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1.
Sci Rep ; 10(1): 1815, 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020007

RESUMO

The purpose of this study was to compare differences of energy expenditure and substrate metabolism between motorized-treadmill and overground running in three different velocities in Chinese middle-aged women. In total, 74 healthy middle-aged women (age, 48 ± 4 years; height, 159.4 ± 4.9 cm; weight, 58.6 ± 6.7 kg; and body-mass index (BMI), 23.1 ± 2.7 kg/m2) volunteered to participate in this study. Bioelectrical-impedance analysis was used to measure body composition. Energy expenditure, carbohydrates (CHO), and fat oxidation were calculated with indirect calorimetry during motorized-treadmill and overground running. Running speed from slow to fast was 7.0, 8.0, and 9.0 km/h. The duration of each velocity was 6 min, separated by 5-15 min rest. There was no significant difference in energy expenditure between overground and treadmill running at the speed of 7 km/h (8.10 ± 1.25 vs. 7.75 ± 1.13 kcal/min, p > 0.05). Energy expenditure of overground running at 8 and 9 km/h was higher than that of treadmill running (9.36 ± 1.40 vs. 8.54 ± 1.21 kcal/min; 10.33 ± 1.55 vs. 9.54 ± 1.36 kcal/min; both p < 0.01). Fat contribution to energy consumption was significantly higher during treadmill running than during overground running (both p < 0.01) at speeds of 8 and 9 km/h. Overground running at high intensity incurred greater energy consumption than treadmill running did. However, results showed greater fat utilization during treadmill running than during overground running at high intensity. It is critical that these differences are taken into account when we prescribe training modes and intensities for middle-aged women.

2.
Microsc Microanal ; : 1-9, 2020 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-32051051

RESUMO

Exosomes derived from hepatocellular carcinoma (HCC) cells are nanovesicles and are involved in the occurrence and development of HCC, they also serve as important carriers and drug targets of nanodrug delivery systems. The external shape and internal structure of exosomes are important indexes of identification, and isolated intact morphology is crucial to biological function integrity. However, given their susceptibility to various influencing factors, the external shape and internal structure of exosomes derived from HCC cells remain incompletely studied. In this study, exosomes purified from HCC cells were isolated at different centrifugation speeds and examined via multiple electron microscopy (EM) techniques. The results demonstrate that exosomes possess a nearly spherical shape and bilipid membranous vesicle with a concave cavity structure containing electron-dense and coated vesicles, suggesting the possible existence of subpopulations of exosomes with specific functions. The exosomes isolated at ultracentrifugation (UC) speed (≥110,000×g) presented irregular and diverse external morphologies, indicating the effect on the integrity of the exosomes. Transforming growth factor signaling bioactive substances (TGF-ß1, S100A8, and S100A9) can be found in exosomes by performing Western blotting, showing that the internal content is associated with metastasis of HCC. These findings show that EMelectron microscopy and UC speed can affect exosome characteristics, including external shape, internal structure, and content of bioactive substances. The electron-dense and coated vesicles that had been discovered in exosomes might become new additional morphological features, which could help to improve the interpretation of experimental results and widen our understanding of exosome morphology.

3.
Chin J Integr Med ; 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919749

RESUMO

OBJECTIVE: To evaluate the effects of a 48-week course of adefovir dipivoxil (ADV) plus Chinese medicine (CM) therapy, namely Tiaogan Jianpi Hexue () and Tiaogan Jiedu Huashi () fomulae, in hepatitis B e antigen (HBeAg)-positive Chinese patients. METHODS: A total of 605 HBeAg-positive Chinese CHB patients were screened and 590 eligible participants were randomly assigned to 2 groups in 1:1 ratio including experimental group (EG, received ADV plus CM) and control group (CG, received ADV plus CM-placebo) for 48 weeks. The major study outcomes were the rates of HBeAg and HBV-DNA loss on week 12, 24, 36, 48, respectively. Secondary endpoints including liver functions (enzymes and bilirubin readings) were evaluated every 4 weeks at the beginning of week 24, 36, and 48. Routine blood, urine, and stool analyses in addition to electrocardiogram and abdominal B scan were monitored as safety evaluations. Adverse events (AEs) were documented. RESULTS: The combination therapy demonstrated superior HBeAg loss at 48 weeks, without additional AEs. The full analysis population was 560 and 280 in each group. In the EG, population achieved HBeAg loss on week 12, 24, 36, and 48 were 25 (8.90%), 34 (12.14%), 52 (18.57%), and 83 (29.64%), respectively; the equivalent numbers in the CG were 20 (7.14%), 41 (14.64%), 54 (19.29%), and 50 (17.86%), respectively. There was a statistically significant difference between these group values on week 48 (P<0.01). No additional AEs were found in EG. Subgroup analysis suggested different outcomes among treatment patterns. CONCLUSION: Combination of CM and ADV therapy demonstrated superior HBeAg clearance compared with ADV monotherapy. The finding indicates that this combination therapy may provide an improved therapeutic effect and safety profile (ChiCTR-TRC-11001263).

4.
Clin Rheumatol ; 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31902032

RESUMO

OBJECTIVE: To investigate characteristics of patients with primary Sjögren's syndrome (pSS)-associated interstitial lung disease (ILD) and relevant features of ILD progression. METHOD: Patients with pSS were retrospectively reviewed, and pSS-ILD and pSS non-ILD were identified. Clinical data, laboratory parameters, pulmonary high-resolution CT (HRCT), and pulmonary function tests (PFTs) were collected. pSS-ILD patients were further categorized into subgroups according to HRCT patterns or PFTs. RESULTS: Eighty-five pSS-ILD patients and 85 pSS non-ILD patients were included. The average age at disease onset and median disease duration were significantly higher in pSS-ILD patients than those in pSS non-ILD patients (p < 0.001). Fever, xerostomia, xerophthalmia, and numbness were more frequent, and white blood cells, C reactive protein, and immunoglobulin G (IgG) levels were higher in pSS-ILD patients when compared to pSS non-ILD patients (p < 0.01). More male patients, older age at disease onset, and less frequent anti-Ro52 antibody were noted in patients with CT-usual interstitial pneumonia (UIP) pattern. In 49 patients with pSS-ILD, who repeated PFTs 6 months from the baseline, 79.6% were stable while 20.4% progressed, with ESR and CT-UIP pattern related with disease progression. CONCLUSIONS: Patients with pSS-ILD were characterized by more frequent fever, xerophthalmia, and elevated IgG levels, while male, older age at disease onset, and less frequent anti-Ro52 antibody were related with CT-UIP pattern. ESR and CT-UIP pattern were potential predictors for ILD progression.Key Points• pSS-ILD patients are characterized by more frequent fever, xerophthalmia and elevated IgG.• Anti-Ro52 antibody is less frequent in patients with CT-UIP pattern compared to non-UIP patterns.• ESR and CT-UIP pattern are associated with pSS-ILD progression.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31905144

RESUMO

Traditional clustering algorithms for medical image segmentation can only achieve satisfactory clustering performance under relatively ideal conditions, in which there is adequate data from the same distribution, and the data is seldom disturbed by noise or outliers. However, a sufficient amount of medical images with representative manual labels are often not available, because medical images are frequently acquired with different scanners (or different scan protocols) or polluted by various noises. Transfer learning improves learning in the target domain by leveraging knowledge from related domains. Given some target data, the performance of transfer learning is determined by the degree of relevance between the source and target domains. To achieve positive transfer and avoid negative transfer, a negative-transfer-resistant mechanism is proposed by computing the weight of transferred knowledge. Extracting a negative-transfer-resistant fuzzy clustering model with a shared cross-domain transfer latent space (called LSS-FTC-NTR) is proposed by integrating negative-transfer-resistant and maximum mean discrepancy (MMD) into the framework of fuzzy c-means clustering. Experimental results show that the proposed LSS-FTC-NTR model outperformed several traditional non-transfer and related transfer clustering algorithms.

6.
J Am Chem Soc ; 142(6): 2889-2896, 2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-31986025

RESUMO

5-Hydroxymethyluracil ( 5hmU ) is found in the genomes of a diverse range of organisms as another kind of 5-hydroxymethylpyrimidine, with the exception of 5-hydroxymethylcytosine ( 5hmC ). The biological function of 5hmU has not been well explored due to lacking both specific 5hmU recognition and single-cell analysis methods. Here we report differentiated visualization of single-cell 5hmU and 5hmC with microfluidic hydrogel encoding (sc 5hmU / 5hmC -microgel). Single cells and their genomic DNA after cell lysis can be encapsulated in individual agarose microgels. The 5hmU sites are then specifically labeled with thiophosphate for the first time, followed by labeling 5hmC with azide glucose. These labeled bases are each encoded into respective DNA barcode primers by chemical cross-linking. In situ amplification is triggered for single-molecule fluorescence visualization of single-cell 5hmU and 5hmC . On the basis of the sc 5hmU / 5hmC -microgel, we reveal cell type-specific molecular signatures of these two bases with remarkable single-cell heterogeneity. Utilizing machine learning algorithms to decode four-dimensional signatures of 5hmU / 5hmC , we visualize the discrimination of nontumorigenic, carcinoma and highly invasive breast cell lines. This strategy provides a new route to analyze and decode single-cell DNA epigenetic modifications.

7.
Liver Int ; 2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31903720

RESUMO

BACKGROUND AND AIMS: Treatment of non-alcoholic steatohepatitis (NASH) is challenging, because suppressing fibrotic progression has not been achieved consistently by drug candidates currently in clinical trials. The aim of this study was to investigate the molecular interplays underlying NASH-associated fibrosis in a mouse NASH model and human specimens. METHODS: Mice were divided into 4 groups: Controls; NASH (high fat/Calorie diet plus high fructose and glucose in drinking water, HFCD-HF/G) for 16 weeks; HFCD-HF/G plus docosahexaenoic acid (DHA) for 16 or 8 weeks. RESULTS: Along with NASH progression, fibrotic deposition was documented in HFCD-HF/G-fed mice. Liver succinate content was significantly increased along with decreased expression of succinate dehydrogenase-A (SDH-A) in these mice; whereas, GPR-91 receptor expression was much enhanced in histology compared to control mice, and co-localized histologically with hepatic stellate cells (HSCs). Succinate content was increased in fatty acid-overloaded primary hepatocytes with significant oxidant stress and lipotoxicity. Exposure to succinate led to up-regulation of GPR-91 receptor in primary and immortalized HSCs. In contrast, suppression of GPR-91 receptor expression abolished succinate stimulatory role in GPR-91 expression and extracellular matrix production in HSCs. All these changes were minimized or abrogated by DHA supplementation in vivo or in vitro. Moreover, GPR-91 receptor expression correlates with severity of fibrosis in human NASH biopsy specimens. CONCLUSION: Succinate accumulation in steatotoic hepatocytes may result in HSC activation through GPR-91 receptor signalling in NASH progression, and the cross-talk between hepatocytes and HSC through GPR-91 signalling is most likely to be the molecular basis of fibrogenesis in NASH.

8.
Oncol Rep ; 43(2): 405-414, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894341

RESUMO

Living tumors are of great scientific value for clinical medicine and basic research, especially for drug testing. An increasing number of drug tests fail due to the use of imperfect models. The aim of the present study was to develop a novel method combining vitrification­based cryopreservation of tumor biopsies and precision­cut slice cultivation for the assessment of anticancer drug responses. Biological characteristics of rectal cancer liver metastasis biopsies could be retained by vitrification­based cryopreservation. The patient­derived xenograft models were successfully established using both fresh and warmed biopsy tissues. Precision­cut slicing provided a similar three­dimensional architecture and heterogeneity to the original tumor. The positive drug responses in the xenograft model were consistent with those in precision­cut slice cultures in vitro. The present study demonstrated that live tumor biopsies could be preserved using vitrification­based cryopreservation. The warmed tissues developed xenograft tumors, which were also useful for either in vivo or in vitro anticancer drug testing. Precision­cut slices derived from the warmed tissues provided an efficient tool to assess anticancer drug response in vitro.

9.
J Biotechnol ; 309: 107-112, 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-31926981

RESUMO

Ginsenoside Rh2, a rare protopanaxadiol (PPD)-type triterpene saponin isolated from Panax ginseng, exhibits notable anticancer and immune-system-enhancing activities. Glycosylation catalyzed by uridine diphosphate-dependent glucosyltransferase (UGT) is the final biosynthetic step of ginsenoside Rh2. In this study, UGT73C5 isolated from Arabidopsis thaliana was demonstrated to selectively transfer a glucosyl moiety to the C3 hydroxyl group of PPD to synthesize ginsenoside Rh2. UGT73C5 was coupled with sucrose synthase (SuSy) from A. thaliana to regenerate costly uridine diphosphate glucose (UDPG) from cheap sucrose and catalytic amounts of uridine diphosphate (UDP). The UGT73C5/SuSy ratio, temperature, pH, cofactor UDP, and PPD concentrations for UGT73C5-SuSy coupled reactions were optimized. Through the stepwise addition of PPD, the maximal ginsenoside Rh2 production was 3.2 mg mL-1, which was the highest yield reported to date. These promising results provided an efficient and cost-effective approach to semisynthesize the highly valuable ginsenoside Rh2.

10.
World Neurosurg ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31954894

RESUMO

PURPOSE: To investigate whether arterial infundibular widening is a preaneurysmal lesion or not. METHODS: Two hundred and nine patients with cerebral angiography were enrolled. The morphology, size and location of infundibula and cerebral aneurysms were studied in two-dimensional angiography and three-dimensional software space. Computational fluid dynamics (CFD) analysis was performed. RESULTS: 234 infundibula and 129 infundibulum-like aneurysms (IFAs) were detected. In two-dimensional space, the typical morphology of an infundibulum was a symmetric dilatation at the arterial branch origin with a small vessel branch emanating from the tip and a wide base connecting the parent artery. In three-dimensional space, the infundibulum was dissymmetric with always one side longer than the other side. Furthermore, the infundibulum tilted upstream rather than downstream, with the longer side located downstream and the shorter side upstream in all cases. All the 129 IFAs occurred on the distal wall of the vessel branch origin, and no IFAs grew from the proximal wall of the branch origin. The possible development process of an infundibulum to an IFA was described in four development stages. The CFD analysis revealed that these lesions were associated with direct flow impingement in all cases. All the hemodynamic parameters on the distal wall of infundibula and IFAs were significantly (P<0.0001 or P<0.05) decreased compared with on the distal wall after virtual lesion removal. CONCLUSION: The infundibulum is a preaneurysmal lesion associated with high total pressure and high wall shear stress resulted from direct flow impingement and will progress to an aneurysm with time.

11.
Pathol Res Pract ; 216(2): 152799, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31932115

RESUMO

This study aimed to investigate the hub protein related to the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway in diffuse large B-cell lymphoma (DLBCL). We used proteomics methods (iTRAQ) to explore the differentially expressed proteins in the non-germinal center B-cell -like (non-GCB) DLBCL in our previous study. In this study, a total of 137 formalin-fixed paraffin-embedded DLBCL tissue samples were analyzed via immunohistochemistry to verify the expression of TCL1, AKT1 + 2+3, IKKß and to determine the differentially expressed proteins associated with the PI3K/AKT signaling pathway. Spearman correlation was used to analyze the relationship between these proteins, and survival analysis was used to investigate their effects on prognosis. Immunohistochemistry analysis indicated that TCL1, AKT1 + 2+3, and IKKß were highly positively expressed in DLBCL. Results showed that the expression of TCL1 was related to ethnicity (p = 0.022), primary site (p = 0.045), Ann Arbor stage (p = 0.037), the International Prognostic Index (p = 0.005), ß2-microglobulin (p = 0.030), BCL2 expression (p < 0.001), and Ki-67 expression (p = 0.008). A positive correlation was found between TCL1 and AKT1 + 2+3 (p < 0.001; r = 0.475). A positive correlation was also found between AKT1 + 2+3 and IKKß (p < 0.001; r = 0.342). In survival analysis, anemia, non-treatment with R­CHOP, positive TCL1 expression, and Ki-67 expression≥50% independently predicted short progression-free survival and overall survival in the total cohort (p < 0.05). Thus, TCL1 as a hub protein is associated with the PI3K/AKT signaling pathway in DLBCL. TCL1 expression indicated a poor prognosis in patients with DLBCL. With further studies, TCL1 may be established as a reliable prognostic biomarker and potential immunotherapeutic target for improving therapeutic efficacy for DLBCL in the future.

12.
Cell ; 180(2): 218-220, 2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31978341

RESUMO

Alcoholic hepatitis is a severe alcohol-associated liver disease with minimal treatment options. A recent study by Duan et al. uncovers that the exotoxin-secreting gut bacterium Enterococcus faecalis is a critical contributor to alcoholic hepatitis. This bacterium can now be eliminated with a bacteriophage, suggesting a new way to treat this life-threatening disease.

13.
Int J Pharm ; 575: 119005, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31899317

RESUMO

Benzalkonium chloride (BC) is a quaternary ammonium antimicrobial agent used in a variety of applications. In this work, BC was prepared into deep eutectic solvent (DES) with acrylic acid (AA) or methacrylic acid (MA). Within the newly prepared DES, BC is responsible for antimicrobial properties, while AA and MA are responsible for polymerization. Three types of microorganisms, E. coli (gram-negative bacilli), S. aureus (gram-positive cocci) and C. albicans (fungi), were assessed for antimicrobial properties through agar diffusion test. DES viscosity measurements and polymerizations were also conducted to assist the antimicrobial performance analysis. From this study, stronger antimicrobial effectiveness of BC-AA DES towards S. aureus and C. albicans was observed, while smaller inhibition zone widths were obtained for BC-AA DES polymer compared to BC-AA DES monomer which may due to the limited active component transportation after polymerization. When changing AA to MA, increased structural complexity and decreased linearity may limit the molecule movement thus reduce the inhibition zone width, which could be proved by the calculated activation energy results. Accurately determined eutectic ratio of DES is recommended to get optimized drug release control. This work offers a new sight for preparation of antimicrobial materials with stronger effectiveness and limited release.

15.
Biomed Pharmacother ; 121: 109310, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31710895

RESUMO

Currently, there is no effective method to prevent renal interstitial fibrosis after acute kidney injury (AKI). In this study, we established and screened a new renal interstitial fibrosis rat model after cisplatin-induced AKI. Our results indicated that rats injected with 4 mg/kg cisplatin once a week for two weeks after firstly administrated with 6.5 mg/kg loading dose of cisplatin could set up a more accurate model reflecting AKI progression to renal interstitial fibrosis. Then, we investigated the effects and possible mechanisms of human umbilical cord blood mononuclear cells (hUCBMNCs) on renal tubular interstitial fibrosis after cisplatin-induced AKI. In rats injected with hUCBMNCs for four times, level of matrix metalloproteinase 7(MMP-7)in serum and urine, urinary albumin/creatinine ratio, tubular pathological scores, the relative collagen area of the tubulointerstitial region, endoplasmic reticulum dilation and the mitochondrial ultrastructural damage were significantly improved. The level of reactive oxygen species, α-smooth muscle actin (α-SMA), [NOD]-like pyrin domain containing protein 3 and cleaved-Caspase 3 in renal tissue decreased significantly. However, in rats injected with hUCBMNCs for two times, no significant difference was discovered in MMP-7 levels and urinary albumin/creatinine ratio. Although expression of α-SMA and the percentage areas of collagen staining in tubulointerstitial tissues were ameliorated in rats injected with hUCBMNCs for two times, the effects were significantly weaker than those in rats injected with hUCBMNCs for four times. Taken together, our study constructed a highly efficient, duplicable novel rat model of renal fibrosis after cisplatin-induced AKI. Multiple injections of hUCBMNCs may prevent renal interstitial fibrosis after cisplatin-induced AKI.

16.
Biomed Pharmacother ; 121: 109662, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810124

RESUMO

Currently, there is no effective method to prevent renal interstitial fibrosis after acute kidney injury (AKI). In this study, we established and screened a new renal interstitial fibrosis rat model after cisplatin-induced AKI. Our results indicated that rats injected with 4 mg/kg cisplatin once a week for two weeks after firstly administrated with 6.5 mg/kg loading dose of cisplatin could set up a more accurate model reflecting AKI progression to renal interstitial fibrosis. Then, we investigated the effects and possible mechanisms of human umbilical cord blood mononuclear cells (hUCBMNCs) on renal tubular interstitial fibrosis after cisplatin-induced AKI. In rats injected with hUCBMNCs for four times, level of matrix metalloproteinase 7 (MMP-7) in serum and urine, urinary albumin/creatinine ratio, tubular pathological scores, the relative collagen area of the tubulointerstitial region, endoplasmic reticulum dilation and the mitochondrial ultrastructural damage were significantly improved. The level of reactive oxygen species, α-smooth muscle actin (α-SMA), [NOD]-like pyrin domain containing protein 3 and cleaved-Caspase 3 in renal tissue decreased significantly. However, in rats injected with hUCBMNCs for two times, no significant difference was discovered in MMP-7 levels and urinary albumin/creatinine ratio. Although expression of α-SMA and the percentage areas of collagen staining in tubulointerstitial tissues were ameliorated in rats injected with hUCBMNCs for two times, the effects were significantly weaker than those in rats injected with hUCBMNCs for four times. Taken together, our study constructed a highly efficient, duplicable novel rat model of renal fibrosis after cisplatin-induced AKI. Multiple injections of hUCBMNCs may prevent renal interstitial fibrosis after cisplatin-induced AKI.

17.
Brain Res Bull ; 154: 51-60, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715311

RESUMO

The central nervous system (CNS) has a poor self-repairing capability after injury because of the inhibition of axonal regeneration by many myelin-associated inhibitory factors. Therefore, ischemic stroke usually leads to disability. Previous studies reported that Ginsenoside Rb1 (GRb1) plays a role in neuronal protection in acute phase after ischemic stroke, but its efficacy in post-stroke and the underlying mechanism are not clear. Recent evidences demonstrated GRb1 promotes neurotransmitter release through the cAMP-depend protein kinase A (PKA) pathway, which is related to axonal regeneration. The present study aimed to determine whether GRb1 improves long-term motor functional recovery and promotes cortical axon regeneration in post-stroke. Adult male C57BL/6 mice were subjected to distal middle cerebral artery occlusion (dMCAO). GRb1 solution (5 mg/ml) or equal volume of normal saline was injected intraperitoneally for the first time at 24 h after surgery, and then daily injected until day 14. Day 3, 7, 14 and 28 after dMCAO were used as observation time points. Motor functional recovery was assessed with Rota-rod test and grid walking task. The expression of growth-associated protein 43 (GAP43) and biotinylated dextran amine (BDA) was measured to evaluate axonal regeneration. The levels of cyclic AMP (cAMP) and PKA were measured by Elisa, PKAc and phosphorylated cAMP response element protein (pCREB) were determined by western blot. Our results shown that GRb1 treatment improved motor function and increased the expression of GAP43 and BDA in ipsilesional and contralateral cortex. GRb1 significantly elevated cAMP and PKA, increased the protein expression of PKAc and pCREB. However, the effects of GRb1 were eliminated by H89 intervention (a PKA inhibitor). These results suggested that GRb1 improved functional recovery in post-stroke by stimulating axonal regeneration and brain repair. The underlying mechanism might be up-regulating the expression of cAMP/PKA/CREB pathway.

18.
Oncol Lett ; 18(6): 6033-6045, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31788078

RESUMO

Differentially methylated genes (DMGs) serve a crucial role in the pathogenesis of glioma via the regulation of the cell cycle, proliferation, apoptosis, migration, infiltration, DNA repair and signaling pathways. This study aimed to identify aberrant DMGs and pathways by comprehensive bioinformatics analysis. The gene expression profile of GSE28094 was downloaded from the Gene Expression Omnibus (GEO) database, and the GEO2R online tool was used to find DMGs. Gene Ontology (GO) functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of the DMGs were performed by using the Database for Annotation Visualization and Integrated Discovery. A protein-protein interaction (PPI) network was constructed with Search Tool for the Retrieval of Interacting Genes. Analysis of modules in the PPI networks was performed by Molecular Complex Detection in Cytoscape software, and four modules were performed. The hub genes with a high degree of connectivity were verified by The Cancer Genome Atlas database. A total of 349 DMGs, including 167 hypermethylation genes, were enriched in biological processes of negative and positive regulation of cell proliferation and positive regulation of transcription from RNA polymerase II promoter. Pathway analysis enrichment revealed that cancer regulated the pluripotency of stem cells and the PI3K-AKT signaling pathway, whereas 182 hypomethylated genes were enriched in biological processes of immune response, cellular response to lipopolysaccharide and peptidyl-tyrosine phosphorylation. Pathway enrichment analysis revealed cytokine-cytokine receptor interaction, type I diabetes mellitus and TNF signaling pathway. A total of 20 hub genes were identified, of which eight genes were associated with survival, including notch receptor 1 (NOTCH1), SRC proto-oncogene (also known as non-receptor tyrosine kinase, SRC), interleukin 6 (IL6), matrix metallopeptidase 9 (MMP9), interleukin 10 (IL10), caspase 3 (CASP3), erb-b2 receptor tyrosine kinase 2 (ERBB2) and epidermal growth factor (EGF). Therefore, bioinformatics analysis identified a series of core DMGs and pathways in glioma. The results of the present study may facilitate the assessment of the tumorigenicity and progression of glioma. Furthermore, the significant DMGs may provide potential methylation-based biomarkers for the precise diagnosis and targeted treatment of glioma.

19.
PLoS Pathog ; 15(12): e1008082, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31805154

RESUMO

The clinical application of conventional peptide drugs, such as the HIV-1 fusion inhibitor enfuvirtide, is limited by their short half-life in vivo. To overcome this limitation, we developed a new strategy to extend the in vivo half-life of a short HIV-1 fusion inhibitory peptide, CP24, by fusing it with the human IgG Fc-binding peptide (IBP). The newly engineered peptide IBP-CP24 exhibited potent and broad anti-HIV-1 activity with IC50 values ranging from 0.2 to 173.7 nM for inhibiting a broad spectrum of HIV-1 strains with different subtypes and tropisms, including those resistant to enfuvirtide. Most importantly, its half-life in the plasma of rhesus monkeys was 46.1 h, about 26- and 14-fold longer than that of CP24 (t1/2 = 1.7 h) and enfuvirtide (t1/2 = 3 h), respectively. IBP-CP24 intravenously administered in rhesus monkeys could not induce significant IBP-CP24-specific antibody response and it showed no obvious in vitro or in vivo toxicity. In the prophylactic study, humanized mice pretreated with IBP-CP24 were protected from HIV-1 infection. As a therapeutic treatment, coadministration of IBP-CP24 and normal human IgG to humanized mice with chronic HIV-1 infection resulted in a significant decrease of plasma viremia. Combining IBP-CP24 with a broad neutralizing antibody (bNAb) targeting CD4-binding site (CD4bs) in gp120 or a membrane proximal external region (MPER) in gp41 exhibited synergistic effect, resulting in significant dose-reduction of the bNAb and IBP-CP24. These results suggest that IBP-CP24 has the potential to be further developed as a new HIV-1 fusion inhibitor-based, long-acting anti-HIV drug that can be used alone or in combination with a bNAb for treatment and prevention of HIV-1 infection.

20.
J Neuroinflammation ; 16(1): 256, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31810470

RESUMO

BACKGROUND: Ischemic stroke is a leading cause of disability worldwide and characteristically accompanied by downregulation of the Wnt/ß-catenin signaling. Activation of Wnt/ß-catenin signaling emerges to attenuate neuroinflammation after ischemic stroke; however, its effect on modulating microglial polarization is largely unknown. Here, we explored whether Wnt/ß-catenin pathway activator TWS119 facilitated long-term neurological recovery via modulating microglia polarization after experimental stroke. METHODS: Ischemic stroke mice model was induced by permanent distal middle cerebral artery occlusion plus 1 h hypoxia. TWS119 was administrated from day 1 to 14 after stroke. Neurological deficits were monitored up to 21 days after stroke. Angiogenesis, neural plasticity, microglial polarization, and microglia-associated inflammatory cytokines were detected in the peri-infarct cortex at days 14 and 21 after stroke. Primary microglia and mouse brain microvascular endothelial cell lines were employed to explore the underlying mechanism in vitro. RESULTS: TWS119 mitigated neurological deficits at days 14 and 21 after experimental stroke, paralleled by acceleration on angiogenesis and neural plasticity in the peri-infarct cortex. Mechanistically, cerebral ischemia induced production of microglia-associated proinflammatory cytokines and priming of activated microglia toward pro-inflammatory polarization, whereas TWS119 ameliorated microglia-mediated neuroinflammatory status following ischemic stroke and promoted angiogenesis by modulating microglia to anti-inflammatory phenotype. The beneficial efficacy of TWS119 in microglial polarization was largely reversed by selective Wnt/ß-catenin pathway blockade in vitro, suggesting that TWS119-enabled pro-inflammatory to anti-inflammatory phenotype switch of microglia was possibly mediated by Wnt/ß-catenin signaling. CONCLUSIONS: Wnt/ß-catenin pathway activator TWS119 ameliorated neuroinflammatory microenvironment following chronic cerebral ischemia via modulating microglia towards anti-inflammatory phenotype, and facilitates neurological recovery in an anti-inflammatory phenotype polarization-dependent manner. Activation of Wnt/ß-catenin pathway following ischemic stroke might be a potential restorative strategy targeting microglia-mediated neuroinflammation.

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