Assessment of Developmental and Reproductive Fitness of Dengue-Resistant Transgenic Aedes aegypti and Improvement of Fitness Using AntibioticsRead the full article
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Mechanisms of Trx2/ASK1-Mediated Mitochondrial Injury in Pemphigus Vulgaris
Objective. Apoptotic events mediated by mitochondrial injury play an important role on the onset of Pemphigus vulgaris (PV). The thioredoxin-2 (Trx2)/apoptosis signal-regulating kinase 1 (ASK1) signaling pathway is considered a key cascade involved on the regulation of mitochondrial injury. Hence, we have investigated the regulatory mechanism of the Trx2/ASK1 signaling in PV-induced mitochondrial injury. Methods. Serum and tissue samples were collected from clinical PV patients to detect the oxidative stress factors, cell apoptosis, and expression of members from Trx2/ASK1 signaling. HaCaT cells were cultured with the serum of PV patients and transfected with Trx2 overexpression or silencing vector. Changes in the levels of reactive oxygen species (ROS), mitochondrial membrane potential (△ψm), and apoptosis were further evaluated. A PV mouse model was established and administered with Trx2-overexpressing plasmid. The effect of ectopic Trx2 expression towards acantholysis in PV mice was observed. Results. A series of cellular and molecular effects, including (i) increased levels of oxidative stress products, (ii) destruction of epithelial cells in the skin tissues, (iii) induction of apoptosis in keratinocytes, (iv) reduction of Trx2 protein levels, and (v) enhanced phosphorylation of ASK1, were detected in PV patients. In vitro experiments confirmed that Trx2 can inhibit ASK1 phosphorylation, alleviate ROS release, decrease △ψm, and lower the apoptotic rate. Injection of Trx2-overexpressing vectors in vivo could also relieve acantholysis and blister formation in PV mice. Conclusion. The Trx2/ASK1 signaling pathway regulates the incidence of PV mediated by mitochondrial injury.
DUOX2 As a Potential Prognostic Marker which Promotes Cell Motility and Proliferation in Pancreatic Cancer
DUOX2 has been reported to highly express in several types of cancers. However, the prognostic significance and the biological function of DUOX2 expression with pancreatic cancer (PC) still remain unclear. The present study is aimed at investigating whether DUOX2 could act as a novel biomarker of prognosis and evaluating its effect on PC cell progression. The mRNA and protein expression of DUOX2 in PC cells and tissues were assessed by quantitative real-time PCR (RT-qPCR) and immunohistochemistry. The effect of DUOX2 expression on PC cell motility and proliferation was evaluated in vitro. The correlation between DUOX2 mRNA expression and clinicopathological features and its prognostic significance were analyzed according to the Gene Expression Profiling Interactive Analysis (GEPIA) website based on The Cancer Genome Atlas (TCGA) and the GTEx databases combined with our clinical information. According to bioinformatics analysis, we forecasted the upstream transcription factors (TFs) and microRNA (miRNA) regulatory mechanism of DUOX2 in PC. The expression of DUOX2 at transcriptional and protein level was dramatically increased in PC specimens when compared to adjacent nontumor specimens. Functionally, DUOX2 knockdown inhibited cell motility and proliferation activities. Our clinical data revealed that the patients had better postoperative overall survival (OS) with lower expression of DUOX2, which is consistent with GEPIA data. Multivariate analysis revealed that high DUOX2 expression was considered as an independent prognostic indicator for OS (). Based on Cistrome database, the top 5 TFs of each positively and negatively association with DUOX2 were predicted. hsa-miR-5193 and hsa-miR-1343-3p targeting DUOX2 were forecasted from TargetScan, miRDB, and DIANA-TarBase databases, which were negatively correlated with OS ( and , respectively) and DUOX2 expression ( and , respectively) in PC from TCGA data. These findings suggest that DUOX2 acts as a promising predictive biomarker and an oncogene in PC, which could be a therapeutic target for PC.
Novel Mutations of COL4A5 Identified in Chinese Families with X-Linked Alport Syndrome and Literature Review
Alport syndrome (AS) is an inherited kidney disease caused by defects in type IV collagen, which is characterized by hematuria, progressive nephritis or end-stage renal disease (ESRD), hearing loss, and occasionally ocular lesions. Approximately 80% of AS cases are caused by X-linked mutations in the COL4A5 gene. This study explored novel deletion and missense mutations in COL4A5 responsible for renal disorder in two Han Chinese families. In pedigree 1, the five male patients all had ESRD at a young age, while the affected female members only presented with microscopic hematuria. Whole exome sequencing and Sanger sequencing identified a novel frameshift deletion mutation (c.422_428del, p.Leu142Valfs11) in exon 7 of COL4A5. In pedigree 2, the 16-year-old male proband had elevated serum creatinine (309 μmol/L) without extrarenal manifestations, while his mother only manifested with hematuria. A missense mutation (c.476G>T, p.Gly159Val) was found in exon 9 of the COL4A5 gene. Neither of these mutations was present in the Exome Variant Server of the NHLBI-ESP database, nor was it found in the ExAC or 1000 Genomes databases. Through the literature review, it was found that male Chinese patients with X-linked AS carried COL4A5 deletion or missense mutations had a more severe phenotype than female patients, particularly in proteinuria and impaired renal function. Compared to male patients with missense mutations, patients in whom deletion mutations were found were more likely to progress to ESRD (15.4% vs. 36.0%, ). This study identified two novel COL4A5 mutations in Chinese families with X-linked AS, expanded the mutational spectrum of the COL4A5 gene, and presented findings that are significant for the screening and genetic diagnosis of AS.
Level of Preparedness for COVID-19 and Its Associated Factors among Frontline Healthcare Providers in South Gondar Public Hospitals, Northwest Ethiopia, 2020: A Multicenter Cross-Sectional Study
Introduction. Although the efforts at global and national levels have attempted to decrease the COVID-19 pandemic, the low level of preparedness among healthcare providers is a challenge mainly in developing countries. Hence, this study is aimed at assessing the level of preparedness for COVID-19 and its associated factors among frontline healthcare providers in South Gondar public hospitals, northwest Ethiopia. Methods and Materials. A hospital-based cross-sectional study was conducted among 207 selected healthcare providers who were working in South Gondar public hospital from July 08 to August 29, 2020. A pretested structured questionnaire was used to collect data. The healthcare providers were selected through simple random sampling techniques. Both bivariable and multivariable logistic regressions with a 95% confidence interval were fitted with 95% CI to establish the associated factors with a low level of preparedness. A value < 0.05 was considered statistically significant. Results. The overall level of preparedness among healthcare providers for COVID-19 was found to be 41.3% (95% CI: 37.4, 44.7). Only 81 (40.1%) healthcare providers had prepared for telling their family and friends if they are infected with COVID-19. Besides, only 23.8% of healthcare providers obtained alcohol-based hand sanitizer in every patient room. Factors associated with a low level of preparedness include being male (, 95% CI: 1.22–4.94), unmarried (, 95% CI: 1.44–8.00), and working experience less than five years (, 95% CI: 1.29-9.09). Conclusion. The level of preparedness among frontline healthcare providers towards COVID-19 was found to be very low. In the future, more emphasis should be placed on healthcare providers who are male, unmarried, and had working experience of lower than five years to decrease the burden of the COVID-19 pandemic.
Correlation between TNF-α -308 and +489 Gene Polymorphism and Acute Exacerbation of Chronic Obstructive Pulmonary Diseases
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is becoming a common respiratory disease, leading to increased morbidity and mortality worldwide. Tumor necrosis factor-alpha (TNF-α) is a powerful proinflammatory cytokine involved in the pathogenesis of AECOPD. Therefore, we proposed a close correlation between the TNF-α polymorphism [-308G/A (rs1800629), +489G/A (rs1800610)] and the disease progress of patients with AECOPD. Comparison of the TNF-α genotypes between the 198 AECOPD diagnosed patients groups and 195 healthy peoples suggested their significant differences of the three genotypes (AA, GA, GG) distribution for TNF-α -308 (), but no differences of that for TNF-α +489. We found that patients with TNF-α -308 GA/AA genotypes showed smaller adjacent arterial diameter, thicker bronchial wall, higher bronchial artery ratio, higher bronchial wall grading, and higher frequency of acute exacerbations than those with TNF-α -308 GG genotype. Patients with TNF-α +489 GA/AA genotypes showed the same AECOPD properties as patients with TNF-α -308 except for the high frequency of acute exacerbations. Further experiment showed that the TNF-α -308 and+489 gene polymorphisms could affect the expression level of TNF-α in macrophages, suggesting the involvement of the macrophage population in disease regulation of AECOPD patients with TNF-α -308G/A and+489G/A genotype heterogeneity. In conclusion, the TNF-α -308 G/A genotype was related to AECOPD susceptibility and progress, while the TNF-α +489G/A genotype was related to AECOPD progress, but not AECOPD susceptibility.
Focal Adhesion Kinase Inhibitor Inhibits the Oxidative Damage Induced by Central Venous Catheter via Abolishing Focal Adhesion Kinase-Protein Kinase B Pathway Activation
The vascular injury induced by central venous catheter (CVC) indwelling is the basis for the occurrence and development of CVC-related complications, such as phlebitis, venous thrombosis, and catheter-related infections. Focal adhesion kinase (FAK) and FAK-protein kinase B (AKT) signaling pathway are of great significance in tissue repair after trauma. Here, we investigated the role and mechanism of the FAK inhibitor (1,2,4,5-phenyltetramine tetrahydrochloride (Y15)) in oxidative damage caused by CVC. EA.hy926 cells were divided into the control group (normal control), CVCs+scratches group (the intercepted CVC segments coculturing with scratched EA.hy926 cells), and CVCs+scratches+Y15 group (Y15 was added to the cell culture supernatant with at a final concentration of 50 μmol·L-1). New Zealand rabbits were randomly divided into the control group (normal control), CVC group (CVC was inserted through the rabbit’s right jugular vein to the junction of the right atrium and superior vena cava), and CVC+Y15 group (CVC was immersed in a 50 μmol·L-1 Y15 solutions before insertion). The levels of markers and proteins related to oxidative damage in cells, cell culture supernatant, serum, and external jugular vein were measured by commercial kits and western blot, respectively. We found that Y15 treatment significantly decreased ROS and MDA levels and increased cell viability, NO, and SOD levels in a time-dependent manner in rabbit serum and cell culture supernatant. In addition, Y15 effectively reduced the CVC-induced pathological changes of damaged vascular tissues. Y15 also downregulated the levels of p-FAK Tyr 397 and p-Akt Ser 473 in damaged external jugular vein and EA.hy926 cells. These findings suggest that Y15 alleviated CVC-induced oxidative damage to blood vessels by suppressing focal FAK-Akt pathway activation.