ABSTRACT
Pulmonary hypertension (PH) is an extremely malignant pulmonary vascular disease of unknown etiology. ADAR1 is an RNA editing enzyme that converts adenosine in RNA to inosine, thereby affecting RNA expression. However, the role of ADAR1 in PH development remains unclear. In the present study, we investigated the biological role and molecular mechanism of ADAR1 in PH pulmonary vascular remodeling. Overexpression of ADAR1 aggravated PH progression and promoted the proliferation of pulmonary artery smooth muscle cells (PASMCs). Conversely, inhibition of ADAR1 produced opposite effects. High-throughput whole transcriptome sequencing showed that ADAR1 was an important regulator of circRNAs in PH. CircCDK17 level was significantly lowered in the serum of PH patients. The effects of ADAR1 on cell cycle progression and proliferation were mediated by circCDK17. ADAR1 affects the stability of circCDK17 by mediating A-to-I modification at the A5 and A293 sites of circCDK17 to prevent it from m1A modification. We demonstrate for the first time that ADAR1 contributes to the PH development, at least partially, through m1A modification of circCDK17 and the subsequent PASMCs proliferation. Our study provides a novel therapeutic strategy for treatment of PH and the evidence for circCDK17 as a potential novel marker for the diagnosis of this disease.
ABSTRACT
Introduction: The role of the Notch signaling pathway in the development of various tumors has received increasing attention, but the relationship between the Notch signaling pathway and the prognosis of bladder cancer has rarely been studied. The aim of this study was to investigate the function and risk evaluation value of Notch signaling pathway-related genes (NRGs) in bladder cancer. Material and methods: The list of genes related to the Notch signaling pathway was obtained from the molecular signature database. The bladder cancer dataset was obtained from The Cancer Genome Atlas (TCGA) database. Cox regression analysis and Lasso regression analysis were used to construct the characteristics for predicting the overall survival of patients with bladder cancer. The CIBERSORT algorithm was used to evaluate the infiltration of peripheral immune cells in different risk subgroups. Results: NRG expression was remarkably dysregulated in bladder cancer. Next, bladder cancer was classified into two subtypes (C1 and C2) based on NRG expression levels. The two subtypes had a significant difference in prognosis and were closely related to clinical characteristics. Further analysis showed that immune cell infiltration and immune scores were also significantly different between the two subtypes. Conclusions: Notch signaling pathway-based bladder cancer typing has different prognoses and may be related to tumor immunity. NRGs can be identified for risk evaluation and help improve clinical decision-making.
ABSTRACT
The ongoing COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an enveloped RNA virus. Despite the high economic and life losses caused by SARS-CoV-2, the detailed viral cycle, especially how it assembles and traffics in the secretory pathway, remains largely unknown. Here, we show that SARS-CoV-2 infection induces global alterations of the host endomembrane system, including dramatic Golgi fragmentation. Disrupting Golgi function with small molecules strongly inhibits viral infection. Furthermore, expression of several SARS-CoV-2 proteins individually is sufficient to trigger Golgi fragmentation. Significantly, SARS-CoV-2 infection down-regulates GRASP55 but up-regulates TGN46 expression, while expression of GRASP55 or knockdown of TGN46 reduces the infection rate of both USA-WA1 and Delta variants of SARS-CoV-2. Our study reveals that SARS-CoV-2 modulates Golgi structure and function via altering GRASP55 and TGN46 expression to facilitate viral trafficking, indicating the Golgi as a novel therapeutic target to block SARS-CoV-2 infection.
ABSTRACT
OBJECTIVE： To evaluate immunomodulatory drugs （IMiDs） in the treatment of deep venous thrombosis （DVT） in patients with multiple myeloma （MM） systematically， and to provide reference for safe drug use in clinic. METHODS： Retrieved and collected randomized controlled trials （RCTs） about the risk of DVT in MM patients treated with IMiDs from PubMed， Web of Science， Cochrane library， CJFD， Wanfang database， VIP， www.ClinicalTrials.gov during database and Dec. 31， 2018. Meta-analysis was conducted for the incidence and relative risk of DVT （RR） by using Stata 12.0 statistical software. Evidence was evaluated and graded by using GRADE system. RESULTS： A total of 11 RCTs were included， involving 3 365 patients （including 3 drugs）. Results of Meta-analysis showed that the incidence of DVT was 7.3％ [95％CI （4.5％， 10.2％）] during IMiDs in the treatment of MM. Compared with conventional chemotherapy， IMiDs had a higher risk of DVT in MM patients [RR＝3.57，95％CI（2.42，5.27）， P＜0.01]. Subgroup analysis in different treatment stage showed that after IMiDs treatment for MM patients at induction stage， the risk of DVT increased by 386％ compared with conventional chemotherapy plan [RR＝4.86， 95％CI （2.85， 8.30）， P＜0.01]， which evidence was moderate. Compared with conventional chemotherapy plan， there was no significant difference in the risk of DVT among MM patients treated with IMiDs at maintenance stage [RR＝2.40， 95％CI （0.70， 8.27）， P＝0.16] and relapse stage [RR＝2.01， 95％CI （0.74， 5.46）， P＝0.17]. The incidence of severe DVT caused by thalidomide and lenalidomide were 11％ [95％CI （9％， 13％）] and 3％ [95％CI （2％， 4％）]. CONCLUSIONS： The current evidence suggests that patients with MM treated with IMiDs are at a high risk of serious DVT， and clinical medication should be cautious.
ABSTRACT
AIM:To study the parameters of supercritical CO_2 extraction of essential oil from valeriana efficinalis by orthogonal design. METHODS: Four factors,such as extraction pressure,extraction temperature,extraction time and separation temperature were chosen by the observation of orthogonal design,each factor was assigned to three levels.Bornyl acetate content was selected as a marker in a position to determine optimal extraction. RESULTS: Pressure and temperature were the main factors in effecting the extraction of bornyl acetate,extraction time was minor factor relatively. CONCLUSION: The optimal extraction is as follow,parameters were extraction pressure:12 MPa,extraction temperature:45 ℃,extraction time:1 hour,separation temperature:35 ℃,it gave the best recoveries of essential oils and bornylacetate.
