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1.
Molecules ; 24(22)2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31717456

RESUMO

Type 2 diabetes mellitus (T2DM) is a metabolic disease accompanied by a series of diseases such as diabetic nephropathy. The drug pair (HS) of Astragalus Radix (HQ) and Dioscoreae Rhizoma (SY) was designed by Dr. Shi Jinmo to improve the treatment of T2DM. However, the exact mechanism involved requires further clarification. In this work, 1H-NMR-based metabonomics and network pharmacology were adopted. Metabolic profiling indicated that the metabolic perturbation was reduced after HS treatment. The results found 21 biomarkers. According to the network pharmacology, we found that the regulation of T2DM was primarily associated with 18 active compounds in HS. These active compounds mainly had an effect on 135 targets. Subsequently, combining network pharmacology and metabonomics, we found four target proteins, which indicated that HS has potential hypoglycemic effects through regulating monoamine oxidases B (MAOB), acetyl-CoA carboxylase 1 (ACACA), carbonic anhydrase 2 (CA2), and catalase (CAT). In conclusion, the result showed that these four targets might be the most relevant targets for the treatment of T2DM with HS. This study clarified the mechanism of HS in the treatment of T2DM and also confirmed the feasibility of combining metabonomics and network pharmacology to study the mechanisms of traditional Chinese medicine (TCM). In the future, this approach may be a potentially powerful tool to discovery active components of traditional Chinese medicines and elucidate their mechanisms.

2.
Part Fibre Toxicol ; 16(1): 41, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699096

RESUMO

BACKGROUND: Silicon dioxide nanoparticles (SiO2 NPs) are one of the most widely utilized NPs in various food sectors. However, the potential endocrine toxicity of SiO2 NPs has not been characterized. RESULTS: In the present study, mice were orally administered a series of doses of SiO2 NPs. All doses of SiO2 NPs were absorbed into the blood, liver, and pancreas of the mice. Administration of 100 mg/kg bw (body weight) of SiO2 NPs significantly increased blood glucose levels in mice. However, the same dose of SiO2 fine-particles (FPs) did not result in altered blood glucose. Whole-genome analysis showed that SiO2 NPs affected the expression of genes associated with reactive oxygen species (ROS) production and endoplasmic reticulum (ER) stress. In addition, we showed that SiO2 NPs activated xenobiotic metabolism, resulting in ER stress. Endoplasmic reticulum stress resulted in increased ROS production, which activated the NF-κB pathway leading to expression of inflammatory cytokines. Increased inflammatory cytokine expression resulted in serine phosphorylation of IRS1, which induced insulin resistance (IR). Furthermore these inflammatory cytokines activated the MAPK pathway, which further promoted the serine phosphorylation of IRS1. Insulin resistance resulted in elevated blood glucose. The ER stress inhibitor 4-phenylbutyric acid (4-PBA) inhibited SiO2 NP-induced ROS production. The ROS scavenger N-acetylcysteine (NAC) did not affect SiO2 NP-induced ER stress, but inhibited SiO2 NP-induced activation of the NF-κB and MAPK pathways, expression of inflammatory cytokines, SiO2 NP-induced serine phosphorylation of IRS1, and SiO2 NP-induced elevations of blood glucose. CONCLUSION: Silicon dioxide NPs induced IR through ER stress and generation of ROS, but SiO2 FPs did not. Therefore, lifelong exposure of humans to SiO2 NPs may result in detrimental effects on blood glucose. The results of this study strongly suggested that non-nanoformed SiO2 should be used as food additives.

3.
J Food Sci ; 2019 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-31762038

RESUMO

To investigate the effect of functional amino acid on meat flavor and eating quality, 60 growing-finishing pigs (Duroc × Large White × Landrace) were dietarily supplemented with or without 1.0% l-arginine, glutamic acid, or l-arginine plus glutamic acid for 2 months. After animals were slaughtered, the muscle fatty acid profile, flavor compounds, and meat sensory quality were comparatively investigated. The results showed that dietary supplementation with arginine, glutamic acid, or arginine plus glutamic acid had little effect on free amino acids, no effect on 5'-nucleotides and meat sensory taste traits, but supplementation with arginine plus glutamic acid significantly increased (P < 0.05) fat accumulation and fatty acid content in muscle, increased (P < 0.05) the formation of multiple fatty acid oxidation-derived volatile compounds, and improved the tenderness, juiciness, and overall eating quality of meat. This study revealed that dietary supplementation with 1.0% l-arginine and glutamic acid could be used to improve meat eating quality in pork production.

4.
Artigo em Inglês | MEDLINE | ID: mdl-31760433

RESUMO

BACKGROUND: Consolation is a type of empathy-like behavior that has recently been observed in some socially living rodents. Despite the growing body of literature suggesting that stress affects empathy, the relationship between stress and consolation remains understudied at the preclinical level. Here, we examined the effects of chronic emotional stress (ES) or physical stress (PS) exposure on consolation and emotional behaviors by using the socially monogamous mandarin vole (Microtus mandarinus) in both males and females. METHOD/RESULTS: PS-voles were exposed to 14-day social defeat stress, whereas ES-voles vicariously experienced the defeat of their partners. We found that PS- but not ES-voles showed reduced grooming toward their defeated partners and increased anxiety- and despair-like behaviors. Meanwhile, PS-voles exhibited decreased neural activity in the anterior cingulate cortex (ACC), which is centrally involved in empathy. The densities of oxytocin receptors (OTRs), dopamine D2 receptors (D2Rs) and serotonin 1A-receptors (5-HT1ARs) within the ACC were significantly decreased in the PS group compared with controls. All the behavioral and physiological changes were similar between the sexes. Finally, we found that the reduced consolation behavior and some anxiety-like syndromes in PS-voles could be alleviated by pretreatment with an OTR, D2R or 5-HT1AR agonist within the ACC, whereas injections of corresponding receptor antagonists to the control voles decreased the consolation behavior and increased some anxiety-like behaviors. CONCLUSIONS: Our results indicated that chronic PS exposure impaired consolation and induced anxiety-like behaviors in mandarin voles and OTRs, 5-HT1ARs and D2Rs within the ACC may play important roles in these processes.

5.
Environ Toxicol ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31769605

RESUMO

Titanium dioxide nanoparticles (TiO2 NPs) are authorized food additives, and children have the highest exposure. Therefore, children are likely more susceptible to the adverse effects of TiO2 NPs than adults. Previous study showed that oral administration of 50 mg/kg body weight (bw) TiO2 NPs increase plasma glucose in mice. However, few studies have directly compared the adverse effects of exposure to TiO2 NPs on plasma glucose metabolism of different age groups. In this study, the developing (age 3 weeks) and adult mice (age 10 weeks) were orally administered with 50 mg/kg bw TiO2 NPs per day. The TiO2 NPs induced hyperglycemia earlier in the developing mice than in the adult mice. Then mechanisms were analyzed after mice were oral administration of TiO2 NPs for 8 weeks and 26 weeks, respectively. Results showed that the treatment with TiO2 NPs activated xenobiotic biodegradation in livers of both developing and adult mice at the early stage. However, only in the developing mice, TiO2 NPs induced endoplasmic reticulum (ER) stress in livers and increased reactive oxygen species in livers and sera in the early stage. The ER stress and ROS activated an inflammation response and mitogen-activated protein kinase pathways, thereby inducing insulin resistance in the livers of developing mice at the early stage. The response of the adult mice was delayed, and these changes were observed in the late stage of the study. The results of this study all suggest that children are more susceptible than adults to the toxicity of orally administered TiO2 NPs.

6.
Biochem Biophys Res Commun ; 520(3): 619-626, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31623832

RESUMO

Elevated plasma free fatty acid (FFA) levels are associated with insulin resistance and can cause lipotoxicity in skeletal muscles. In response to FFAs, skeletal muscle can secrete a variety of cytokines. Irisin, one such muscle-secreted cytokine, can improve glucose tolerance, glucose uptake, and lipid metabolism. It is produced by the transmembrane protein fibronectin type Ⅲ domain containing 5 (FNDC5) by specific proteases. The purpose of this study was to investigate the regulatory mechanisms of the FNDC5 response to palmitate and their relationships with insulin resistance in C2C12 myotubes. RNA sequencing analysis results from C2C12 myotubes treated with palmitate showed that palmitate could activate the TGF-ß signaling pathway. Palmitate directly affected the expression of Smad3, but not its phosphorylation level, in C2C12 myotubes. Furthermore, knockdown and knockout of Smad3 alleviated the inhibitory effect of palmitate on the expression of FNDC5. In contrast, overexpression of Smad3 aggravated the inhibition of FNDC5 expression. There is a Smad3 binding motif in the -660 bp to -649 bp region of the Fndc5 promoter. CRISPR/Cas9 knockout of this region also alleviated the inhibition of FNDC5 expression in response to palmitate. More importantly, inhibition of FNDC5 expression mediated by Smad3 led to a decrease in insulin sensitivity in C2C12 myotubes. Collectively, these findings suggest that palmitate could induce insulin resistance through Smad3-mediated down-regulation of the Fndc5 gene.

7.
Life Sci ; : 116910, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31610211

RESUMO

AIMS: Tomoregulin-2 (TMEFF2) is a single-pass transmembrane protein whose specific functions and mechanisms in endometrial carcinoma (EC) remain unclear. The aim of this study was to investigate the expression, prognostic role, and potential regulatory mechanisms of TMEFF2 in EC. MATERIALS AND METHODS: The expression and prognosis of TMEFF2 in EC were analyzed via bioinformatics and verified by immunohistochemistry and survival analysis. Proliferation, invasion, and migration of EC cells in vitro were assessed by cell functional assays, while epithelial-mesenchymal transition (EMT) markers and key signaling pathway proteins were evaluated by western blotting. KEY FINDINGS: The expression of TMEFF2 in EC was significantly higher than that in atypical hyperplasia and normal endometrium, the high expression of TMEFF2 was correlated with advanced stage, poor differentiation, and lymph node metastasis, and also predicted a poor prognosis of EC. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that TMEFF2 and its related genes were enriched in the central nervous system, cell adhesion, signal transduction, and several critical signaling pathways. We also elucidated TMEFF2 networks of kinase, microRNA, and transcription factor targets. In vitro, the proliferation, invasion, and migration abilities of EC cells decreased after TMEFF2 downregulation. Downregulation of TMEFF2 reduced the activation of MAPK and PI3K signaling pathways, and inhibited EMT. SIGNIFICANCE: TMEFF2 plays an important role in the initiation, development, and malignant behavior of EC and can be a potential target for early diagnosis and treatment in EC.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31622005

RESUMO

Increasing life expectancy in the population means that the prevalence of hypertension in China will increase over the coming decades. Although awareness and control rates have improved, the absolute rates remain unacceptably low. Cardiovascular disease (CVD) is the biggest killer in China, and sharp increases in the prevalence of CVD risk factors associated with rapid lifestyle changes will contribute to ongoing morbidity and mortality. This highlights the importance of effectively diagnosing and managing hypertension, where home blood pressure monitoring (HBPM) has an important role. Use of HBPM in China is increasing, particularly now that Asia-specific guidance is available, and this out-of-office BP monitoring tool will become increasingly important over time. To implement these recommendations and guidelines, a Web-based and WeChat-linked nationwide BP measurement system is being established in China. Local guidelines state that both HBPM and ambulatory blood pressure monitoring should be implemented where available. In China, hypertension is managed most often using calcium channel blockers, followed by angiotensin receptor blockers or angiotensin-converting enzyme inhibitors. Key barriers to hypertension control in China are low awareness and control rates.

9.
Anal Chem ; 91(21): 13349-13354, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31588733

RESUMO

Biomarker receptors on cancer cells can sense and recruit extracellular ligands and ligand-conjugated imaging agents/drugs, providing a critical basis upon which to develop an active tumor-targeting strategy. However, such a strategy can be confounded by both the limited number of cancer biomarker receptors and the inherent heterogeneity of cancer cells. Therefore, we herein report a simple strategy to deploy an exogenous physical label on the surface of cancer cells as an artificial receptor (AR) for active tumor targeting. It can be driven by the tumor extracellular acidic microenvironment to insert into the plasma membrane of cancer cells. Our studies demonstrated that an AR could efficiently sense and recruit the extracellular imaging agent Cy5-streptavidin conjugate to cancer cells, cancer cell spheroids, and an in vivo tumor. Based on the easy synthesis and chemical modification diversity of the peptide, our AR holds promise as a novel tumor-targeted strategy.

10.
Int J Biochem Cell Biol ; 116: 105617, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31550546

RESUMO

Previously, we reported that the expression of human epididymis protein (HE4) was correlated with the expression of RAB23 in ovarian cancer cells. Rab23 is a member of the Ras-related small GTPase superfamily, which plays a key role in the Sonic Hedgehog (Shh) signaling pathway. However, the function of Rab23 in ovarian cancer remains unclear. In this study, we explored the location and expression of Rab23 in ovarian cancer tissues and cells (CaoV3 and A2780), and further investigated the function and potential mechanism of Rab23 in malignant biological behaviors including the epithelial-mesenchymal transition (EMT) process in ovarian cancer for the first time. Rab23 is highly expressed in ovarian cancer tissues and associated with advanced stage, and shortened overall survival time of ovarian cancer patients. We are the first to report that human epididymis protein (HE4) can regulate the expression of the Rab23 protein, and that knockdown of RAB23 decreases the proliferation, invasion, and migration abilities as well as inhibits the epithelial-mesenchymal transition (EMT) process in ovarian cancer cells. Furthermore, downregulation of Rab23 significantly inhibited Shh-Gli1 and PI3K-AKT signaling pathways. Collectively, our results indicate that Rab23 plays a critical role in the malignant biological behavior of ovarian cancer and may serve as a potential biomarker and therapeutic target for ovarian cancer.

11.
J Transl Med ; 17(1): 275, 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31474227

RESUMO

BACKGROUND: Annexins are involved in vesicle trafficking, cell proliferation and apoptosis, but their functional mechanisms in ovarian cancer remain unclear. In this study, we analyzed Annexins in ovarian cancer using different databases and selected Annexin A8 (ANXA8), which showed the greatest prognostic value, for subsequent validation in immunohistochemical (IHC) assays. METHODS: The mRNA expression levels, genetic variations, prognostic values and gene-gene interaction network of Annexins in ovarian cancer were analyzed using the Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), cBioPortal, Kaplan-Meier plotter and GeneMANIA database. ANXA8 was selected for analyzing the biological functions and pathways of its co-expressed genes, and its correlation with immune system responses via the Database for Annotation, Visualization, and Integrated Discovery (DAVID) and the TISIDB database, respectively. We validated the expression of ANXA8 in ovarian cancer via IHC assays and analyzed its correlation with clinicopathological parameters and prognosis. RESULTS: ANXA2/3/8/11 mRNA expression levels were significantly upregulated in ovarian cancer, and ANXA5/6/7 mRNA expression levels were significantly downregulated. Prognostic analysis suggested that significant correlations occurred between ANXA2/4/8/9 mRNA upregulation and poor overall survival, and between ANXA8/9/11 mRNA upregulation and poor progression-free survival in patients with ovarian serous tumors. Taken together, results suggested that ANXA8 was most closely associated with ovarian cancer tumorigenesis and progression. Further analyses indicated that ANXA8 may be involved in cell migration, cell adhesion, and vasculature development, as well as in the regulation of PI3K-Akt, focal adhesion, and proteoglycans. Additionally, ANXA8 expression was significantly correlated with lymphocytes and immunomodulators. The IHC results showed that ANXA8 expression was higher in the malignant tumor group than in the borderline and benign tumor groups and normal ovary group, and high ANXA8 expression was an independent risk factor for survival and prognosis of ovarian cancer patients (P = 0.013). CONCLUSIONS: Members of the Annexin family display varying degrees of abnormal expressions in ovarian cancer. ANXA8 was significantly highly expressed in ovarian cancer, and high ANXA8 expression was significantly correlated with poor prognosis. Therefore, ANXA8 is a high candidate as a novel biomarker and therapeutic target for ovarian cancer.

12.
Nanotoxicology ; : 1-18, 2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519126

RESUMO

Zinc oxide nanoparticles (ZnO NPs) represent an important class of commercially applied materials. Recently, adverse effects of ZnO NPs were found in humans and animals following ingestion, although the effects on endocrine system disease remain unclear. In this study, ZnO NPs were orally administered to mice, and at doses of 25 mg/kg bw (body weight) ZnO NPs and above, plasma glucose increased significantly. The genome-wide effects of ZnO NPs were then investigated using RNA-sequencing technology. In the cluster analysis, the most significantly enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways concerned membranes and their close association with endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation. Biochemical and gene and protein expression analyses revealed that ZnO NPs activated a xenobiotic biodegradation response and increased the expression of cytochrome P450 (CYP) enzymes in mice livers, leading to ER stress. The ER stress increased ROS generation. The high levels of ROS activated the MAPK and NF-κB pathways and induced an inflammation response, resulting in the phosphorylation of insulin receptor substrate 1. Thus, the insulin resistance that developed was the primary mechanism for the increase in the plasma glucose of mice treated orally with ZnO NPs.

13.
Clin Cancer Res ; 25(21): 6511-6523, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31375512

RESUMO

PURPOSE: PD-1 checkpoint blockade immunotherapy induces long and durable response in patients with advanced melanoma. However, only a subset of patients with melanoma benefit from this approach. The mechanism triggering the innate resistance of anti-PD-1 therapy remains unclear.Experimental Design: Whole-exome sequencing (WES) and RNA sequencing (RNA-Seq) analyses were performed in a training cohort (n = 31) using baseline tumor biopsies of patients with advanced melanoma treated with the anti-PD-1 antibody. Copy-number variations (CNVs) for the genes CDK4, CCND1, and CDKN2A were assayed using a TaqMan copy-number assay in a validation cohort (n = 85). The effect of CDK4/6 inhibitors combined with anti-PD-1 antibody monotherapy was evaluated in PD-1-humanized mouse (C57BL/6-hPD-1) and humanized immune system (HIS) patient-derived xenograft (PDX) models. RESULTS: WES revealed several significant gene copy-number gains in the patients of no clinical benefit cohort, such as 12q14.1 loci, which harbor CDK4. The association between CDK4 gain and innate resistance to anti-PD-1 therapy was validated in 85 patients with melanoma (P < 0.05). RNA-Seq analysis of CDK4-normal cell lines and CDK4-normal tumors showed altered transcriptional output in TNFα signaling via NF-κB, inflammatory response, and IFNγ response gene set. In addition, CDK4/6 inhibitor (palbociclib) treatment increased PD-L1 protein levels and enhanced efficacy (P < 0.05) in the C57BL/6-hPD-1 melanoma cell and the HIS PDX model. CONCLUSIONS: In summary, we discovered that genetic aberrations in the CDK4 pathway are associated with innate resistance to anti-PD-1 therapy in patients with advanced melanoma. Moreover, our study provides a strong rationale for combining CDK4/6 inhibitors with anti-PD-1 antibody for the treatment of advanced melanomas.

14.
Environ Toxicol ; 34(11): 1221-1235, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31298478

RESUMO

Titanium dioxide nanoparticles (TiO2 NPs) are reported to increase plasma glucose levels in mice at specific doses. The production and accumulation of reactive oxygen species (ROS) is potentially the most important factor underlying the biological toxicity of TiO2 NPs but the underlying mechanisms are unclear at present. Data from genome-wide analyses showed that TiO2 NPs induce endoplasmic reticulum (ER) stress and ROS generation, leading to the inference that TiO2 NP-induced ER stress contributes to enhancement of ROS in mice. Resveratrol (Res) effectively relieved TiO2 NP-induced ER stress and ROS generation by ameliorating expression of a common set of activated genes for both processes, signifying that ER stress and ROS are closely related. TiO2 NP-induced ER stress occurred earlier than ROS generation. Upon treatment with 4-phenylbutyric acid to relieve ER stress, plasma glucose levels tended toward normal and TiO2 NP increased ROS production was inhibited. These results suggest that TiO2 NP-induced ER stress promotes the generation of ROS, in turn, triggering increased plasma glucose levels in mice. In addition, Res that displays the ability to reduce ER stress presents a dietary polyphenol antioxidant that can effectively prevent the toxicological effects of TiO2 NPs on plasma glucose metabolism.

15.
Pathol Res Pract ; 215(9): 152523, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31300294

RESUMO

Mammary carcinoma (MC) is one of most common malignancy in women, and ring finger protein 2 (RNF2) possesses various roles in vast human tumors. In MC tissues as well as in cell lines RNF2 exhibited high expression, had significant association with tumor size, lymph node status, TNM stage, patients' poor survival, and promoted cell proliferation, colony formation, cell migration and invasion of MC cell lines which was mediated by downregulation of E-cadherin protein. These data reveal that RNF2 protein plays a vital role in the development of MC and may be a potential therapy target of MC.

16.
Sensors (Basel) ; 19(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340467

RESUMO

Antenna sensors have been employed for crack monitoring of metallic materials. Existing studies have mainly focused on the mathematical relationship between the surface crack length of metallic material and the resonant frequency. The influence of the crack depth on the sensor output and the difference of whether the crack is depth-penetrated remains unexplored. Therefore, in this work, a numerical simulation method was used to investigate the current density distribution characteristics of the ground plane (metallic material) with different crack geometric parameters. The data reveals that, compared with the crack length, the crack depth has a greater influence on the resonant frequency. The relationship between the frequency and the crack geometric parameters was discussed by characterizing the current density and sensor output under different crack lengths and depths. Therefore, the feasibility of monitoring another common damage of metallic materials, i.e., corrosion pit, was explored. Furthermore, the influences of crack and corrosion pit geometric parameters on the output results were validated by experiments.

17.
Mar Drugs ; 17(7)2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31261836

RESUMO

N-Acylhomoserine lactonase degrades the lactone ring of N-acylhomoserine lactones (AHLs) and has been widely suggested as a promising candidate for use in bacterial disease control. While a number of AHL lactonases have been characterized, none of them has been developed as a commercially available enzymatic product for in vitro AHL quenching due to their low stability. In this study, a highly stable AHL lactonase (AhlX) was identified and isolated from the marine bacterium Salinicola salaria MCCC1A01339. AhlX is encoded by a 768-bp gene and has a predicted molecular mass of 29 kDa. The enzyme retained approximately 97% activity after incubating at 25 °C for 12 days and ~100% activity after incubating at 60 °C for 2 h. Furthermore, AhlX exhibited a high salt tolerance, retaining approximately 60% of its activity observed in the presence of 25% NaCl. In addition, an AhlX powder made by an industrial spray-drying process attenuated Erwinia carotovora infection. These results suggest that AhlX has great potential for use as an in vitro preventive and therapeutic agent for bacterial diseases.

18.
Biomed Res Int ; 2019: 2686875, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31355251

RESUMO

Objectives: A growing body of evidence has shown that aberrant alternative splicing (AS) is closely related to the occurrence and development of cancer. However, prior studies mainly have concentrated on a few genes that exhibit aberrant AS. This study aimed to determine AS events through whole genome analysis and construct a prognostic model of endometrial cancer (EC). Methods: We downloaded gene expression RNAseq data from UCSC Xena, and seven types of AS events from TCGA SpliceSeq. Univariate Cox regression was employed to analyze the prognostic-related alternative splicing events (PASEs) and splicing factors; multivariate Cox regression was conducted to analyze the effect of risk score (All) and clinicopathological parameters on EC prognosis. An underlying interaction network of PASEs of EC was constructed by Cytoscape Reactome FI, GO, and KEGG pathway enrichment was performed by DAVID. ROC curves and Kaplan-Meir analysis were used to assess the diagnostic value of prognostic model. The correlation between PASEs and splicing factors was analyzed by GraphPad Prism; then a network was constructed using Cytoscape. Results: In total, 28,281 AS events in EC were identified, which consisted of 1166 PASEs. RNPS1, NEK2, and CTNNB1 were the hub genes in the network of the top 600 PASEs. The area under the curve (AUC) of risk score (All) reached 0.819. Risk score (All) together with FIGO stage, cancer status, and primary therapy outcome success was risk factors of the prognosis of EC patients. Splicing factors YBX1, HNRNPDL, and HNRNPA1 were significantly related to the overall survival (OS). The splicing network indicated that the expression of splicing factors was significantly correlated with percent-splice-in (PSI) value of PASEs. Conclusion: We constructed a model for predicting the prognosis of EC patients based on PASEs using whole genome analysis of AS events and thereby provided a reliable theoretical basis for EC clinical prognosis evaluation.

19.
Fish Shellfish Immunol ; 93: 278-287, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349013

RESUMO

In order to illustrate the immunometabolic changes of fish during bacterial infection, grass carp (Ctenopharyngodon idellus) was injected with Flavobacteriumcolumnare(F.columnare) and then the immune response, nutrient metabolism and related signaling pathways were assayed from 6 h post injection (hpi) to 7 days post injection (dpi). After F.columnare injection, gill lamellae showed obvious fusion and higher mRNA expression levels of pro-inflammatory cytokines. The mRNA expression levels of TNF-α, IL-1ß and IL-8 in the head kidney were also significantly upregulated at 6 hpi and 3 dpi. Moreover, the expression of IgZ in the gill was significantly upregulated at 3 dpi and 7 dpi, while the expression of IgM in the head kidney was significantly upregulated at 1 dpi and 3 dpi after F.columnare injection. During bacterial infection, the systematic nutrient metabolism was also significantly affected. Hepatic glycolysis, indicated by GK mRNA expression and PK activity, was significantly upregulated at 1 dpi, while glucogenesis, indicated by PEPCK mRNA expression and enzyme activity, was significantly increased at later time, which resulted in the decreased hepatic glycogen content at 1dpi but increased glycogen content at 7 dpi in the experimental group. LPL, which catalyzed the lipid catabolism, showed decreased mRNA expression and enzyme activity at 6 hpi, while ACC, which was rate-limiting of FA synthesis, was significantly increased at 6 hpi, 3 dpi and 7 dpi. During this process, the nutrient sensing signaling was also significantly affected. TOR signaling in grass carp was significantly activated while ERK signaling was significantly inhibited after F.columnare infection, both of which might function as the sensor and regulator of fish immunometabolic changes.

20.
Vaccine ; 37(31): 4382-4391, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31202521

RESUMO

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8+ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα+ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.

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