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1.
Biomed Pharmacother ; 122: 109697, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31918271

RESUMO

TRPV4 is a type of nonselective cation channel, and activation of TRPV4 in the gastrointestinal tract causes experimental colitis in mice. A previous study found that tyrosine-phosphorylated claudin-7 is increased in experimental colitis. The relationship between tyrosine-phosphorylated claudin-7 and TRPV4 remains undefined. In the present study, we developed a claudin-7 mutant by replacing tyrosine with glutamic acid at position 210, named cld7-Y210E colonic cells. We found that activation of TRPV4 by GSK1016790A increased the permeability of control colonic cell monolayers, which was decreased by the TRPV4 antagonist HC067047. In monolayers of cld7-Y210E colonic cells, no differences in permeability were found between GSK1016790A and HC067047 treatments. GSK1016790A increased the aggregation of claudin-7 at the cell membrane in control colonic cells, and the effect was diminished by HC067047. In cld7-Y210E colonic cells, neither GSK1016790A nor HC067047 apparently changed the aggregation of claudin-7. Neither GSK1016790A nor HC067047 altered the TRPV4 protein level in vector colonic cells. In cld7-wild colonic cells, GSK1016790A did not alter the TRPV4 protein level, while HC067047 increased the TRPV4 protein level. The TRPV4 protein level was increased in cld7-Y210E colonic cells, decreased by GSK1016790A and further decreased by HC067047. Calcium influx was not significantly changed in the control colonic cells treated with GSK1016790A. However, GSK1016790A significantly increased calcium influx in cld7-Y210E colonic cells. We concluded that tyrosine-phosphorylated claudin-7 affects the TRPV4-modulated intestinal epithelial barrier, TRPV4-mediated calcium influx, and the protein expression of TRPV4 in human colonic cells. We suggest that tyrosine-phosphorylated claudin-7 affects the TRPV4-modulated intestinal epithelial barrier, which might be related to TRPV4 expression and TRPV4-mediated calcium influx.

2.
Int J Biochem Cell Biol ; : 105685, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31917284

RESUMO

The epigenetic silencing mechanism of suppressor 3 of cytokine signaling (SOCS3) in cancers has not been fully elucidated. Polycomb repressive complexes 2 (PRC2), an important epigenetic regulatory factors, exerts a critical role in repressing the initial phase of gene transcription. Whether PRC2 participates the down- regulation of SOCS3 in Hepatocellular carcinoma (HCC) remains unclear and how does PRC2 be recruited target gene still needs to explore. In this study, Using TCGA HCC dataset, and detecting HCC tissue specimens and cell lines, we found that SOCS3 expression in HCC was inversely related to that of EZH2, and depended on its promoter methylation status. CTCF, Vigilin, EZH2 and H3K27me3 were enriched at CTCF and EZH2 binding sites on the methylated SOCS3 gene promoter. The depletion of CTCF did not affect expression of EZH2 and DNMT1, but decrease recruitment of CTCF, Vigilin, EZH2 and H3K27me3. Further, knockdown of CTCF led to a loss of methylation of the methylated SOCS3 promoter, which sequentially increased the expression of SOCS3 and decreased the expression of pSTAT3, the downstream effector. These findings suggest that the CTCF dependent recruitment of EZH2 to the SOCS3 gene promoter is likely to participate in the epigenetic silencing of SOCS3 and in regulating its gene expression.

3.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(6): 2003-2008, 2019 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-31839074

RESUMO

AAbstractObjective:To compare and analyze the metabolic and functional changes in platelets stored at 4 ℃ and ones stored at 22 ℃ with agitation so as to provide an experimental basis for the cryopreservation technology of platelets. METHODS: Samples were collected from platelets stored at 4 ℃ in 2, 4, 6, 11, 15 and 21 days, and from ones stored at 22 ℃ with agitation during the same days, the metabolism indicators and thromboelastogram (TEM) were analysed. RESULTS: In metabolism, there were no significant changes of pH, GLU,PCO2, PCO2 and MPV levels of platelets stored at 4 ℃ for <6 days (P>0.05), However, the Plt count decreased, the PDW and LDH level incrseased (P<0.05). At the same time, only MPV had no changes of platelets stored at 22 ℃ during above-mentioned same days (P>0.05), while the pH, PCO2, GLU, Plt all decreased, and PO2, LDH, PDW incrseased (P<0.05). There were significant changes about the pH value, PO2, Plt, MPV, LDH, GLU levels between the two kinds of stored platelets during the same storing period (P<0.05). The pH value and MPV of platelets stored at 4 ℃ were obviously lower than ones stored at 22 ℃, while GLU, PO2, LDH and Plt levels showed reverse changes (P<0.05). Meanwhile, the PCO2 of platelets stored at 4 ℃ not could be detected and the Plt count reduced rapidly from d15. In function, the MA level of platelets stored at 4 ℃ was slower than that of platelets stored at 22 ℃, that is, the MA level of platelets stored at 4 ℃ were higher than that of platelets stored at 22 ℃ during the same storeing period (P<0.05). CONCLUSION: Platelets stored at 4 ℃ have much slower metabolism than ones stored at 22 ℃, and the aggregation is stronger of platelets stored at 4 ℃ than that of ones at 22 ℃ during the same conservation period.

4.
Aging (Albany NY) ; 112019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821170

RESUMO

Clear cell renal cell carcinoma (ccRCC) is the most common pathological subtype of renal cell carcinoma, and immune-related genes (IRGs) are key contributors to its development. In this study, the gene expression profiles and clinical data of ccRCC patients were downloaded from The Cancer Genome Atlas database and the cBioPortal database, respectively. IRGs were obtained from the ImmPort database. We analyzed the expression of IRGs in ccRCC, and discovered 681 that were differentially expressed between ccRCC and normal kidney tissues. Univariate Cox regression analysis was used to identify prognostic differentially expressed IRGs (PDEIRGs). Using Lasso regression and multivariate Cox regression analyses, we detected seven optimal PDEIRGs (PLAU, ISG15, IRF9, ARG2, RNASE2, SEMA3G and UCN) and used them to construct a risk model to predict the prognosis of ccRCC patients. This model accurately stratified patients with different survival outcomes and precisely identified patients with different mutation burdens. Our findings suggest the seven PDEIRGs identified in this study are valuable prognostic predictors in ccRCC patients. These genes could be used to investigate the developmental mechanisms of ccRCC and to design individualized treatments for ccRCC patients.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31828297

RESUMO

As a highly malignant tumor, hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. In most HCC patients, the development of HCC begins with hepatitis, which is followed by fibrosis and cirrhosis before progressing to HCC. Cancer-associated fibroblasts (CAFs), which are generally believed to be derived from activated hepatic stellate cells (HSCs), are highly involved in the development of HCC through the secretion of cytokines and angiogenic factors. The results of our study showed that a considerable number of CAFs highly expressed CD90 and were enriched in HCC tissues. Bioinformatics analysis of the transcriptome of HCC tissues revealed that placental growth factor (PlGF) is significantly correlated with CD90 expression. The isolated primary CAFs and activated HSCs overexpressed PlGF and CD90. In addition, the results of gene expression profiling interactive analysis based on The Cancer Genome Atlas showed that high levels of both PlGF and CD90 are correlated with tumor angiogenesis markers (CD31, CD34, and CD105) and predict poor HCC patient prognosis. In summary, our results suggest that CAFs can generate PlGF and may provide an effective target for CAFs-regulated neoangiogenesis in HCC.

6.
Bioinformatics ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31793982

RESUMO

MOTIVATION: Emerging evidence indicates that circular RNA (circRNA) plays a crucial role in human disease. Using circRNA as biomarker gives rise to a new perspective regarding our diagnosing of diseases and understanding of disease pathogenesis. However, detection of circRNA-disease associations by biological experiments alone is often blind, limited to small-scale, high-cost and time-consuming. Therefore, there is an urgent need for reliable computational methods to rapidly infer the potential circRNA-disease associations on a large scale and to provide the most promising candidates for biological experiments. RESULTS: In this paper, we propose an efficient computational method based on multi-source information combined with deep convolutional neural network to predict circRNA-disease associations. The method first fuses multi-source information including disease semantic similarity, disease Gaussian interaction profile kernel similarity, and circRNA Gaussian interaction profile kernel similarity, and then extracts its hidden deep feature through the convolutional neural network, and finally sends them to the extreme learning machine classifier for prediction. The five-fold cross-validation results show that the proposed method achieves 87.21% prediction accuracy with 88.50% sensitivity at the AUC of 86.67% on the CIRCR2Disease dataset. In comparison with the state-of-the-art SVM classifier and other feature extraction methods on the same dataset, the proposed model achieves the best results. In addition, we also obtained experimental support for prediction results by searching published literature. As a result, 7 of the top 15 circRNA-disease pairs with the highest scores were confirmed by literature. These results demonstrate that the proposed model is a suitable method for predicting circRNA-disease associations and can provide reliable candidates for biological experiments. The source code and datasets explored in this work are available at https://github.com/look0012/circRNA-Disease-association. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31796414

RESUMO

Long noncoding RNAs (lncRNAs) is an important class of non-protein coding RNAs. MicroRNAs (miRNAs) have been confirmed to be closely related to the regulation of various human diseases. Recent studies have suggested that lncRNAs could interact with miRNAs to modulate their regulatory roles. Hence, predicting lncRNA-miRNA interactions are biologically significant due to their potential roles in determining the effectiveness of diagnostic biomarkers and therapeutic targets for various human diseases. In this work, we present a novel computational approach called LMNLMI for such purpose. LMNLMI works in several phases. First, it learns patterns from expression, sequences and functional data. Based on the patterns, it then constructs several networks including an expression-similarity network, a functional-similarity network, and a sequence-similarity network. Based on a measure of similarities between these networks, LMNLMI computes an interaction score for each pair of lncRNA and miRNA in the database. The novelty of LMNLMI lies in the use of a network fusion technique to combine the patterns inherent in multiple similarity networks and a matrix completion technique in predicting interaction relationship. Using a set of real data, we show that LMNLMI can be a very effective approach for the accurate prediction of lncRNA-miRNA interactions.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31804065

RESUMO

Complete tumor eradication is the ultimate goal of cancer therapy. However, majority of anticancer drugs cause non-immunogenic cell death and only exert on-site anticancer activities. The intrinsic genomic instability of cancer allows for the persistence and later expansion of treatment-resistant clones after surviving a sort of Darwinian selection of chemotherapy. Additional incorporation of an immunotherapy which is robust and individualized could be game changing. Herein, we report a combination strategy that delivers non-immunogenic cell death inducer Cisplatin to treat primary tumors and converts the tumor cells into vaccines that spurs a long-lasting immune response against residual tumors to prevent tumor recurrence and metastasis. Cisplatin(Ⅳ) prodrug was linked to the N-(2-hydroxypropyl) methacrylamide HPMA copolymer (P-Cis) and co-administered with digoxin (Dig), which eventually launched two attacks to cancer cells. Firstly, P-Cis exhibited superior tumor retention and cytotoxicity over free Cisplatin (to inhibit the primary tumor growth). Then, Dig reversed the inability of Cisplatin to trigger calreticulin exposure, and HPMA copolymer amplified Cisplatin-induced ATP release. These complementary mechanisms induced potent immunogenic cell death that promotes dendritic cell maturation and activates CD8+ T cell responses. In established tumor models, P-Cis+Dig combination completely eradicate tumors with no residual cancer cells remaining. Cancer cells succumbing to P-Cis+Dig could protect syngeneic mice against the subsequent challenge with living cells of the same type, and stimulated robust abscopal and anti-metastatic effects. Such strategy might be promising to restore the immunogenicity of non-immunogenic drugs and generate vaccine-like functions for improved immunochemotherapy.

9.
Oncol Lett ; 18(6): 6443-6450, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31807167

RESUMO

Desmoid tumors (DTs), derived from the abdomen, are a type of rare and aggressive borderline tumor exhibiting high recurrence and malignant potential. The aim of the present study was to investigate the clinicopathological and molecular characteristics of abdominal DT in a Chinese population and to provide clues for selecting the optimal treatment strategy for different types of abdominal DT. The clinicopathological data of 15 consecutive patients with DT was collected. Matched fresh-frozen tumor tissues and peripheral blood samples were used to detect mutations of adenomatous polyposis coli gene (APC), ß-catenin (CTNNB1) and MutY DNA glycosylase (MUTYH) using Sanger sequencing. Pearson's test was conducted to analyze the differences between sporadic DT and familial adenomatous polyposis (FAP) associated with DT. Time to progress (TTP) and overall survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. A review of the patient clinicopathological characteristics revealed that FAP-associated DT exhibited a higher rate of abdominal surgery history (P=0.011), with no significant differences in any other characteristics. Sequencing revealed that mutations in the APC, CTNNB1 and MUTYH genes were common in DT, and only one patient harbored no mutations in these genes. Survival analyses revealed that patients with FAP exhibited shorter TTP (P=0.030). Log-rank test demonstrated a tendency towards shorter TTP in the cases where an R2 resection was performed (P=0.072) and a tendency towards poor prognosis in the cases of DT associated with FAP (P=0.087). In conclusion, Abdominal DTs were prone to occur in patients with FAP with a history of abdominal surgery. Mutations in the APC, CTNNB1 and MUTYH genes were detected in patients with DTs. To the best of our knowledge, this is the first study of abdominal DT occurrence in patients with MUTYH-associated FAP. The prognosis of DT associated with FAP may be worse compared with that of sporadic DT.

10.
Aging (Albany NY) ; 112019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31809267

RESUMO

The malignant bone tumors that are categorized as chondrosarcomas display a high potential for metastasis in late-stage disease. Higher-grade chondrosarcomas contain higher levels of expression of platelet-derived growth factor (PDGF) and its receptor. The phosphorylation of sphingosine by sphingosine kinase enzymes SphK1 and SphK2 generates sphingosine-1-phosphate (S1P), which inhibits human chondrosarcoma cell migration, while SphK1 overexpression suppresses lung metastasis of chondrosarcoma. We sought to determine whether S1P mediates levels of PDGF-A expression and angiogenesis in chondrosarcoma. Surprisingly, our investigations found that treatment of chondrosarcoma cells with S1P and transfecting them with SphK1 cDNA increased PDGF-A expression and induced angiogenesis of endothelial progenitor cells (EPCs). Ras, Raf, MEK, ERK and AP-1 inhibitors and their small interfering RNAs (siRNAs) inhibited S1P-induced PDGF-A expression and EPC angiogenesis. Our results indicate that S1P promotes the expression of PDGF-A in chondrosarcoma via the Ras/Raf/MEK/ERK/AP-1 signaling cascade and stimulates EPC angiogenesis.

11.
Mol Med ; 25(1): 53, 2019 Dec 06.
Artigo em Inglês | MEDLINE | ID: mdl-31810440

RESUMO

Pre-clinical animal studies have shown that triiodothyronine (T3) replacement therapy improves cardiac contractile function after myocardial infarction (MI). We hypothesized that T3 treatment could prevent adverse post-infarction cardiomyocyte remodeling by maintaining transverse-tubule (TT) structures, thus improving calcium dynamics and contractility. METHODS: Myocardial infarction (MI) or sham surgeries were performed on female Sprague-Dawley rats (aged 12 wks), followed by treatment with T3 (5µg/kg/d) or vehicle in drinking water for 16 wks (n = 10-11/group). After in vivo echocardiographic and hemodynamic analyses, left ventricular myocytes were isolated by collagenase digestion and simultaneous calcium and contractile transients in single cardiomyocytes were recorded using IonOptix imaging. Live cardiomyocytes were stained with AlexaFluor-488 conjugated wheat germ agglutinin (WGA-488) or di-8-ANEPPS, and multiple z-stack images per cell were captured by confocal microscopy for analysis of TT organization. RTqPCR and immunoblot approaches determined expression of TT proteins. RESULTS: Echocardiography and in vivo hemodynamic measurements showed significant improvements in systolic and diastolic function in T3- vs vehicle-treated MI rats. Isolated cardiomyocyte analysis showed significant dysfunction in measurements of myocyte relengthening in MI hearts, and improvements with T3 treatment: max relengthening velocity (Vmax, um/s), 2.984 ± 1.410 vs 1.593 ± 0.325, p < 0.05 and time to Vmax (sec), 0.233 ± 0.037 vs 0.314 ± 0.019, p < 0.001; MI + T3 vs MI + Veh, respectively. Time to peak contraction was shortened by T3 treatment (0.161 ± 0.021 vs 0.197 ± 0.011 s., p < 0.01; MI + T3 vs MI + Veh, respectively). Analysis of TT periodicity of WGA- or ANEPPS-stained cardiomyocytes indicated significant TT disorganization in MI myocytes and improvement with T3 treatment (transverse-oriented tubules (TE%): 9.07 ± 0.39 sham, 6.94 ± 0.67 MI + Veh and 8.99 ± 0.38 MI + T3; sham vs MI + Veh, p < 0.001; MI + Veh vs MI + T3, p < 0.01). Quantitative RT-PCR showed that reduced expression of BIN1 (Bridging integrator-1), Jph2 (junctophilin-2), RyR2 (ryanodine receptor) and Cav1.2 (L-type calcium channel) in the failing myocardium were increased by T3 and immunoblot analysis further supporting a potential T3 effect on the TT-associated proteins, BIN1 and Jph2. In conclusion, low dose T3 treatment initiated immediately after myocardial infarction attenuated adverse TT remodeling, improved calcium dynamics and contractility, thus supporting the potential therapeutic utility of T3 treatment in heart failure.

12.
ACS Omega ; 4(23): 20381-20393, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31815242

RESUMO

A series of novel trimethoxyphenyl-derived chalcone-benzimidazolium salts were synthesized. The biological properties of the compounds were screened in vitro against five different human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole or 2-methyl-benzimidazole ring as well as the 2-naphthylmethyl, 4-methylbenzyl, or 2-naphthylacyl substituent at position-3 of the benzimidazole ring was important to the cytotoxic activity. Notably, (E)-5,6-dimethyl-3-(naphthalen-2-ylmethyl)-1-(3-(4-(3-(3,4,5-trimethoxyphenyl)acryloyl)phenoxy)propyl)-1H-benzo[d]imidazol-3-ium bromide (7f) was more selective to HL-60, MCF-7, and SW-480 cell lines with IC50 values 8.0-, 11.1-, and 5.8-fold lower than DDP. Studies of the antitumor mechanism of action showed that compound 7f could induce cell-cycle G1 phase arrest and apoptosis in SMMC-7721 cells.

13.
Curr Med Sci ; 39(6): 899-905, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31845220

RESUMO

Absent in melanoma 2 (AIM2) inflammasome is a crucial link bridging the innate host defense and the subsequent adaptive immunity when activated by exogenous double stranded DNA (dsDNA). Through establishing models of disseminated murine cytomegalovirus (MCMV) infection in BALB/c and C57BL/6 mice, we evaluated dynamic expression of AIM2 inflammasome components and its relationship with pathological damage and viral replication, trying to figure out whether AIM2 inflammasome is related to the chronic mechanism of MCMV. BALB/c and C57BL/6 mice were sacrificed on day 0, 1, 3, 7, 14 and 28 post infection. Expression levels of AIM2, pro-caspase-1, caspase-1 p20, pro-IL1ß and mature IL1ß in primary peritoneal macrophages (PMs) and spleens were detected by Western blotting. Contents of IL18 in the serum were detected by ELISA. Pathological examinations of livers were performed, and mRNA levels of MCMV glycoprotein B (gB) in salivary glands also assessed. Results showed that expression levels of AIM2 in PMs and spleens of C57BL/6 mice increased on day 3, even continued to day 28; caspase-1 p20 and mature IL1ß increased on day 7, 14 and 28; the persistently high expression of IL18 in the serum started on day 1, showing a double peak curve. As for BALB/c mice, expression of AIM2 in PMs increased on day 1 and day 7, while contents of AIM2 in spleens increased on day 1 and day 3; caspase-1 p20 and mature IL1ß merely increased 7 days fter infection. Thereafter, expression levels of AIM2, caspase-1 p20, mature IL1ß and IL18 were limited; the duration of AIM2 inflammasome activation in BALB/c mice was much shorter than that in C57BL/6 mice. The severer pathological damage and more viral replications in BALB/c mice further proved the deficient antiviral immunity to MCMV. In conclusion, the activation of AIM2 inflammasome in BALB/c mice was short-lived, which is quite possibly related to the chronicity of MCMV infection.

14.
Photodiagnosis Photodyn Ther ; : 101618, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31841685

RESUMO

Carbuncle, a collection of interconnected furuncles with multiple pustular openings, is usually caused by Staphylococcus aureus (S. aureus). In this condition, both skin and subcutaneous tissue of the lesion show severe inflammation. It often occurs in immunocompromized patients such as those with diabetes, nephritis, malnutrition, heart failure, hypogammaglobulinemia, exfoliative dermatitis, or pemphigus or those using corticosteroids for long-term. Antibiotics and aggressive debridement are the primary recommended treatments for carbuncle. We report a case of carbuncle that received satisfactory response, in which the inflammation subsided and the wound healed after the administration of ALA photodynamic therapy for three times.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31862139

RESUMO

Hyperglycemia is an independent risk factor for diabetic heart failure. However, the mechanisms that mediate hyperglycemia-induced cardiac damage remain poorly understood. Previous studies have shown an association between lysosomal dysfunction and diabetic heart injury. The present study examined if mimicking hyperglycemia in cultured cardiomyocytes could induce lysosomal membrane permeabilization (LMP), leading to the release of lysosome enzymes and subsequent cell death. High glucose (HG) reduced the number of lysosomes with acidic pH as shown by a fluorescent pH indicator. Also, HG induced lysosomal membrane injury as shown by an accumulation of Galectin3-RFP puncta, which was accompanied by the leakage of cathepsin D (CTSD), an aspartic protease that normally resides within the lysosomal lumen. Furthermore, CTSD expression was increased in HG-cultured cardiomyocytes and in the hearts of 2 mouse models of type 1 diabetes. Either CTSD knockdown with siRNA or inhibition of CTSD activity by pepstatin A markedly diminished HG-induced cardiomyocyte death, while CTSD overexpression exaggerated HG-induced cell death. Together, these results suggested that HG increased CTSD expression, induced LMP and triggered CTSD release from the lysosomes, which collectively contributed to HG-induced cardiomyocyte injury.

16.
ACS Appl Mater Interfaces ; 11(47): 44751-44757, 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31689074

RESUMO

By adjusting the stretch state of a triethylenetetramine (TETA) chain in an amine-functionalized porous organic polymer (POP), two adsorbents were designed to study the rational microenvironment for heavy metal ion removal. The quantum calculation elucidated that the hooped amino chains in FC-POP-CH2TETA-H exhibited stronger interactions with Pb(II) than the extended one in FC-POP-CH2TETA-E, not only through metal-ligand chelation but also metal coordination. The high binding energy of -2624 kJ mol-1 as well as the constructed microenvironment by the hooped amino chains ensured an extremely high Pb(II) capacity of 1134 mg g-1 on FC-POP-CH2TETA-H. Meanwhile, no more than 5 min to approach adsorption equilibrium revealed its ultrafast adsorption rate. It also showed excellent broad removal capability for multiple metal ions and nonsensitivity to pH. Therefore, by controlling the microenvironmental structures with suitable porosity, functional group stretching states, and coordination modes, the removal efficiency of heavy metal ions would be significantly enhanced, which further provided a promising strategy for designing a rational microenvironment to improve the task-specific separation properties.

17.
Int J Med Sci ; 16(10): 1397-1403, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31692815

RESUMO

Vascular endothelial growth factor C (VEGF-C) promotes angiogenesis, a prominent feature in rheumatoid synovitis, contributing to the perpetuation of the global burden of rheumatoid arthritis (RA). VEGF-C gene polymorphisms predict the risk of developing various human diseases, such as urothelial cell carcinoma, oral cancer and coronary artery disease. We sought to determine whether single nucleotide polymorphisms (SNPs) of the VEGF-C gene can predict the risk of RA. Our study recruited 210 patients with RA and 373 healthy controls between 2007 and 2015, and performed comparative genotyping for SNPs rs7664413, rs11947611, rs1485766, rs2046463 and rs3775194. In analyses adjusted for potential covariates, we found that compared with subjects with the A/A genotype of SNP rs11947611, those with the A/G genotype were 40% more likely to develop RA (adjusted odds ratio [AOR] 0.61; 95% confidence interval [CI] 0.40 to 0.92; p = 0.02). In addition, subjects lacking the A/A genotype (A/G, G/G) of SNP rs2046463 were more than twice as likely as those with the A/A genotype to require methotrexate (AOR 2.23, 95% CI 1.25 to 3.98; p = 0.01), while those who lacked the G/G genotype (G/C, C/C) in the SNP rs3775194 had a significantly lower risk of requiring prednisolone as compared with those with the G/G genotype (AOR 0.39, 95% CI 0.19 to 0.79; p = 0.01). Our findings suggest that VEGF-C gene polymorphisms might serve as a diagnostic marker and therapeutic target for RA therapy. Pharmacotherapies that modulate the activity of the VEGF-C gene may be promising for RA treatment.

18.
Autophagy ; : 1-21, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31696776

RESUMO

Macroautophagy/autophagy plays key roles in development, oncogenesis, and cardiovascular and metabolic diseases. Autophagy-specific class III phosphatidylinositol 3-kinase complex I (PtdIns3K-C1) is essential for autophagosome formation. However, the regulation of this complex formation requires further investigation. Here, we discovered that STYK1 (serine/threonine/tyrosine kinase 1), a member of the receptor tyrosine kinases (RTKs) family, is a new upstream regulator of autophagy. We discovered that STYK1 facilitated autophagosome formation in human cells and zebrafish, which was characterized by elevated LC3-II and lowered SQSTM1/p62 levels and increased puncta formation by several marker proteins, such as ATG14, WIPI1, and ZFYVE1. Moreover, we observed that STYK1 directly binds to the PtdIns3K-C1 complex as a homodimer. The binding with this complex was promoted by Tyr191 phosphorylation, by means of which the kinase activity of STYK1 was elevated. We also demonstrated that STYK1 elevated the serine phosphorylation of BECN1, thereby decreasing the interaction between BECN1 and BCL2. Furthermore, we found that STYK1 preferentially facilitated the assembly of the PtdIns3K-C1 complex and was required for PtdIns3K-C1 complex kinase activity. Taken together, our findings provide new insights into autophagy induction and reveal evidence of novel crosstalk between the components of RTK signaling and autophagy.Abbreviations: AICAR: 5-aminoimidazole-4-carboxamide ribonucleotide; AMPK: adenosine 5'-monophosphate (AMP)-activated protein kinase; ATG: autophagy related; ATP: adenosine triphosphate; BCL2: BCL2 apoptosis regulator; BECN1: beclin 1; Bre A: brefeldin A; Co-IP: co-immunoprecipitation; CRISPR: clustered regularly interspaced short palindromic repeats; DAPI: 4',6-diamidino-2-phenylindole; EBSS: Earle's balanced salt solution; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; GSEA: gene set enrichment analysis; MAP1LC3/LC3, microtubule associated protein 1 light chain 3; MAPK8/JNK1: mitogen-activated protein kinase 8; mRFP: monomeric red fluorescent protein; MTOR: mechanistic target of rapamycin kinase; MTT: 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide; PIK3C3: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4: phosphoinositide-3-kinase regulatory subunit 4; qRT-PCR: quantitative reverse transcription PCR; RACK1: receptor for activated C kinase 1; RUBCN: rubicon autophagy regulator; siRNA: small interfering RNA; SQSTM1: sequestosome 1; STYK1/NOK: serine/threonine/tyrosine kinase 1; TCGA: The Cancer Genome Atlas; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; UVRAG: UV radiation resistance associated; WIPI1: WD repeat domain, phosphoinositide interacting 1; ZFYVE1: zinc finger FYVE-type containing 1.

19.
Aging (Albany NY) ; 11(21): 9767-9777, 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31719210

RESUMO

Over the last two decades, there have been no significant changes in patient outcomes in relation to the treatment of osteosarcoma, an aggressive malignant neoplasm. It is known that vascular endothelial growth factor-A (VEGF-A) plays a crucial role in angiogenesis and in osteosarcoma. Moreover, VEGF-A expression correlates with clinical stages of osteosarcoma. The adipokine resistin exhibits proinflammatory, proangiogenic and metastatic properties, and evidence suggests that resistin may serve as a prognostic biomarker linking obesity and inflammation to cancer. However, whether resistin has a role in osteosarcoma angiogenesis is unclear. This investigation shows that resistin promotes VEGF-A expression in human osteosarcoma cells and activates the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 signaling pathways, while ERK, JNK, and p38 inhibitors or their small interfering RNAs (siRNAs) inhibit resistin-induced VEGF-A expression as well as endothelial progenitor cell (EPC) migration and tube formation. We also found that resistin upregulates VEGF-A expression by enhancing activation of the transcription factor nuclear factor-kappa B (NF-κB). Finally, resistin promotes angiogenesis in the chick chorioallantoic membrane (CAM) model. Resistin appears to be a promising target for human osteosarcoma.

20.
Front Plant Sci ; 10: 1290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781131

RESUMO

During early periods of salt stress, reduced stomatal opening can prevent water loss and wilting. Abscisic acid (ABA) signal plays an important role in this process. Here, we show that cucumber grafted onto pumpkin exhibits rapid stomatal closure, which helps plants to adapt to osmotic stress caused by salinity. Increased ABA contents in the roots, xylem sap, and leaves were evaluated in two grafting combinations (self-grafted cucumber and cucumber grafted onto pumpkin rootstock). The expression levels of ABA biosynthetic or signaling related genes NCED2 (9-cis-epoxycarotenoid dioxygenase gene 2), ABCG22 (ATP-binding cassette transporter genes 22), PP2C (type-2C protein phosphatases), and SnRK2.1 (sucrose non-fermenting 1-related protein kinases 2) were investigated. Results showed that a root-sourced ABA signal led to decreased stomatal opening and transpiration in the plants grafted onto pumpkin. Furthermore, plants grafted onto pumpkin had increased sensitivity to ABA, compared with self-grafted cucumbers. The inhibition of ABA biosynthesis with fluridon in roots increased the transpiration rate (Tr) and stomatal conductance (Gs) in the leaves. Our study demonstrated that the roots of pumpkin increases the sensitivity of the scion to ABA delivered from the roots to the shoots, and enhances osmotic tolerance under NaCl stress. Such a mechanism can be greatly exploited to benefit vegetable production particularly in semiarid saline regions.

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