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1.
Biochem Biophys Res Commun ; 499(4): 815-821, 2018 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-29621541

RESUMEN

Krüppel-like factor 9 (KLF9) has been implicated in mediating a diverse range of biological processes. However, the expression pattern and biological functions of KLF9 in pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here, we evaluated the role of KLF9 in pancreatic ductal adenocarcinoma (PDAC). Overexpression of KLF9 significantly inhibited proliferation and clone formation in PDAC cells, while silencing KLF9 expression dramatically promoted this effect in vitro. Knocking down the expression of KLF9 also promoted the tumorigenesis in the PDAC mouse xneograft model. In in vitro mechanism study, KLF9 negatively regulated the activity of wnt/beta-catenin pathway in Top/Fop reporter assay. Frizzled-5, a key component involving in this pathway, was sharp inhibited by KLF9 both in mRNA and protein level. Furthermore, a KLF9-binding site (BTE) was identified in the promoter region of Frizzled-5. Mutation or deletion of this BTE strongly disrupted the KLF9's regulatory effect on Frizzled-5. More importantly, the expression level of KLF9 was significantly lower in clinical PDAC tissue compared to matched normal tissues and inversely associated with survival of the patients. Together, our findings indicated that KLF9 suppressed tumorigenicity of the pancreatic ductal adenocarcinoma by negatively regulating frizzled-5.


Asunto(s)
Carcinogénesis/genética , Carcinogénesis/patología , Carcinoma Ductal Pancreático/patología , Receptores Frizzled/genética , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción de Tipo Kruppel/metabolismo , Neoplasias Pancreáticas/patología , Animales , Secuencia de Bases , Carcinoma Ductal Pancreático/genética , Línea Celular Tumoral , Proliferación Celular/genética , Receptores Frizzled/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Ratones Desnudos , Neoplasias Pancreáticas/genética , Regiones Promotoras Genéticas/genética , Vía de Señalización Wnt , Neoplasias Pancreáticas
3.
Curr Med Sci ; 42(2): 317-326, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35290603

RESUMEN

OBJECTIVE: To examine the independent risk factors of type-2 myocardial infarction (T2MI) elicited by acute upper gastrointestinal bleeding (AUGIB), and to establish a nomogram model for the prediction of AUGIB-induced T2MI. METHODS: A nomogram model was established on the basis of a retrospective study that involved 533 patients who suffered from AUGIB in the Department of Critical Care Medicine (CCM) or Emergency Intensive Care Unit (EICU) of Renmin Hospital of Wuhan University, Wuhan, China, from January 2017 to December 2020. The predictive accuracy and discriminative power of the nomogram were initially evaluated by internal validation, which involved drawing the receiver operating characteristic (ROC) curve, calculating the area under the curve (AUC), plotting the calibration curve derived from 1000 resampled bootstrap data sets, and computing the root mean square error (RMSE). The predictive ability of the nomogram was further validated through the prospective and multicenter study conducted by the investigators, which enrolled 240 AUGIB patients [including 88 cases from Renmin Hospital of Wuhan University, 73 cases from Qilu Hospital of Shandong University (Qingdao), and 79 cases from Northern Jiangsu People's Hospital)], who were admitted to the Department of CCM or EICU, from February 2021 to July 2021. RESULTS: Among the 533 patients in the training cohort, 78 (14.6%) patients were assigned to the T2MI group and 455 (85.4%) patients were assigned to the non-T2MI group. The multivariate analysis revealed that age >65, hemorrhagic shock, cerebral stroke, heart failure, chronic kidney disease, increased blood urea nitrogen, decreased hematocrit, and elevated D-Dimer were independent risk factors for AUGIB-induced T2MI. All these factors were incorporated into the nomogram model. The AUC for the nomogram for predicting T2MI was 0.829 (95% CI, 0.783-0.875) in the internal validation cohort and 0.848 (95% CI, 0.794-0.902) in the external validation cohort. The calibration curve for the risk of T2MI exhibited good consistency between the prediction by the nomogram and the actual clinical observation in both the internal validation (RMSE=0.016) and external validation (RMSE=0.020). CONCLUSION: The nomogram was proven to be a useful tool for the risk stratification of T2MI in AUGIB patients, and is helpful for the early identification of AUGIB patients who are prone to T2MI for early intervention, especially in emergency departments and intensive care units.


Asunto(s)
Infarto del Miocardio , Nomogramas , Enfermedad Aguda , Hemorragia Gastrointestinal/diagnóstico , Hemorragia Gastrointestinal/etiología , Humanos , Infarto del Miocardio/diagnóstico , Infarto del Miocardio/epidemiología , Pronóstico , Estudios Prospectivos , Estudios Retrospectivos
4.
Oxid Med Cell Longev ; 2021: 6675264, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33728026

RESUMEN

Acute lung injury (ALI) is a serious respiratory syndrome characterized with uncontrolled inflammatory response. Oxyberberine has strong potential for clinical usage since it showed strong anti-inflammatory, antifungal, and antiarrhythmic effects in various diseases. In the present study, we evaluated whether oxyberberine can inhibit lipopolysaccharide- (LPS-) induced ALI in vivo and further evaluated the possible involvement of mitophagy in vitro by using A549 cells, a human lung epithelial cell line. Our in vivo study shows that oxyberberine significantly inhibited LPS-induced lung pathological injury and lung edema, as indicated by the changes in lung wet/dry ratio and total protein levels in the BALF in mice. Moreover, oxyberberine inhibited inflammation, as indicated by the changes of neutrophil accumulation and production of proinflammatory cytokines including tumor necrosis factor α (TNF-α), interleukin 1ß (IL-1ß), and IL-6 in both the lung and bronchoalveolar lavage fluid (BALF) in ALI mice. Our in vitro study shows that LPS significantly decreased the protein level of mitochondrial proteins, including cytochrome c oxidase subunit IV (COX IV), p62, and mitofusin-2 (Mfn2) in A549 cells. In addition, LPS induced significant Parkin1 translocation from cytoplasm to mitochondria. These changes were significantly inhibited by oxyberberine. Notably, the inhibitory effect of oxyberberine was almost totally lost in the presence of lysosome fusion inhibitor bafilomycin A1 (Baf), a mitophagy inhibitor. In conclusion, the present study demonstrated that oxyberberine alleviated LPS-induced inflammation in ALI via inhibition of Parkin-mediated mitophagy.


Asunto(s)
Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/prevención & control , Berberina/uso terapéutico , Mitofagia , Células A549 , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/patología , Animales , Apoptosis/efectos de los fármacos , Berberina/farmacología , Líquido del Lavado Bronquioalveolar , Edema/patología , Humanos , Inflamación/patología , Lipopolisacáridos , Pulmón/efectos de los fármacos , Pulmón/patología , Macrólidos/farmacología , Masculino , Ratones Endogámicos BALB C , Mitofagia/efectos de los fármacos , Neutrófilos/efectos de los fármacos , Neutrófilos/patología , Especies Reactivas de Oxígeno/metabolismo
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