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1.
J Cell Mol Med ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670483

RESUMO

Chronic heart failure (CHF) has poor prognosis and polygenic heritability, and the genetic risk score (GRS) to predict CHF outcome has not yet been researched comprehensively. In this study, we sought to establish GRS to predict the outcomes of CHF. We re-analysed the proteomics data of failing human heart and combined them to filter the data of high-throughput sequencing in 1000 Chinese CHF cohort. Cox hazards models were used based on single nucleotide polymorphisms (SNPs) to estimate the association of GRS with the prognosis of CHF, and to analyse the difference between individual SNPs and tertiles of genetic risk. In the cohort study, GRS encompassing eight SNPs harboured in seven genes were significantly associated with the prognosis of CHF (P = 2.19 × 10-10 after adjustment). GRS was used in stratifying individuals into significantly different CHF risk, with those in the top tertiles of GRS distribution having HR of 3.68 (95% CI: 2.40-5.65 P = 2.47 × 10-10 ) compared with those in the bottom. We developed GRS and demonstrated its association with first event of heart failure endpoint. GRS might be used to stratify individuals for CHF prognostic risk and to predict the outcomes of genomic screening as a complement to conventional risk and NT-proBNP.

2.
Biofouling ; : 1-14, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31603000

RESUMO

Microbial contamination during fuel storage can cause fuel system fouling and corrosion. Characterizing microbial contamination is critical for preventing and solving these problems. In this study, culture-based combing with the culture-independent methods, were used to profile the microbial contamination in aviation fuel. High-throughput sequencing (HTS) modified by propidium monoazide (PMA) revealed a higher diversity of contaminating microorganisms in samples than the culture method. Proteobacteria (47%), Actinobacteria (21%) and Ascomycota (>99%, fungi) were the most abundant phyla, and the neglected archaea was also detected. Additionally, qPCR-based methods revealed all samples contained a heavy level of microbial contamination, which was more accurate than its culturable counterparts, and fungal contamination was still a problem in aviation fuel. The application of a PCR-based method gives deeper insight into microbial contamination in aviation fuel than the conventional culture method, thus using it for regular detection and accurate description of fuel contamination is strongly recommended in the case of explosive microbial growth.

3.
Harmful Algae ; 88: 101642, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31582157

RESUMO

Toxic cyanobacterial blooms, occurring frequently worldwide, have posed serious threats to human health and aquatic ecosystem. RNA-based quantitative PCR, which could detect potential toxin-producing cyanobacteria that are actively transcribing toxin genes, is a more reliable method, compared to DNA-based qPCR. However, single-stranded mRNA is labile, and their degradation may lead to an underestimate of gene expression level, even misleading toxic risk management, and thus impeding its application. Here, the mRNA stability of microcystin synthetase genes (mcyA-J) was systematically evaluated in unicellular and colonial Microcystis with various treatments (-80 ℃, -196 ℃, 4 °C or 25 °C with RNases inhibitors). Results revealed the highly instability of toxin gene transcripts, affected by transcript structures and cell aggregation. The -196 ℃ treatment was the most effective for stabilizing these transcripts. RNAstore® (4 °C) could stabilize these transcripts effectively for a short time (less than 7 d), but their stability was strikingly reduced in colonial Microcystis. Furthermore, decay kinetics of mcyA-J transcripts in various treatments was developed, and showed that their decay rates were varied (0.0018-3.014 d-1), due to different molecular structures. The mcyH transcripts had the lowest decay rate (0.0018 d-1 at -196 ℃), attributed to the fewest AU sites and stem-loops involved in its secondary structure. Thus, mcyH was the most proper target gene for monitoring toxic cyanobacterial bloom. These findings provided new insight into mRNA stability of toxin genes, and contributed to monitoring toxic cyanobacterial blooms and water managements using RNA-based molecular techniques.

4.
Cell Biol Int ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31642564

RESUMO

Recent studies have found that the acetaldehyde dehydrogenase 1A3 (ALDH1A3) gene is a marker of glioma stem cells. A total of 115 brain glioma specimens were collected and classified into grade I-IV, while non-tumor brain tissue specimens, taken from 12 patients of vascular malformation surgery, were used as control. ALDH1A3 gene promoter methylation in glioma tissues was detected by pyrosequencing, while immunohistochemistry and Western blot were used to detect ALDH1A3 protein expressions in different grades of glioma tissues and normal brain tissues. The expression of ALDH1A3 in the glioma cell line U87 was detected by quantitative real-time PCR and RNA-Seq technology was applied to investigate differentially expressed genes before and after silencing the ALDH1A3 gene. Among the 115 glioma tissue specimens, 50 (43.48%) showed low and 65 (56.52%) high expression of ALDH1A3, but no expression was detected in the control. Univariate and multivariate COX regression analyses showed that the patient's tumor pathological grade, the methylation status of ALDH1A3 promoter, and the expression of ALDH1A3 protein were risk factors for PFS and OS (all P <0.05) and the OS of mice with silenced ALDH1A3 in a glioma nude mouse model was prolonged. U87 experiments revealed, that ALDH1A3 expression had significant effects on apoptosis, proliferation, cell cycle, mitochondrial membrane potential, glucose consumption, lactate production, invasion ability, and expression of the pyruvate kinase M2 (PKM2) and hexokinase 2 (HK2) in glioma cells. ALDH1A3 protein expression is a marker for poor PFS and OS in glioma patients. This article is protected by copyright. All rights reserved.

5.
Pharmacol Ther ; : 107414, 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31647974

RESUMO

The UDP glycosyltransferase (UGT) superfamily of enzymes is responsible for the metabolism and clearance of thousands of lipophilic chemicals including drugs, toxins and endogenous signaling molecules. They provide a protective interface between the organism and its chemical-rich environment, as well as controlling critical signaling pathways to maintain healthy tissue function. UGTs are associated with drug responses and interactions, as well as a wide range of diseases including cancer. The human genome contains 22 UGT genes; however as befitting their exceptionally diverse substrate ranges and biological activities, the output of these UGT genes is functionally diversified by multiple processes including alternative splicing, post-translational modification, homo- and hetero-oligomerization, and interactions with other proteins. All UGT genes are subject to extensive alternative splicing generating variant/truncated UGT proteins with altered functions including the capacity to dominantly modulate/inhibit cognate full-length forms. Heterotypic oligomerization of different UGTs can alter kinetic properties relative to monotypic complexes, and potentially produce novel substrate specificities. Moreover, the recently profiled interactions of UGTs with non-UGT proteins may facilitate coordination between different metabolic processes, as well as providing opportunities for UGTs to engage in novel 'moonlighting' functions. Herein we provide a detailed and comprehensive review of all known modes of UGT functional diversification and propose a UGTome model to describe the resulting expansion of metabolic capacity and its potential to modulate drug/xenobiotic responses and cell behaviours in normal and disease contexts.

6.
Cancer Med ; 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31518054

RESUMO

BACKGROUND: CXCR4 chemokine receptors play an important role in leukemia proliferation, extramedullary migration, infiltration, adhesion, and resistance to chemotherapy drugs. METHODS: The CXCR4 expression by flow cytometry in 122 acute myeloid leukemia (AML) patients between 2010 and 2014 was analyzed. RESULTS: The expression of CXCR4 in AML-M4/M5 was found to be significantly higher than that of other subtypes according to both FAB subtype and WHO classification. The FLT3-ITD mutant was significantly higher in high CXCR4 expression group (P = .0086). Our data also showed that CXCR4 expression was correlated with CD64 expression. Low CXCR4 expression on AML cells was associated with better prognosis, and the median overall survival (OS) for low CXCR4 expression patients was 318 days, compared with 206 days for patients with high CXCR4 expression (P = .045). Multivariate analysis revealed that CXCR4 expression, age, and extramedullary infiltration were independent prognostic factors. CONCLUSIONS: Our study demonstrated that CXCR4 expression in AML was an independent prognostic predictor for disease survival that could be rapidly and easily determined by flow cytometry at disease presentation.

7.
Oncogene ; 2019 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-31420608

RESUMO

Protease-activated receptor 1 (PAR1), a thrombin-responsive G protein-coupled receptor (GPCR), is implicated in promoting metastasis in multiple tumor types, including both sarcomas and carcinomas, but the molecular mechanisms responsible remain largely unknown. We previously discovered that PAR1 stimulation in endothelial cells leads to activation of NF-κB, mediated by a protein complex comprised of CARMA3, Bcl10, and the MALT1 effector protein (CBM complex). Given the strong association between NF-κB and metastasis, we hypothesized that this CBM complex could play a critical role in the PAR1-driven metastatic progression of specific solid tumors. In support of our hypothesis, we demonstrate that PAR1 stimulation results in NF-κB activation in both osteosarcoma and breast cancer, which is suppressed by siRNA-mediated MALT1 knockdown, suggesting that an intact CBM complex is required for the response in both tumor cell types. We identify several metastasis-associated genes that are upregulated in a MALT1-dependent manner after PAR1 stimulation in cancer cells, including those encoding the matrix remodeling protein, MMP9, and the cytokines, IL-1ß and IL-8. Further, exogenous expression of PAR1 in MCF7 breast cancer cells confers highly invasive and metastatic behavior which can be blocked by CRISPR/Cas9-mediated MALT1 knockout. Importantly, we find that PAR1 stimulation induces MALT1 protease activity in both osteosarcoma and breast cancer cells, an activity that is mechanistically linked to NF-κB activation and potentially other responses associated with aggressive phenotype. Several small molecule MALT1 protease inhibitors have recently been described that could therefore represent promising new therapeutics for the prevention and/or treatment of PAR1-driven tumor metastasis.

8.
Biol Open ; 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31362949

RESUMO

The effects of exposure to magnetic fields (MFs) at city electric frequencies (50-60 Hz) on carcinogenicity are still in debate. Besides, whether exposure to MFs affects the heart is also a debated issue. This study aimed to determine whether exposure to extremely low frequency magnetic fields (ELF-MFs) induced DNA damage in cardiomyocytes both in vitro and in vivo. Human ventricular cardiomyocytes were exposed to 50 Hz ELF-MF at 100 µT for 1 hr continuously or 75 min intermittently. The effects of the treatments were evaluated by DNA damage, redox status changes, and relative signal molecular expression. Moreover, ten male Sprague-Dawley rats were exposed to a 50 Hz MF at 100 µT for 7 days, while another 10 rats were sham exposed. The protein levels of p53 and Hsp70 in heart tissue were analyzed by western blot. The results showed that exposure to ELF-MF did not induce DNA damage, cell cycle distribution change, or increased ROS level. No significant differences were detected in p53 and Hsp70 expression level between the ELF-MF and sham-exposure groups both in vitro and in vivo. All these data indicated that MFs at power-frequency may not cause DNA damage in cardiomyocyte.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31392506

RESUMO

Microbial contamination poses a great threat to aviation system security through mechanisms such as microbiologically influenced corrosion (MIC), fuel filter clogging, and fuel deterioration. In this study, a survey of microbial contamination in aviation fuel obtained from aircraft fuel tanks was performed to test the relationship between microbial contamination and aircraft service life. The contaminating microorganisms were counted, isolated, identified, and subjected to preliminary characterization. A low risk of microbial contamination in the selected samples was confirmed, and there was no significant difference in the counts between culturable bacteria and fungi (p > 0.05). Phylogenetic analysis tree indicated that the diversity of culturable microorganisms was rather low, with 17 bacterial isolates belonging to 13 genera and 12 fungal isolates belonging to 5 genera. No yeast was isolated. The growth characteristics of these isolates indicated that the aircraft fuel tanks harbored various microorganisms that were able to utilize the aviation fuel as a source of carbon and energy. Meanwhile, some isolates caused emulsification and produced acid. The conclusions of this study were that various hazardous microorganisms can root in aircraft aviation fuel tanks. There was no relationship between microbial contamination and aircraft service life (p > 0.05), and continuous good maintenance suppressed microbial proliferation.

10.
J Microbiol Methods ; 164: 105684, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31394120

RESUMO

RNA-based molecular technique (RT-qPCR) is a promising method for microcystin monitoring in lakes and reservoirs, but great lability of RNA in cyanobacterial samples limits its application. To date, no studies have investigated how to effectively preserve RNA in cyanobacterial samples. In this study, four different treatments (-80 °C freezer, -196 °C liquid nitrogen, 4 °C or 25 °C preservation after adding RNA protective fluid) were employed to preserve RNA in pure culture and field Microcystis samples, and RNA degradation in these treatments were systematically evaluated. Results showed liquid nitrogen was the most effective treatment to preserve RNA in pure culture and field Microcystis samples. RNA preservation using RNA protective fluid was temperature dependent. Low temperature (4 °C) could effectively slow down RNA degradation within a short time (1-7 d), since decay rate of mcyH mRNA (k = 0.00094 d-1) was much lower at 4 °C than that at 25 °C (0.0549 d-1) (P < 0.05). However, for field samples, RNA degradation was much faster than pure culture samples with the same treatment. Therefore, to better preserve RNA in field samples, a practical strategy for RNA preservation combining RNA protective fluid and liquid nitrogen, was proposed. Tests of field experiments showed it was more effective than individual treatment for RNA preservation in Microcystis samples during field sampling. Thus, this strategy could be employed to preserve RNA in cyanobacterial samples during field sampling, which will contribute to the application of RT-qPCR technique for microcystin monitoring in lakes and reservoirs.

11.
Infect Immun ; 87(10)2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31358568

RESUMO

Development of long-term memory is crucial for vaccine-induced adaptive immunity against infectious diseases such as Staphylococcus aureus infection. Toxic shock syndrome toxin 1 (TSST-1), one of the superantigens produced by S. aureus, is a possible vaccine candidate against infectious diseases caused by this pathogen. We previously reported that vaccination with less toxic mutant TSST-1 (mTSST-1) induced T helper 17 (Th17) cells and elicited interleukin-17A (IL-17A)-mediated protection against S. aureus infection 1 week after vaccination. In the present study, we investigated the host immune response induced by mTSST-1 vaccination in the memory phase, 12 weeks after the final vaccination. The protective effect and IL-17A production after vaccination with mTSST-1 were eliminated because of IL-10 production. In the presence of IL-10-neutralizing monoclonal antibody (mAb), IL-17A production was restored in culture supernatants of CD4+ T cells and macrophages sorted from the spleens of vaccinated mice. Vaccinated mice treated with anti-IL-10 mAb were protected against systemic S. aureus infection in the memory phase. From these results, it was suggested that IL-10 produced in the memory phase suppresses the IL-17A-dependent vaccine effect through downregulation of IL-17A production.

12.
Macromol Biosci ; 19(9): e1900047, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31318163

RESUMO

Significant attention has been focused on bone tumor therapy recently. At present, the treatment in clinic typically requires surgical intervention. However, a few tumor cells remain around bone defects after surgery and subsequently proliferate within several days. Thus, fabrication of biomaterials with dual functions of tumor therapy and bone regeneration is significant. Herein, the injectable hydrogel containing cisplatin (DDP) and polydopamine-decorated nano-hydroxyapatite is prepared via Schiff base reaction between the aldehyde groups on oxidized sodium alginate and amino groups on chitosan. The hydrogel exhibits sustained release properties for DDP due to the immobilization of DDP via abundant functional groups on polydopamine (PDA). Additionally, given the intense absorption of PDA in the near-infrared region, the hydrogel exhibits excellent photothermal effects when exposed to the NIR laser (808 nm). Based on the properties, the hydrogel effectively ablates tumor cells (4T1 cells) in vitro and suppresses tumor growth in vivo. Furthermore, the hydrogel promotes the adhesion and proliferation of bone mesenchymal stem cells in vitro due to the abundant functional groups on PDA and further induces bone regeneration in vivo. Therefore, the study extends research on novel biomaterials with dual functions of tumor therapy and bone regeneration.

14.
World J Pediatr ; 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31342465

RESUMO

BACKGROUND: A number of clinical trials evaluated the efficacy and adverse effects of oral propranolol in the treatment of infantile hemangioma (IH), but the treatment has not yet been standardized. This meta-analysis aims to reevaluate the efficacy and adverse effects of oral propranolol in comparative studies and to provide a reliable basis for clinical administration in the therapy for IH. METHODS: Data were obtained from PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure and Wanfang database, from inception to December 1st, 2018. The pooled risk ratios (RR) with 95% confidence intervals (95% CI) were calculated and used to evaluate the effect size. The meta-analysis was performed using the random-effects model due to heterogeneity between the studies. The Cochrane Collaboration 6 aspects of bias, methodological index for non-randomized studies and the Newcastle-Ottawa Scale were used to assess the risk for bias. Sensitivity analysis, publication bias and subgroup analysis were performed. RESULTS: Eighteen unique studies involving 2701 unique children were included in the analysis. The response rate was reported in 18 trials, which compared oral propranolol with other treatments. The heterogeneity was statistically significant (P < 0.00001, I2 = 95%). The difference in the response rate was statistically significant (RR = 1.40, 95% CI 1.13-1.75) while compared with the controls. However, no significant difference in the adverse events rate (RR = 0.78, 95% CI 0.45-1.34) and relapse rate (RR = 1.45, 95% CI 0.66-3.16) were found. Otherwise, the subgroup analysis indicated that the RR was 1.64 (95% CI 0.24-11.36) for low-dose propranolol (1 mg/kg/day), 1.42 (95% CI 1.12-1.80) for medium dose (2 mg/kg/day) and 1.46 (95% CI 1.17-1.82) for high dose (3 mg/kg/day), but the high dose had higher adverse events rate than medium dose, with 3.60% and 86.22%, respectively. The effectiveness of propranolol therapy among cases of treatment duration less than 6 months (RR = 1.24, 95% CI 1.05-1.47) was inferior to that of treatment duration greater than or equal to 6 months (RR = 1.46, 95% CI 1.11-1.92). CONCLUSIONS: This meta-analysis reveals that oral propranolol is superior to other treatments in improving response rate of IH and can be used as the first-line therapy for IH children. A dosage of 2 mg/kg/day propranolol orally may be a good choice for IH. However, further studies are essential.

15.
J Cell Mol Med ; 23(8): 5317-5328, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31148336

RESUMO

Receptor-interacting protein kinase 3 (RIP3) is a key determinant of necroptosis and participates in ischaemia-and oxidative stress-induced necroptosis, myocardial remodelling and heart failure (HF). In this study, we tested the hypothesis that common variants in RIP3 gene were associated with the risk and prognosis of HF in the Chinese Han population. By re-sequencing and luciferase assays, we identified a common functional variant in the RIP3 promoter region. The rs3212247-T allele suppressed RIP3 promoter activity by facilitating transcription factor SOX17 binding, but not the C allele. We further recruited 2961 control participants and 3194 HF patients who underwent a mean follow-up of 19 months (6-31 months) for this study. Rs3212247 and another missense variant rs3212254 were genotyped. Although rs3212247 did not significantly associate with increased risk of HF (odds ratio = 1.00, 95% CI = 0.92-1.08, P = 0.91), it raised the risk for cardiovascular death and cardiac transplantation (hazard ratio = 1.47, 95% CI = 1.13-1.91, P = 0.004). Moreover, participants carrying the rs3212247 CC genotype had higher plasma levels of RIP3 than those carrying the TT or TC genotype (p for trend = 0.02) in New York Heart Association class III HF group. No association was found between the RIP3 missense variant rs3212254 and risk or prognosis of HF after adjustment for traditional risk factors. In conclusion, genetic variant in RIP3 promoter region is associated with increased RIP3 transcription, thus contributed to the poor prognosis of HF patients. Clinical Trial Registration: https://www.clinicaltrials.gov/ct2/show/NCT03461107?term=03461107&cond=Heart+Failure&cntry=CN&rank=1. Unique identifier: NCT03461107.

16.
Reprod Toxicol ; 87: 108-117, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31170451

RESUMO

Cryptorchidism is a common disorder in children and may cause infertility in adults. The BTB is essential for maintaining the microenvironment necessary for normal spermatogenesis. This study investigated whether retinoic acid (RA) may regulate the proteins that are essential for integrity of the BTB in cryptorchidism. Female Sprague-Dawley rats were administrated flutamide during late pregnancy to induce a model of cryptorchidism in male offspring. The concentrations of RA and BTB tight and gap junction protein levels were significantly lower in untreated cryptorchid pups compared with normal pups, but almost normal in cryptorchid pups given RA. Studies in vitro corroborated these findings. The sperm quality of RA-treated model pups was better compared with the untreated model. RA treatment may have therapeutic potential to restore retinoic acid and proteins associated with integrity of the BTB in cryptorchid testis.

17.
J Transl Med ; 17(1): 191, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31171000

RESUMO

BACKGROUND: Elevated protein expressions of CD markers such as IL2RA/CD25, CXCR4/CD184, CD34 and CD56 are associated with adverse prognosis in acute myeloid leukemia (AML). However, the prognostic value of mRNA expressions of these CD markers in AML remains unclear. Through our pilot evaluation, IL2RA mRNA expression appeared to be the best candidate as a prognostic biomarker. Therefore, the aim of this study is to characterize the prognostic value of IL2RA mRNA expression and evaluate its potential to refine prognostification in AML. METHODS: In a cohort of 239 newly diagnosed AML patients, IL2RA mRNA expression were measured by TaqMan realtime quantitative PCR. Morphological, cytogenetics and mutational analyses were also performed. In an intermediate-risk AML cohort with 66 patients, the mRNA expression of prognostic biomarkers (BAALC, CDKN1B, ERG, MECOM/EVI1, FLT3, ID1, IL2RA, MN1 and WT1) were quantified by NanoString technology. A TCGA cohort was analyzed to validate the prognostic value of IL2RA. For statistical analysis, Mann-Whitney U test, Fisher exact test, logistic regression, Kaplan-Meier and Cox regression analyses were used. RESULTS: In AML cohort of 239 patients, high IL2RA mRNA expression independently predicted shorter relapse free survival (RFS, p < 0.001) and overall survival (OS, p < 0.001) irrespective of age, cytogenetics, FLT3-ITD or c-KIT D816V mutational status. In core binding factor (CBF) AML, high IL2RA mRNA expression correlated with FLT3-ITD status (p = 0.023). Multivariable analyses revealed that high IL2RA expression (p = 0.002), along with c-KIT D816V status (p = 0.013) significantly predicted shorter RFS, whereas only high IL2RA mRNA expression (p = 0.014) significantly predicted shorter OS in CBF AML. In intermediate-risk AML in which multiple gene expression markers were tested by NanoString, IL2RA significantly correlated with ID1 (p = 0.006), FLT3 (p = 0.007), CDKN1B (p = 0.033) and ERG (p = 0.030) expressions. IL2RA (p < 0.001) and FLT3 (p = 0.008) expressions remained significant in predicting shorter RFS, whereas ERG (p = 0.008) and IL2RA (p = 0.044) remained significant in predicting shorter OS. Similar analyses in TCGA intermediate-risk AML showed the independent prognostic role of IL2RA in predicting event free survival (p < 0.001) and OS (p < 0.001). CONCLUSIONS: High IL2RA mRNA expression is an independent and adverse prognostic factor in AML and specifically stratifies patients to worse prognosis in both CBF and intermediate-risk AML.

18.
Dis Markers ; 2019: 2829798, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31191746

RESUMO

The molecular mechanism for colorectal cancer to develop remains unelucidated. To find biomarkers related to colorectal cancer development, we analyzed the gene expression profile of 380 colorectal cancer patients and 51 healthy controls by R software. Finally, 1579 upregulated differential expression genes (DEGs) and 3218 downregulated DEGs were identified. Then, the top 20 upregulated DEGs were compared with 181 upregulated DEGs that we reported previously, and 11 overlapped DEGs were found. NFE2L3 (nuclear factor, erythroid 2-like 3) was among those overlapped DEGs and was rarely reported in colorectal cancer. Real-time polymerase chain reaction (PCR) results showed that higher NFE2L3 expression levels were identified in paired tumor samples than in paratumor samples (48 paired samples). Flow cytometry analysis revealed that the cell cycle was arrested at the G0/G1 phase after inhibition of NFE2L3 in both HCT116 and SW480 cell lines. Western blot detection showed that CCND1 and phosphorylated Rb transcriptional corepressor 1 at ser-807/811 (pRb1-ser807/811) expression levels were downregulated when NFE2L3 was inhibited in those two cell lines. A significant positive correlation was observed between NFE2L3 and CCND1 expression levels in colorectal tissue samples. These evidences indicate that downregulation of NFE2L3 induces cell cycle arrest at the G0/G1 phase through downregulation of CCND1 and pRb1-ser807/811.

19.
EBioMedicine ; 44: 98-111, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31101597

RESUMO

BACKGROUND: Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The malignant and invasive feature of TNBCs is correlated with its high cancer stem cell population. Recent results from us and others have unveiled an oncogenic role for the PRMT5-KLF4 axis in regulating tumor progression by orchestrating the stemness in mammary tumor cell as well as genome stability. Methylation of KLF4 by PRMT5 leads to KLF4 stabilization, resulting in promoting mitogenesis. METHODS: We have developed a small molecule inhibitor, WX2-43, that specifically intercepts the interaction between PRMT5 and KLF4, thereby enhancing KLF4 degradation. FINDINGS: Results from our characterization demonstrate that WX2-43 binds to the region between amino acids L400-M500 on PRMT5. Degradation of KLF4 down-regulates KLF4-mediated genes transcription. We have characterized the potent effect for WX2-43 in inhibiting PRMT5-KLF4 binding that, in turns, suppresses tumor progression and induces tumor cell death in both TNBC cultured-cell and animal models. INTERPRETATION: WX2-43-mediated inhibition of KLF4 methylation by PRMT5 could be a potential strategy for anti-TNBC treatment. FUND: This work was supported, in whole or in part, by National Institutes of Health grants CA202963 and CA202948 (Wan), R21HL109654 (Xie), P30DA035778 (Xie and Bahar) and P41GM103712 (Bahar).

20.
PLoS Pathog ; 15(5): e1007803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31112582

RESUMO

Staphylococcal enterotoxins (SEs) produced by Staphylococcus aureus are known as causative agents of emetic food poisoning. We previously demonstrated that SEA binds with submucosal mast cells and evokes mast cell degranulation in a small emetic house musk shrew model. Notably, primates have been recognized as the standard model for emetic assays and analysis of SE emetic activity. However, the mechanism involved in SEA-induced vomiting in primates has not yet been elucidated. In the present study, we established common marmosets as an emetic animal model. Common marmosets were administered classical SEs, including SEA, SEB and SEC, and exhibited multiple vomiting responses. However, a non-emetic staphylococcal superantigen, toxic shock syndrome toxin-1, did not induce emesis in these monkeys. These results indicated that the common marmoset is a useful animal model for assessing the emesis-inducing activity of SEs. Furthermore, histological analysis uncovered that SEA bound with submucosal mast cells and induced mast cell degranulation. Additionally, ex vivo and in vivo pharmacological results showed that SEA-induced histamine release plays a critical role in the vomiting response in common marmosets. The present results suggested that 5-hydroxytryptamine also plays an important role in the transmission of emetic stimulation on the afferent vagus nerve or central nervous system. We conclude that SEA induces histamine release from submucosal mast cells in the gastrointestinal tract and that histamine contributes to the SEA-induced vomiting reflex via the serotonergic nerve and/or other vagus nerve.

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