismo , Oxiesteroles/toxicidad , Epitelio Pigmentado de la RetinaRESUMEN
At present, there are widespread financing difficulties in China's trade circulation industry. Supply chain finance can provide financing for small- and medium-sized enterprises in China's trade circulation industry, but it will produce financing risks such as credit risks. It is necessary to analyze the causes of the risks in the supply chain finance of the trade circulation industry and measure these risks by establishing a credit risk assessment system. In this article, a supply chain financial risk early warning index system is established, including 4 first-level indicators and 29 third-level indicators. Then, on the basis of the supply chain financial risk early warning index system, combined with the method of convolution neural network, the supply chain financial risk early warning model of trade circulation industry is constructed, and the evaluation index is measured by the method of principal component analysis. Finally, the relevant data of trade circulation enterprises are selected to make an empirical analysis of the model. The conclusion shows that the supply chain financial risk early warning model and risk control measures established in this article have certain reference value for the commercial circulation industry to carry out supply chain finance. It also provides guidance for trade circulation enterprises to deal with supply chain financial risks effectively.
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Industrias , Redes Neurales de la Computación , China , Medición de RiesgoRESUMEN
Currently, the prevention of ischemic diseases such as myocardial infarction associated with ischemia/reperfusion (I/R) injury remains to be a challenge. Thus, this study was designed to explore the effects of tripartite motif protein 11 (TRIM11) on cardiomyocytes I/R injury and its underlying mechanism. Cardiomyocytes AC16 were used to establish an I/R injury cell model. After TRIM11 downregulation in I/R cells, cell proliferation (0, 12, 24, and 48 h) and apoptosis at 48 h as well as the related molecular changes in oxidative stress-related pathways was detected. Further, after the treatment of TRIM11 overexpression, SP600125, or DUSP1 overexpression, cell proliferation, apoptosis, and related genes were detected again. As per our findings, it was determined that TRIM11 was highly expressed in the cardiomyocytes AC16 after I/R injury. Downregulation of TRIM11 was determined to have significantly reduced I/R-induced proliferation suppression and apoptosis. Besides, I/R-activated c-Jun N-terminal kinase (JNK) signaling and cleaved caspase 3 and Bax expression were significantly inhibited by TRIM11 downregulation. In addition, the overexpression of TRIM11 significantly promoted apoptosis in AC16 cells, and JNK1/2 inhibition and DUSP1 overexpression potently counteracted the induction of TRIM11 overexpression in AC16 cells. These suggested that the downregulation of TRIM11 attenuates apoptosis in AC16 cells after I/R injury probably through the DUSP1-JNK1/2 pathways.