Abstract Background: Chronic diabetes accelerates vascular dysfunction often resulting in cardiomyopathy but underlying mechanisms remains unclear. Recent studies have shown that the deregulated unfolded protein response (UPR) dependent on highly conserved IRE1α-spliced X-box- binding protein (XBP1s) and the resulting endoplasmic reticulum stress (ER-Stress plays a crucial role in the occurrence and development of diabetic cardiomyopathy (DCM). In the present study, we determined whether targeting MAPK/ERK pathway using MEK inhibitor U0126 could ameliorate DCM by regulating IRE1α-XBP1s pathway. Method: Three groups of 8-week-old C57/BL6 mice were studied: one group received saline injection as control (n=8) and two groups were made diabetic by streptozotocin (STZ) (n=10 each). 18 weeks after STZ injection and stable hyperglycemia, one group had saline treatment while the second group was treated with U0126 (5mg/kg/day), 8 weeks later, all groups were sacrificed. Cardiac function/histopathological changes were determined by echocardiogram examination, Millar catheter system, hematoxylin-eosin staining and western blot analysis. H9c2 cardiomyocytes were employed for in vitro studies. Results: Echocardiographic, hemodynamic and histological data showed overt myocardial hypertrophy and worsened cardiac function in diabetic mice. Chronic diabetic milieu enhanced SUMOylation and impaired nuclear translocation of XBP1s. Intriguingly, U0126 treatment significantly ameliorated progression of DCM, and this protective effect was achieved through enriching XBP1s’ nuclear accumulation. Mechanistically, U0126 inhibited XBP1s’ phosphorylation on S348 and SUMOylation on K276 promoting XBP1s’ nuclear translocation. Collectively, these results identify that MEK inhibition restores XBP1s-dependent UPR and protects against diabetes-induced cardiac remodeling. Conclusion: The current study identifies previously unknown function of MEK/ERK pathway in regulation of ER-stress in DCM. U0126 could be a therapeutic target for the treatment of DCM.
Gastric cancer (GC) is a considerable global health burden. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) are aberrantly expressed in many cancers and play important roles in GC. However, only a few lncRNAs have been functionally characterized. In this study, we identified that long intergenic non-protein coding RNA 941 (LINC00941) is a potential biomarker for diagnosis and prognosis from the cancer genome atlas (TCGA), and we found that the expression of LINC00941 is associated with tumor depth and distant metastasis in GC. Furthermore, functional enrichment analysis of LINC00941 co-expression network demonstrated that LINC00941 might be an essential regulator of tumor metastasis and cancer cell proliferation. To validate our findings, we utilized the loss-of-function analysis to reveal the biological function of LINC00941 in GC cells. Loss-of-function analysis revealed that silence of LINC00941 inhibits GC cells proliferation, migration, and invasion in vitro and modulates tumor growth in vivo. Our findings confirmed that LINC00941 plays an important oncogenic function in GC and may serve as a potential biomarker for diagnosis and prognosis of GC.
Aims: Obstructive sleep apnea syndrome (OSAS) has been increasingly recognized as an independent risk factor for aortic dissection (AD) and it is strongly associated with the extent of intermittent hypoxia and re-oxygenation (IH).This study aimed to clarify role of ROS-HIF-1α-MMPs pathway in the pathogenesis of AD and whether the HIF-1α inhibitor attenuates AD formation.Methods and results: 8-week-old male ApoE -/mice were given β-aminopropionitrile at a concentration of 0.1 % for 3 weeks and infused via osmotic mini pumps with either saline or 2,500 ng/min/kg angiotensin II (Ang II) for 2 weeks.To mimic the OSAS, one group was exposed to IH, which consisted of alternating cycles of 20.9% O2/8% O2 FiO2 (30 episodes per hour) with 20 s at the nadir FiO2 during the 12-h light phase, 2 weeks before Ang II infusion.After Ang II infusion, we assessed remodeling in the aorta by echocardiography, histological and immunohistochemical analysis.IH treatment resulted in significant enlargement of the luminal area, destruction of the media, marked thickening of the adventitia, higher incidence of AD formation and lower survival rate in compared with the Ang II only group.Moreover, IH exposure markedly increased the aortic ROS production and subsequent HIF-1α expression, which in turn promoted the expressions of VEGF, MMP2 and MMP9 and finally leading to the progression of AD.Besides, in vitro study confirmed that IH induced HIF-1α expression plays an important role in the induction of MMPs and that is regulated by the PI3K/AKT/FRAP pathway.Intriguingly, a selective HIF-1α inhibitor KC7F2 could significantly ameliorate IH exposure induced aforementioned deleterious effects in vitro and in vivo.Conclusion: OSAS induced IH can promote the occurrence and progression of AD via a ROS-HIF-1α-MMPs associated pathway.The selective HIF-1α inhibitor KC7F2 could be a novel therapeutic agent for AD patient with OSAS.
Evidence has accumulated enough to prove non-coding RNAs (ncRNAs) play important roles in cellular biological processes and disease pathogenesis. High throughput techniques have produced a large number of ncRNAs whose function remains unknown. Since the accurate identification of ncRNAs family is helpful to the research of their function, it is of necessity and urgency to predict the family of each ncRNAs. Although several traditional excellent methods are applicable to predict the family of ncRNAs, their complex procedures or inaccurate performance remain major problems confronting us. The main idea of those methods is first to predict the secondary structure, and then identify ncRNAs family according to properties of the secondary structure. Unfortunately, the multi-step error superposition, especially the imperfection of RNA secondary structure prediction tools, maybe the cause of low accuracy. In this paper, a novel end-to-end method `ncRFP' was proposed to complete the prediction task based on Deep Learning. Instead of predicting the secondary structure, ncRFP predicts the ncRNAs family by automatically extracting features from ncRNAs sequences. Compared with other methods, ncRFP not only simplifies the process but also improves accuracy. The source code of ncRFP can be available at https://github.com/linyuwangPHD/ncRFP.
Background: Tumor microenvironment (TME) contributes to tumor development, progression, and treatment response.In this study, we detailed the cell composition of the TME in neuroblastoma (NB) and constructed a cell risk score model to predict the prognosis of NB.Methods: xCell score was calculated through transcriptomic data from the datasets GSE49711 and GSE45480 based on the xCell algorithm.The random forest method was employed to select important features and the coefficient was obtained via multivariate cox regression analysis to construct a prognostic model, and the performance was validated in another two independent datasets GSE16476 and TARGET-NBL. Results:We found that both immune and non-immune cells varies significantly in different prognostic groups, and were correlated with survival time.The proposed prognostic cell risk score (pCRS) model we constructed can be an independent prognostic indicator for overall survival (OS) and event-free survival (EFS) (training: OS, HR 1.579, EFS, HR 1.563; validation: OS, HR 1.665, 3.848, EFS, HR 2.203, all p-values < 0.01) and only independent prognostic factor in International Neuroblastoma Risk Group high risk patients (HR 1.339, 3.631; p-value 1.76e-2, 3.71e-5), rather than MYCN amplification.Besides, pCRS model showed good performance in grouping, in discriminating MYCN status, the area under the curve (AUC) was 0.889, 0.933, and 0.861 in GSE49711, GSE45480, and GSE16476, respectively.In separating high risk groups, the AUC was 0.904 in GSE49711. Conclusion:This study details the cellular components in the TME of NB through gene expression data, the proposed pCRS model might provide a basis for treatment selection of high risk patients or targeting cellular components of TME in NB.
To evaluate the feasibility of Pegaspargase instead of L-asparaginase to treat children with advanced-stage lymphoblastic lymphoma (LBL) on the Berlin-Frankfurt-Munster (BFM)-95 protocol.Fifty-four newly diagnosed patients with stage III or IV LBL and without any treatment were enrolled in this study. Pegaspargase took place of L-asparaginase in BFM-95. The complications and treatment responses of patients treated on the BFM-95 protocol and modified BFM-95 protocol were then evaluated respectively. Findings : For LBL patients treated with BFM-95 protocol or modified BFM-95 protocol, the complete response, event-free survival, overall survival were similar. Stage 4 myelosuppression was the most common complication in both groups. Besides that, among 31 patients receiving modified BFM-95 protocol, coagulation defects were the most common complication. In contrast, anaphylactic reaction was the most common complication in the other 23 patients receiving BFM-95 protocol.Modified BFM-95 protocol is available to children with advanced-stage LBL with an equal outcome and enhances its compliance and decreases the incidence of anaphylactic reaction, compared to BFM-95 protocol. Coagulation defects are the major complication and tolerable in modified one.
Background New evidence implies that the imbalance of gut microbiota is associated with the progression of alcoholic liver disease (ALD) and that the composition of gut microbiota is altered in ALD patients. However, the predominant bacterium in patients involved in the progress of ALD has not been identified. The purpose of this study is to investigate the predominant bacterium in the early and end-stages of ALD as well as the relationship between the bacterium and the degree of liver injury. Methods We enrolled 21 alcoholic fatty liver (AFL) patients, 17 alcoholic liver cirrhosis (ALC) patients and 27 healthy controls, and sequenced the 16S rRNA gene of their fecal microbiota. The gut microbiota composition and its relationship with the indicators of clinical hepatic function were assessed using canonical correspondence analysis (CCA), spearman correlation heatmap and multivariate association with linear (MaAsLin) Models. Results The composition and structure of gut microbiota changed greatly in different stages of ALD, and the degree of disorder was aggravated with the progression of ALD, even in the early stage. Moreover, the relative abundance of Streptococcus was highly enriched only in patients with ALC (P <0.001), and positively correlated with AST level (P = 0.029). The abundance of Streptococcus distinguished the liver injury of ALC patients from the controls with an area under the receiver-operating characteristic curve (AUC) of 0.877 (P < 0.001). Conclusions These findings indicate that the imbalance of gut microbiota exists at the early and end-stages of ALD, and the degree of disorder is aggravated with the progression of ALD. Streptococcus , as the predominant bacterium, may be a microbiological marker to evaluate the severity of liver injury in ALD patients.
Abstract Hepatocellular carcinoma (HCC) is a common malignancy affecting many people worldwide. Baicalin is a flavonoid extracted from the dried root of Scutellaria baicalensis Georgi . It can effectively inhibit the occurrence and development of HCC. Nonetheless, the mechanism through which Baicalin inhibits HCC growth and metastasis remain unknown. This work discovered that Baicalin inhibited HCC cell proliferation, invasion, metastasis while inducing cell cycle arrest at the G0/G1 phase and apoptosis. In vivo HCC xenograft results indicated that Baicalin inhibited HCC growth. Western blotting analysis indicated that Baicalin suppressed the expressions of ROCK1, p‐GSK‐3β, and β‐catenin, whereas it up‐regulated the expressions of GSK‐3β and p‐β‐catenin. Baicalin also reduced the expressions of Bcl‐2, C‐myc, Cyclin D1, MMP‐9, and VEGFA, while increasing the expression of Bax. Molecular docking revealed that Baicalin docked in the binding site of the ROCK1 agonist, with a binding energy of −9 kcal/mol between the two. In addition, lentivirus‐mediated suppression of ROCK1 expression improved the inhibitory effect of Baicalin on the proliferation, invasion, and metastasis of HCC and the expression of proteins associated with ROCK1/GSK‐3β/β‐catenin signaling pathway. Moreover, restoring ROCK1 expression decreased the anti‐HCC efficacy of Baicalin. These findings suggest that Baicalin may decrease HCC proliferation and metastasis by suppressing ROCK1/GSK‐3β/β‐catenin signaling.
Background: The gut microbiome is known to change following HIV infection. However, previous studies have generated inconsistent results regarding the differences in the gut microbiome between HIV positive and negative individuals.Methods: A bioinformatics analysis was performed on nine 16S rRNA gene sequencing data generated from 1082 stool samples (646 from HIV positive individuals and 436 from HIV negative individuals). We compared the differences in the gut microbiome between HIV positive and negative individuals across various factors.Results: The diversity of the gut microbiome differed between HIV positive and negative individuals with respect to age, gender, and whether or not antiretroviral therapy (ART) was initiated. Our analysis showed that ART did not restore the diversity of the gut microbiome. HIV infection changed the dominant genera of the intestine such that the prevalence of Prevotella increased and that of Bacteroides decreased in HIV positive individuals, especially in men who have sex with men (MSMs). Sutterella, Butyricimonas, Lachnospira etc. had significant correlations with the number of CD4+T cells and HIV viral load. In addition, the differentially enriched genera were found to be associated with functional pathways that correlated with ART.Conclusions: This study explored the changes in the gut microbiome in HIV positive individuals and revealed the association between differentially enriched genera and functional pathways involved in ART, which might help to elucidate the effects of HIV infection on the human gut microbiome.Funding Statement: This study was supported by the National Natural Science Foundation of China (NSFC, 81660334), Guangxi Natural Science Foundation (2017GXNSFAA198190, 2018GXNSFAA050099), National Key Science and Technology Project of China (2018ZX10101002-001-006). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The authors stated: "Reusable data for our analysis complied with all relevant ethical regulations."
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