Melatonin alleviates hyperoxia-induced lung injury through elevating MSC exosomal miR-18a-5p expression to repress PUM2 signaling.

Mesenchymal stem cells (MSC)-derived exosomes (Exo) are a possible option for hyperoxia-induced lung injury (HLI). We wanted to see if melatonin (MT)-pretreated MSC-derived exosomes (MT-Exo) were more effective against HLI, and we also tried to figure out the underlying mechanism. HLI models were established by hyperoxia exposure. HE staining was adopted to analyze lung pathological changes. MTT and flow cytometry were used to determine cell viability and apoptosis, respectively. The mitochondrial membrane potential (MMP) was analyzed using the JC-1 probe. LDH, ROS, SOD, and GSH-Px levels were examined by the corresponding kits. The interactions between miR-18a-5p, PUM2, and DUB3 were analyzed by molecular interaction experiments. MT-Exo could effectively inhibit hyperoxia-induced oxidative stress, inflammatory injury, and apoptosis in lung epithelial cells, while these effects of MT-Exo were weakened by miR-18a-5p knockdown in MSCs. miR-18a-5p reduced PUM2 expression in MLE-12 cells by directly targeting PUM2. In addition, PUM2 inactivated the Nrf2/HO-1 signaling pathway by promoting DUB3 mRNA decay post-transcriptionally. As expected, PUM2 overexpression or DUB3 knockdown abolished the protective effect of MT-Exo on hyperoxia-induced lung epithelial cell injury. MT-Exo carrying miR-18a-5p reduced hyperoxia-mediated lung injury in mice through activating Nrf2/HO-1 pathway. MT reduced PUM2 expression and subsequently activated the DUB3/Nrf2/HO-1 signal axis by increasing miR-18a-5p expression in MSC-derived exosomes to alleviate HLI.

Upregulation of miR-184 and miR-19a-3p induces endothelial dysfunction by targeting AGO2 in Kawasaki disease.

BACKGROUND: Endothelial dysfunction is a marked feature of Kawasaki disease during convalescence, but its pathogenesis is currently unclear. Circulating microRNAs (miRNAs) are associated with the progression of Kawasaki disease. However, the role and mechanism of circulating miRNAs in endothelial dysfunction are largely unknown. Kawasaki disease patients were found to have a unique circulating miRNA profile, including upregulation of miRNA-210-3p, miR-184 and miR-19a-3p, compared to non-Kawasaki disease febrile controls. This study aimed to investigate the effects of these three miRNAs on endothelial function. METHODS: Overexpression of miRNAs in human umbilical vein endothelial cells was done by transfection of miRNA mimics. The tube formation assay was used to evaluate the function of human umbilical vein endothelial cells. The potential binding sites of miRNAs on 3'untranslated regions were predicted by using TargetScan database and validated by dual luciferase reporter assay. The protein expression of AGO2, PTEN and VEGF in human umbilical vein endothelial cells was detected by Western blot. Overexpression of AGO2 in human umbilical vein endothelial cells was done by transfection of AGO2 expression plasmids. RESULTS: Overexpression of miRNA-184 and miRNA-19a-3p, but not miR-210-3p, impaired the function of human umbilical vein endothelial cells. Mechanistically, miR-184 and miR-19a-3p could target the 3'untranslated regions of AGO2 mRNA to downregulate its expression and subsequently impede the AGO2/PTEN/VEGF axis. To be noted, the rescue of the expression of AGO2 remarkably recovered the function that was impaired by overexpression of miRNA-184 and miRNA-19a-3p. CONCLUSIONS: This study suggested that miR-184 and miR-19a-3p could target AGO2/PTEN/VEGF axis to induce endothelial dysfunction in Kawasaki disease.

Impaired SUMOylation of FoxA1 promotes nonalcoholic fatty liver disease through down-regulation of Sirt6.

Abnormal SUMOylation is implicated in non-alcoholic fatty liver disease (NAFLD) progression. Forkhead box protein A1 (FoxA1) has been shown to protect liver from steatosis, which was down-regulated in NAFLD. This study elucidated the role of FoxA1 deSUMOylation in NAFLD. NAFLD models were established in high-fat diet (HFD)-induced mice and palmitate acid (PAL)-treated hepatocytes. Hepatic steatosis was evaluated by biochemical and histological methods. Lipid droplet formation was determined by BODIPY and Oil red O staining. Target molecule levels were analyzed by RT-qPCR, Western blotting, and immunohistochemistry staining. SUMOylation of FoxA1 was determined by Ni-NTA pull-down assay and SUMOylation assay Ultra Kit. Protein interaction and ubiquitination were detected by Co-IP. Gene transcription was assessed by ChIP and dual luciferase reporter assays. Liver FoxA1 knockout mice developed severe liver steatosis, which could be ameliorated by sirtuin 6 (Sirt6) overexpression. Nutritional stresses reduced Sumo2/3-mediated FoxA1 SUMOylation at lysine residue K6, which promoted lipid droplet formation by repressing fatty acid ß-oxidation. Moreover, Sirt6 was a target gene of FoxA1, and Sirt6 transcription activity was restrained by deSUMOylation of FoxA1 at site K6. Furthermore, nutritional stresses-induced deSUMOylation of FoxA1 promoted the ubiquitination and degradation of FoxA1 with assistance of murine double minute 2 (Mdm2). Finally, activating FoxA1 SUMOylation delayed the progression of NAFLD in mice. DeSUMOylation of FoxA1 at K6 promotes FoxA1 degradation and then inhibits Sirt6 transcription, thereby suppressing fatty acid ß-oxidation and facilitating NAFLD development. Our findings suggest that FoxA1 SUMOylation activation might be a promising therapeutic strategy for NAFLD.

Idiopathic mesenteric phlebosclerosis missed by a radiologist at initial diagnosis: A case report.

BACKGROUND: Idiopathic mesenteric phlebosclerosis (IMP) is a rare type of ischemic colitis characterized by thickening of the wall of the right hemicolon and calcification, sclerosis, and fibrosis of mesenteric veins. The diagnosis of IMP is based on typical clinical features and imaging findings. We report a case of IMP that was initially missed by the radiologist. CASE SUMMARY: A 77-year-old woman was admitted to the hospital due to chronic diarrhea for over 2 months. She had been consuming Chinese patent medicines (CPM) containing fructus gardeniae for more than 15 years. Colonoscopy revealed an edematous mucosa, bluish-purple discoloration, erosions, and ulcerations throughout the colorectal area. Abdominal computed tomography (CT) showed diffuse mural thickening of the entire colorectum, with tortuous thread-like calcifications in the right hemicolon, left hemicolon, and rectum. Most of the calcifications were located in the mesenteric vein. The diagnosis of IMP was established based on medical history, colonoscopy, CT findings, and histopathological examination. The patient was treated conservatively with papaverine and rifaximin, and CPM was stopped. Her diarrhea symptoms improved, indicating the effectiveness of the treatment. Over the next several years, she took opium alkaloids for an extended period and did not require hospitalization for the aforementioned gastrointestinal disorder. CONCLUSION: IMP is a rare gastrointestinal disease affecting Asian populations, possibly related to long-term herbal medicine intake. Accurate imaging analysis is crucial for diagnosis, but insufficient understanding of the disease can lead to misdiagnosis or missed diagnosis. Treatment strategies should be personalized.

Exploring the diagnostic value of CLR and CPR in differentiating Kawasaki disease from other infectious diseases based on clinical predictive modeling.

Background: Kawasaki disease (KD) is an important cause of acquired heart disease in children and adolescents worldwide. KD and infectious diseases can be easily confused when the clinical presentation is inadequate or atypical, leading to misdiagnosis or underdiagnosis of KD. In turn, misdiagnosis or underdiagnosis of KD can lead to delayed use of intravenous immunoglobulin (IVIG), increasing the risk of drug resistance and coronary artery lesions (CAL). Objectives: The purpose of this study was to develop a predictive model for identifying KD and infectious diseases in children in the hope of helping pediatricians develop timely and accurate treatment plans. Methods: The data Patients diagnosed with KD from January 2018 to July 2022 in Shenzhen Longgang District Maternity & Child Healthcare Hospital, and children diagnosed with infectious diseases in the same period will be included in this study as controls. We collected demographic information, clinical presentation, and laboratory data on KD before receiving IVIG treatment. All statistical analyses were performed using R-4.2.1 (https://www.rproject.org/). Logistic regression and Least Absolute Shrinkage with Selection Operator (LASSO) regression analyses were used to build predictive models. Calibration curves and C-index were used to validate the accuracy of the prediction models. Results: A total of 1,377 children were enrolled in this study, 187 patients with KD were included in the KD group and 1,190 children with infectious diseases were included in the infected group. We identified 15 variables as independent risk factors for KD by LASSO analysis. Then by logistic regression we identified 7 variables for the construction of nomogram including white blood cell (WBC), Monocyte (MO), erythrocyte sedimentation rate (ESR), alanine transaminase (ALT), albumin (ALB), C-reactive protein to procalcitonin ratio (CPR) and C-reactive protein to lymphocyte ratio (CLR). The calibration curve and C-index of 0.969 (95% confidence interval: 0.960-0.978) validated the model accuracy. Conclusion: Our predictive model can be used to discriminate KD from infectious diseases. Using this predictive model, it may be possible to provide an early determination of the use of IVIG and the application of antibiotics as soon as possible.

Exploring the diagnostic value of eosinophil-to-lymphocyte ratio to differentiate Kawasaki disease from other febrile diseases based on clinical prediction model.

Kawasaki disease (KD) is a febrile disease that affects children under 5 years of age and leads to serious cardiovascular complications such as coronary artery disease. The development of markers that can predict early is important to reduce the under- and misdiagnosis of KD. The aim of this research was to develop a diagnostic predictive model to differentiate Kawasaki disease (KD) from other febrile diseases using eosinophil-to-lymphocyte ratio (ELR) and other biomarkers. We recruited a total of 190 children with KD and 1604 children with other febrile diseases. We retrospectively collected clinical information from the children, which included laboratory data on the day of admission, such as white blood cells (WBC), hemoglobin (HGB), calcitoninogen (PCT), hypersensitive c-reactive protein (CRP), snake prognostic nutritional index (PNI), peripheral blood neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and ELR. We performed analyses using univariate analysis, multivariate logistic regression, and column line plots, and evaluated the diagnostic parameters of the predictive models. ELR was significantly increased in patients with KD. After multivariate logistic regression, WBC, HGB, CRP, NLR, ELR and PNI were finally included as indicators for constructing the prediction model. The ROC curve analysis suggested that the C-index of the diagnostic prediction model was 0.921. The calibration curve showed good diagnostic performance of the columnar graph model. The cut-off value of ELR alone for KD was 0.04, the area under the ROC curve was 0.809. Kids with KD show highly expressive level of ELR compared to children with febrile disease, which can be used to diagnose KD, and column line graphs constructed together with other indicators can help pediatricians to identify KD more effectively from febrile children.