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Atherosclerosis, a chronic inflammatory condition that leads to a variety of life-threatening cardiovascular diseases, is a worldwide public health concern. Endothelial cells (ECs), which line the inside of blood vessels, play an important role in atherogenic initiation. Endothelial activation and inflammation are indispensable for the early stage of atherosclerosis. Ubiquitin-specific protease 14 (USP14), a deubiquitinating enzyme that regulates the stability and activity of target proteins, has been identified as a potential therapeutic target for many inflammatory diseases. However, the role of USP14 on ECs is undefined. In this study, we found that USP14 is downregulated in either atherosclerosis patient specimens or oxidized low-density lipoprotein (ox-LDL)-stimulated ECs as compared to the control group. Overexpression of USP14 in ECs restrains ox-LDL-stimulated nuclear transcription factor kappa B (NF-κB) activation and subsequent adhesion molecule production. USP14 inhibits endothelium proinflammatory activation by suppressing the degradation of the negative regulator of NF-κB signaling, nod-like receptor family caspase recruitment domain family domain containing 5 (NLRC5). Finally, our in vivo experiments confirmed that USP14 adenovirus injection in apolipoprotein E deficient (ApoE-/-) mice fed with a western diet reduced the atherosclerotic lesion size, inhibited macrophage accumulation in the intima, and restricted the progression of atherosclerosis. Our results reveal that USP14 may represent a new therapeutic target for atherosclerosis.

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Allograft rejection is a major obstacle for the long-term survival of heart transplantation (Htx) patients. The cardiac allograft rejection requires the activation of macrophages and effector T cells. In this study, we explored the role of zinc-finger and BTB domain containing protein 20 (ZBTB20) in the regulation of heart allograft rejection. Flow cytometry analysis of the spleen cells from mice undergoing an acute cardiac rejection revealed that the ZBTB20 protein expression was upregulated in both T and B cells(n = 4，P < 0.01). In addition, ZBTB20 gene knockdown significantly prolonged the survival of heart allografts in mice(n = 4，P < 0.01). Lack of ZBTB20 increased the expression of Foxp3 and limited the response of T helper 1 (Th1) cells(n = 4，P < 0.01). The ZBTB20-related regulation occurred through the activation of the NFкB pathway. In conclusion, our data suggest that ZBTB20 is involved in the regulation of T cells involved in acute heart allograft rejection. Hence, downregulation of ZBTB20 expression may inhibit T cells to prolong heart transplant survival.

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OBJECTIVE: The objective of this study was to investigate population-based epidemiology, survival outcomes, and prognostic factors of malignant carotid body tumors (CBTs). METHODS: Patients with malignant CBTs who were diagnosed between 1975 and 2018 were screened from nine registries of the Surveillance, Epidemiology, and End Results (SEER) database. Cases that were coded as "carotid body tumor, malignant" or malignant tumors with the primary site recorded as "carotid body" were screened for inclusion in the study. The incidence of malignant CBT was calculated with SEER∗Stat software. Survival outcomes were analyzed using the Kaplan-Meier method and log-rank tests. RESULTS: A total of 72 patients with malignant CBT were screened for inclusion in the study, including 41 females (56.9%) and 31 males (43.1%). Based on the SEER program data, the incidence of malignant CBT was found to fluctuate between 0 to 0.02 cases per 100,000 people per year, with a slow but noticeable uptick after 1990. The most commonly affected populations included women and patients between the ages of 35 and 44, which accounted for 59.9% and 27.8% of patients in the study, respectively. During a median follow-up of 82 months, four patients were lost to follow-up, and 28 deaths were identified. Of those, 20 were considered disease-specific deaths. Further analysis found that the 5-year and 10-year overall survival rates were 78.9% and 67.8%, respectively, whereas the 5-year and 10-year disease-specific survival rates were 84.5% and 75.2%, respectively. The Kaplan-Meier method and log-rank tests indicated that age <50 years, sex, race, tumor number, and surgical treatment were unrelated to both overall survival and disease-specific survival. CONCLUSIONS: A retrospective review of the SEER database found that the incidence of malignant CBT was extremely rare and prone to fluctuation, but that it slowly trended upward over time. Malignant CBT was found to more likely affect females, and it could be diagnosed at any age. The overall prognosis for malignant CBT appeared to be good, with acceptable 5-year and 10-year survival rates. Due to a number of factors complicating malignant CBT surgery, surgical treatment should be considered with caution.

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BACKGROUND: With the progress of shock therapy and the establishment and promotion of methods such as thrombolytic therapy and percutaneous coronary intervention (PCI), many tissues and organs have been reperfused after ischemia which may cause even worse disorder called ischemia-reperfusion injury (IRI). mRNAs have been found to have significant impacts on ischemia-reperfusion through various mechanisms. In view of the accessibility of mRNAs from blood, we aimed to find the association between mRNA and ischemia-reperfusion. METHODS: We used the GSE83472 dataset from the Gene Expression Omnibus (GEO) database to find differential RNA expression between ischemia-reperfusion tissue and control samples. In addition, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to find the biological property of 449 RNAs from GSE83472 via the Database for Annotation, Visualization, and Integrated Discovery (DAVID). Besides, Gene Set Enrichment Analysis (GSEA), a tool to find the pathway orientation of a gene set, was used for further study in the four most significant KEGG pathways. Furthermore, we constructed a protein-protein interaction (PPI) network. In the end, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blotting to measure and compare the expression of Spp1 in patients who accepted percutaneous coronary intervention. RESULTS: The bioinformatics analyses suggested that Spp1 was a hub gene in reperfusion after ischemia. The qRT-PCR result showed that the Spp1 expression was significantly downregulated in ischemia-reperfusion cells after PCI compared with normal samples and so as the western blotting. CONCLUSION: Spp1 might play an essential role in acute myocardial infarction after ischemia and reperfusion injury.

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Atherosclerosis (AS) is a chronic metabolic disease in arterial walls, characterized by lipid deposition and persistent aseptic inflammation. AS is regarded as the basis of a variety of cardiovascular and cerebrovascular diseases. It is widely acknowledged that macrophages would become foam cells after internalizing lipoprotein particles, which is an initial factor in atherogenesis. Here, we showed the influences of Bruton's tyrosine kinase (BTK) in macrophage-mediated AS and how BTK regulates the inflammatory responses of macrophages in AS. Our bioinformatic results suggested that BTK was a potential hub gene, which is closely related to oxidative stress, ER stress, and inflammation in macrophage-induced AS. Moreover, we found that BTK knockdown could restrain ox-LDL-induced NK-κB signaling activation in macrophages and repressed M1 polarization. The mechanistic studies revealed that oxidative stress, mitochondrial injury, and ER stress in macrophages were also suppressed by BTK knockdown. Furthermore, we found that sh-BTK adenovirus injection could alleviate the severity of AS in ApoE-/- mice induced by a high-fat diet in vivo. Our study suggested that BTK promoted ox-LDL-induced ER stress, oxidative stress, and inflammatory responses in macrophages, and it may be a potential therapeutic target in AS.

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Atherosclerosis (AS) is one of the most serious and common cardiovascular diseases affecting human health. AS is featured by the accumulation of plaques in vessel walls. The pathophysiology of AS is relevant in the low-density lipoprotein (LDL) uptake by macrophages, as well as the conversion of macrophages to foam cells. However, the mechanisms about how macrophages regulate AS have not been fully elucidated. In this study, we aimed to illuminate the roles of ZBTB20 and to excavate the underlying regulative mechanisms of ZBTB20 in AS. The microarray analysis revealed that ZBTB20 was a hub gene in the oxidative stress and inflammatory responses induced by oxidized LDL (ox-LDL) in AS. Correspondingly, our validation studies showed that ZBTB20 increased in either the human atherosclerotic lesion or the ox-LDL-stimulated macrophages. Moreover, the knockdown of ZBTB20 decreased M1 polarization, suppressed the proinflammatory factors, inhibited mitochondrial fission, and reduced the oxidative stress level of macrophages induced by ox-LDL. The mechanistic studies revealed that the ZBTB20 knockdown suppressed NF-κB/MAPK activation and attenuated the mitochondrial fission possibly via regulating the nucleus translocation of NRF2, a pivotal transcription factor on redox homeostasis. Our in vivo studies showed that the sh-ZBTB20 adenovirus injection could reduce the progression of AS in apolipoprotein E-deficient (ApoE-/-) mice. All in all, these results suggested that ZBTB20 positively regulated the oxidative stress level, mitochondrial fission, and inflammatory responses of macrophages induced by ox-LDL, and the knockdown of ZBTB20 could attenuate the development of AS in ApoE-/- mice.

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BACKGROUND: The aim of the present study was to investigate the therapeutic potential of metformin in preventing cyclosporine A (CsA)-induced nephrotoxicity. METHODS: Three groups of adult male Sprague-Dawley rats were treated with vehicle, CsA, and CsA + metformin for 4 weeks following 1 week on low sodium diet, respectively. At the end of treatment, all animals were euthanized, and the samples of kidney, urine, and blood were collected for functional, morphological, and molecular biological evaluation. RESULTS: Metformin effectively prevented CsA-induced renal dysfunction with increased creatinine clearance rate and reduced blood urea nitrogen and serum creatinine, as well as less proteinuria in comparison to the CsA group. Morphologically, metformin ameliorated CsA-induced renal fibrosis and tissue collapse in the areas of arteries, glomeruli, and proximal tubules. We further demonstrated that the antifibrotic effects of metformin in kidneys treated with CsA were associated with decreased phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2). CONCLUSIONS: In conclusion, our study revealed new therapeutic potential of metformin to attenuate calcineurin inhibitor-induced renal fibrosis, which was closely related to the suppression of MEK/ERK1/2 pathway.

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