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SARS-Cov-2 infection causes local and systemic inflammation mediated by pro-inflammatory cytokines and COX-2 eicosanoid products with metabolic dysfunction and tissue damage that can lead to patient death. These effects are primarily induced by IL-1 cytokines, which are involved in the elevation of hepatic acute phase proteins and fever. IL-1 has a broad spectrum of biological activities and participates in both innate and acquired immunity. In infections, IL-1 induces gene expression and synthesis of several cytokines/chemokines in both macrophages and mast cells (MCs). The activation of MCs triggers the secretion of mediators stored in the granules, and the de novo synthesis of pro-inflammatory cytokines. In microorganism infections, the release of IL-1 macrophage acts on adhesion molecules and endothelial cells leading to hypotension and septic shock syndrome. IL-1 activated by SARS-CoV-2 stimulates the secretion of TNF, IL-6 and other cytokines, a pro-inflammatory complex that can lead to cytokine storm and be deleterious in both lung and systemically. In SARS-CoV-2 septic shock, severe metabolic cellular abnormalities occur which can lead to death. Here, we report that SARS-CoV-2 induces IL-1 in macrophages and MCs causing the induction of gene expression and activation of other pro-inflammatory cytokines. Since IL-1 is toxic, its production from ubiquitous MCs and macrophages activated by SARS-CoV-2 can also provokes both gastrointestinal and brain disorders. Furthermore, in these immune cells, IL-1 also elevates nitric oxide, and the release of inflammatory arachidonic acid products such as prostaglndins and thromboxane A2. All together these effects can generate cytokine storm and be the primary cause of severe inflammation with respiratory distress and death. Although, IL-1 administered in low doses may be protective; when it is produced in high doses in infectious diseases can be detrimental, therefore, IL-1 blockade has been studied in many human diseases including sepsis, resulting that blocking it is absolutely necessary. This definitely nurtures hope for a new effective therapeutic treatment. Recently, two interesting anti-IL-1 cytokines have been widely described: IL-37 and IL-1Ra. IL-37, by blocking IL-1, has been observed to have anti-inflammatory action in rodents in vivo and in transfected cells. It has been reported that IL-37 is a very powerful protein which inhibits inflammation and its inhibition can be a valid therapeutic strategy. IL-37 is a natural suppressor of inflammation that is generated through a caspase-1 that cleaves pro-IL-37 into mature IL-37 which translocates to the nucleus and inhibits the transcription of pro-inflammatory genes; while IL-1Ra inhibits inflammation by binding IL-1 to its IL-1R (receptor). We firmly believe that blocking IL-1 with an anti-inflammatory cytokine such as IL-37 and/or IL-1Ra is an effective valid therapy in a wide spectrum of inflammatory disorders including SARS-CoV-2-induced COVID-19. Here, we propose for the first time that IL-37, by blocking IL-1, may have an important role in the therapy of COVID-19.
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COVID-19 pandemic emerged as a condition that changed our entire life and led us to develop new perspectives on diseases. Cancers are generally additional risk factors for COVID-19, and this has implications also for skin cancer patients. Those patients require special attention, due to situations such as an increased risk of infection as a result of visiting the hospital for treatment. It is imperative that the diagnosis and treatment of patients who have a cancer that progresses rapidly, such as malignant melanoma, high-risk squamous cell carcinoma and a high risk of metastasis, are delayed. Due to the relatively long-lasting nature of basal cell carcinoma and, as almost no metastasis would be expected, its treatment may be postponed, except for those that occur in areas such as the eyes and mouth. Diagnosis and treatment of skin cancers is a process that requires many procedures. Throughout this process, physicians should take appropriate precautions that are sufficient to protect both the patient and themselves in the best way without leading to any delay in the procedures.
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Biobanks are considered to be important resources of Departments of Pathology and Laboratory Medicine allowing the clarification of relevant disease mechanisms and the improvement of the diagnosis, prognosis, and treatment of both pediatric and adult cardiovascular diseases. To successfully establish a cardiovascular biobank, it is important to consider the public opinion and views on it and the factors involved in the willingness of the public to participate in the donation of genetic material. The literature was systematically reviewed to identify the attitude and willingness of patients affected by congenital and acquired heart disease to participate in biobanking research. Six relevant studies were identified in which it was indicated that psychosocial and demographic characteristics, as well as the patient's medical condition, could influence patient and family members' attitudes and willingness to participate in research. In both congenital and acquired heart diseases, participation in biobank research activities was higher if patients and their families were approached when hospitalized, but not during the acute moment of their illness. Other quantitative and qualitative studies are required to improve patient and family participation in these research initiatives.
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Chemotherapy resistance has become a major obstacle to effective treatment of human cancer. This study aimed to investigate the effect of lncRNA XIST on cell proliferation and cisplatin (CDDP) of oral squamous cell carcinoma (OSCC). RT-qPCR and Western blot analysis were used to detect mRNA and protein expression. CCK-8 and flow cytometry assays were explored to evaluate CDDP sensitivity in OSCC cells. The relationship between lncRNA XIST and miR-27b-3p was confirmed by luciferase reporter assay. The results showed that lncRNA XIST was upregulated in OSCC tissues, cell lines, and CDDP-resistant OSCC cells. Functionally, upregulation of lncRNA XIST promoted cell proliferation, enhanced CDDP resistance, and inhibited apoptosis in OSCC cells. In addition, lncRNA XIST acts as a molecular sponge for miR-27b-3p in OSCC. Downregulation of miR-27b-3p partially reversed the tumor suppression effect and CDDP chemosensitivity of XIST knockdown in CDDP-resistant OSCC cells. In conclusion, lncRNA XIST promotes cell proliferation and enhances resistance to CDDP in OSCC by downregulating miR-27b-3p.
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This study investigated the tolerance and safety of pasteurized donor human milk (PDHM) given either alone or together with commercially-used supplements in a porcine model of premature infants. A porcine model, mimicking human neonates at 30-32 weeks of gestational age, was used. The 7-day experiment was performed on 20 piglets. After birth, the piglets were infused with porcine immunoglobulins via the umbilical artery and surgically fitted with a stomach port. The piglets were then randomized into five groups and fed either PDHM, different variants of fortified PDHM or 'raw' human milk (RHM). Preterm piglets fed PDHM showed signs of gastrointestinal intolerance. Four piglets across the various PDHM-fed groups died, none of them were from the group fed PDHM supplemented with long-chain polyunsaturated fatty acids (LC PUFA). In all groups fed PDHM, macroscopic features of enterocolitis were observed, however, these pathological gut changes were less manifested in piglets receiving PDHM supplemented with LC PUFA. The piglets fed RHM had no specific signs of gut damage. The poor tolerance to PDHM suggests changes in milk composition caused by the Holder pasteurization. The supplementation with LC PUFA probably improves tolerance to PDHM.
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Small nucleolar RNA host genes (SNHGs) as a subset of long non-coding RNAs (lncRNAs) act critical roles in tumor progression. The present study aimed to elucidate the role and mechanisms of SNHG3 in non-small cell lung cancer (NSCLC). The correlation of SNHG3/miR-340-5p/HOXA10 with the clinicopathological features and outcomes in NSCLC was analyzed by TCGA cohort. In vitro and in vivo functional experiments were conducted to assess the role of SNHG3 in NSCLC cells. Bioinformatic analysis and luciferase gene reporter were used to estimate the interaction between miR-340-5p and SNHG3/HOXA10 3'UTR. The effects of SNHG3 and (or) miR-340-5p on HOXA10 expression were detected by qRT-PCR and Western blot analysis. As a consequence, the elevated expression of SNHG3 and HOXA10 or lowered expression of miR-340-5p was related to the lymph node infiltration, distant metastases and unfavorable prognosis in NSCLC. Ectopic expression of SNHG3 boosted the proliferation and invasion of NSCLC cells in vitro and in vivo, whereas downregulation of SNHG3 reversed these effects. Moreover, SNHG3 could bind with miR-340-5p and reduce its expression levels, and miR-340-5p attenuated SNHG3-induced tumor proliferation and HOXA10 expression in NSCLC cells. Our findings unveiled that SNHG3 might be an oncogenic factor in NSCLC by downregulating miR-340-5p.
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Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and several neurodegenerative disorders. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation, however, the detailed underlying mechanisms are largely unknown. In this study, we demonstrate that CYP46A1 genes are key determinants of MSC increasing lipid droplet formation. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. To address this issue, we used an adenoassociated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on the human mesenchymal stem cell (hU-MSCs). CYP46A1 expression was assessed with Western blotting and quantitative reverse transcription PCR. We found that CYP46A1 expression was increased during adipogenesis, and treatment with exogenous CYP46A1 increased adipogenesis. Thus, we hypothesize that CYP46A1 overexpression in hU-MSCs would significantly enhance cholesterol turnover in the brain of hypoxic-ischemic encephalopathy (HIE). CYP46A1 can potentially serve as a specific target to modify the therapeutic and biological effects of hU-MSCs on HIE patients.
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The aim of this study was to screen the differentially expressed circular ribonucleic acid (circRNA) in non-small cell lung cancer (NSCLC) and explore its functional mechanism. Differentially expressed circRNAs in tumor tissues of NSCLC patients were detected via gene microarray and reverse transcriptionquantitative polymerase chain reaction (RT-qPCR). The associaton between their expressions and the clinical phenotypes was explored combined with clinical data. The effect of overexpression of hsa_circ_0004050 on the proliferation of A549 cells was detected via cell counting kit-8 (CCK-8) assay and CFSE assay. The effect of overexpression of hsa_circ_0004050 (human circular ribonucleic acid_0004050) on the apoptosis of A549 cells was detected using the Annexin V-FITC/PI kit. Then the direct-acting miRNAs of hsa_circ_0004050 were screened using bioinformatics software and luciferase reporter assay, and the direct targets of miR- 1233-3p were explored using bioinformatics software and luciferase reporter assay combined with RTqPCR and Western blotting. The effects of overexpression of miR-1233-3p or knockdown of dual specificity phosphatase 9 (DUSP9) on the cell proliferation and apoptosis affected by overexpression of hsa_circ_0004050 were detected. Western blotting was performed to detect the effects of hsa_circ_0004050 on the extracellular signal-regulated kinase (ERK)/c-Jun N-terminal kinase (JNK) signaling pathway. The expression of hsa_ circ_0004050 was significantly lower in tumor tissues than that in para-carcinoma tissues in NSCLC patients. The expression of hsa_circ_0004050 was significantly correlated with TNM stage, tumor size and lymph node metastasis. The results of survival analysis showed that the survival time of patients with a high expression of hsa_circ_0004050 was obviously prolonged. According to the results of phenotype assay, hsa_circ_0004050 could promote apoptosis and inhibit proliferation of A549 cells. In terms of its mechanism, hsa_circ_0004050 could markedly increase the protein expression of DUSP9 via targeting miR-1233-3p in A549 cells, thereby inhibiting the ERK/JNK signaling pathway. Hsa_circ_0004050 may serve as a potential therapeutic target for NSCLC or a biomarker for the diagnosis of NSCLC in the future.
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Long non-coding ribonucleic acids (lncRNAs) have been recognized as markers in several cancers and play important roles in glioblastoma (GBM). But the role of lncRNA X inactive-specific transcript (XIST) in GBM and its possible mechanisms are rarely studied in depth. This study was conducted to explore the detailed roles of XIST in cell proliferation, migration, and invasion of GBM. Expressions of XIST, miR-448, and ρ associated coiled coil containing protein kinase 1 (ROCK1) were detected by qRT-PCR or Western blot in A172 and U251 cells. The interactions among XIST, miR-448 and ROCK1 were verified through luciferase reporter assay and RNA immunoprecipitation (RIP) assay. Cell Counting Kit-8 (CCK-8) assay and Transwell assay were introduced to detect how XIST knockdown, miR-448 overexpression, or along with ROCK1 overexpression affect cellular malignancy of GBM cells. XIST and ROCK1 were up-regulated while miR-448 expression was decreased in GBM cells. XIST knockdown or miR-448 overexpression could dramatically inhibit GBM cell proliferation, migration, and invasion. Moreover, XIST negatively regulated miR-448 expression through the function as competing endogenous RNA (ceRNA), thus leading to the up-regulation of ROCK1, one miR-448 target gene. Moreover, ROCK1 overexpression could reverse the suppression of XIST knockdown or miR-448 upregulation on cellular malignancy. In brief, the effects of XIST may promote cellular malignancy of GBM through miR-448/ROCK1 axis, which will provide new understanding of GBM pathogenesis and progression.
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Despite the amazing progress in the treatment of gastric cancer (GC), it is still the third leading cause of cancer death in the world. This study explored the key genes that are related to the prognosis and pathogenesis of GC. Data from the cancer genome atlas (TCGA) and Oncomine were applied to evaluate the expression of cystatin 2 (CST2) in GC samples. Kaplan-Meier plotter was carried out to detect the overall survival of GC patients with different expression levels of CST2. Gene Set Enrichment Analysis (GSEA) was carried out to investigate the functions and pathways connected with CST2 expression. Quantitative real-time polymerase chain reaction (qPCR) and Western blot assays were used to assess CST2 expression. The biological properties of GC cells were assessed with the support of cell proliferation and Transwell assays. Important proteins involved in the regulation of CST2 in GC cell behaviors were evaluated by Western blot. Through analysis of the database, we found that CST2 expression was significantly upregulated in GC samples and actively related to GC patients' poor outcomes. Importantly, the analysis of GSEA showed that GST2 expression was closely connected with the proliferation and migration of cells, as well as the TGF-β1 signaling pathway. In addition, biological assays illustrated that over-expression of CST2 strengthened the activity and metastasis of GC cells. After the upregulation of CST2, the expression of cyclin D1, N-cadherin, vimentin, TGF-β1, and Smad4 increased, and E-cadherin expression decreased. Our findings revealed that over-expression of CST2 enhanced the growth, migration, and invasion of GC cells through modulating the epithelial-mesenchymal transition (EMT) and TGF-β1 signaling pathway, affording a possible biomarker for the treatment of GC.
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The aim of this study was to explore the dynamic changes in characteristic serum metabolic markers and pathways during early sepsis in rats. By using cecal ligation and puncture (CLP), we made rat models of sepsis, which were randomly divided into 5 groups with 10 rats in each group: group A, group B, group C, group D, and group E. We collected 2 mL of arterial blood at 0, 6, 12, 24, and 48 hours from rats in group A-E respectively and isolated serum via centrifugation. Next, adopting metabolomics analysis methods, we screened for metabolites from the animal serum with statistically and biologically significant abundance changes, and used the KEGG database to analyze the respective metabolic pathways. In all, our findings reveal that D-glucosamine 6-phosphate, D-glucosamine phosphate, α-D-glucosamine 1-phosphate, D-glucosamine 1-phosphate, and 5-hydroxy isocyanate decline continuously from 12 hours, while L-phenylalanine, (S) -α-amino-β-phenylpropionic acid, 5-methoxy indole acetic acid salt, 5-methoxy indole acetic acid, goose deoxyglycolic acid salt, goose deoxyglycolic acid, and Chen's deoxygenated sugar alcohol started to decrease from 6 hours. Additionally, 3.2,3-Bis-O-(geranyl geranyl)-sn-glycerol- 1-phosphoric acid-L-serine levels rose continuously from 12 hours. We found 13 differentially regulated ions, primarily ones involved in pathways responsible for the metabolism of sugar, amino acids, and lipids, which are related to the disorder of energy metabolism. Our findings mark serum-derived D-glucosamine and its phosphorous derivatives as characteristic metabolic markers of sepsis in rats.
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