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1.
Chemosphere ; 248: 126080, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32032883

RESUMO

Tooeleite (Fe6(AsO3)4(SO4)(OH)4·4H2O), the only known ferric arsenite sulfate bearing mineral, has great potential for arsenic remediation due to its structure favoring incorporation of As(III). Based on the natural attenuation of removing As(III) directly by the formation of tooeleite via microorganisms, an iron-oxidizing bacterial strain Acidithiobacillus ferrooxidans ATCC 23270 (At.ferrooxidans) was selected to facilitate the formation of tooeleite. The optimized condition for the biogenic tooeleite was obtained at pH of 2.0, 30 °C and an initial arsenic of 500 mg/L. The process of biological mineralization is accompanied by the removal of 95.4% arsenic. What's more, biosynthetic tooeleite crystallization via a three-stage process was revealed using a combination of liquid and solid analyses (ICP-OES, XRD, XPS, FT-IR, SEM, STEM, particle distribution). The three stages included Fe2+ oxidation by At.ferrooxidans, Fe3+ hydrolysis and an initial Fe-As amorphous precursors formation, and finally transforming to tooeleite crystal. Moreover, RT-qPCR was used to reveal the relationship between functional gene expression of At.ferrooxidans and the mineral formation. The results showed the biogenic tooeleite exerts significant control on the geochemistry of arsenic contaminated systems.

2.
Dig Liver Dis ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32008975

RESUMO

BACKGROUND: We sought to explore the association of red blood cell distribution width (RDW) with the severity and long-term prognosis of chronic hepatitis B (CHB)-related liver diseases. METHODS: 1482 treatment-naïve CHB patients without liver cirrhosis (LC), 485 CHB-related LC (CHB-LC) patients and 325 healthy controls (HCs) were enrolled. The median follow-up time for CHB-LC patients was 33.9 months. RESULTS: RDW was significantly higher in CHB-LC (15.0%) than CHB (12.7%) patients or HCs (12.5%). RDW was slightly higher in CHB patients than HCs (p < 0.001). Among CHB patients, the RDW of immune clearance and HBeAg negative hepatitis patients was significantly higher than immune-tolerant and low-replicative phase patients. RDW was positively correlated with Child-Turcotte-Pugh (r = 0.363; p < 0.001) and the model of end-stage liver disease scores (r = 0.218; p < 0.001). The areas under the receiver operating characteristic curve of RDW in predicting one-year, three-year, five-year and global mortality rates were 0.696, 0.668, 0.628 and 0.660, respectively. Through multivariable Cox regression analysis, RDW (p = 0.048) was identified as an independent predictor of liver-related mortality. Over a median follow-up of 33.9 months, CHB-LC patients with RDW ≥ 15.1% had significantly higher liver-related mortality than RDW < 15.1% patients (18.8% vs. 8.6%; p = 0.002). CONCLUSIONS: RDW is positively associated with the severity of CHB and can independently predict the long-term prognosis of CHB-LC patients.

3.
Nat Commun ; 11(1): 57, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31896753

RESUMO

Atom-thin transition metal dichalcogenides (TMDs) have emerged as fascinating materials and key structures for electrocatalysis. So far, their edges, dopant heteroatoms and defects have been intensively explored as active sites for the hydrogen evolution reaction (HER) to split water. However, grain boundaries (GBs), a key type of defects in TMDs, have been overlooked due to their low density and large structural variations. Here, we demonstrate the synthesis of wafer-size atom-thin TMD films with an ultra-high-density of GBs, up to ~1012 cm-2. We propose a climb and drive 0D/2D interaction to explain the underlying growth mechanism. The electrocatalytic activity of the nanograin film is comprehensively examined by micro-electrochemical measurements, showing an excellent hydrogen-evolution performance (onset potential: -25 mV and Tafel slope: 54 mV dec-1), thus indicating an intrinsically high activation of the TMD GBs.

4.
J Viral Hepat ; 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981279

RESUMO

Noninvasive tests (NITs) for liver fibrosis are highly needed for chronic hepatitis B (CHB) patients. We aimed to investigate whether plateletcrit (PCT) could be used as a NIT in predicting liver fibrosis for CHB patients. Five hundred and sixty-seven treatment-naïve CHB patients with available liver biopsies were included. Patients were randomly divided into a derivation cohort (n = 378) and a validation cohort (n = 189). The diagnostic accuracy of PCT was evaluated using receiver operating characteristic (ROC) curves. In the derivation cohort, PCT in CHB patients with S2-S4 (0.14%), S3-S4 (0.13%) and S4 (0.12%) was lower than patients with S0-S1 (0.17%, P < .001), S0-S2 (0.17%, P < .001) and S0-S3 (0.16%, P < .001), respectively. PCT was an independent predictor of significant fibrosis (≥S2), advanced fibrosis (≥S3) and cirrhosis (S4). The area under the ROC curve (AUROC) of PCT in predicting significant fibrosis, advanced fibrosis and cirrhosis was 0.645, 0.709 and 0.714, respectively. The AUROC of PCT was higher than the aspartate transaminase to platelet ratio index (APRI) in identifying advanced fibrosis and cirrhosis, while this was comparable with APRI in identifying significant fibrosis. The diagnostic value of PCT was comparable with fibrosis-4 score (FIB-4) in predicting significant fibrosis, advanced fibrosis and cirrhosis. In the validation cohort, PCT could also identify significant fibrosis, advanced fibrosis and cirrhosis with similar diagnostic accuracy as in the derivation cohort. PCT represents a simple and inexpensive indictor for liver fibrosis in CHB patients. PCT is just as good or better than other more complex tools for staging liver fibrosis in CHB patients.

5.
Appl Microbiol Biotechnol ; 104(3): 1187-1199, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31834438

RESUMO

A microbial floc consisting of a community of microbes embedded in extracellular polymeric substances matrix can provide microbial resistances to toxic chemicals and harsh environments. Phenol is a toxic environmental pollutant and a typical lignin-derived phenolic inhibitor. In this study, we genetically engineered Escherichia coli cells by expressions of diguanylate cyclases (DGCs) to promote proteinaceous and aliphatic biofloc formation. Compared with the planktonic E. coli cells, the biofloc-forming cells improved phenol removal rate by up to 2.2-folds, due to their substantially improved tolerance (up to 149%) to phenol and slightly enhanced cellular activity (20%) of phenol hydroxylase (PheH). The engineered bioflocs also improved E. coli tolerance to other toxic compounds such as furfural, 5-hydroxymethylfurfural, and guaiacol. Additionally, the strategy of the engineered biofloc formation was applicable to Pseudomonas putida and enhanced its tolerance to phenol. This study highlights a strategy to form engineered bioflocs for improved cell tolerance and removal of toxic compounds, enabling their universality of use in bioproduction and bioremediation.

6.
Biomed Pharmacother ; 121: 109553, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31704611

RESUMO

OBJECTIVES: miRNAs in salivary exosomes are used as novel non-invasive biomarkers for detection strategies of human disease. Here, we aimed to investigate the diagnostic potential of salivary exosomal miRNAs as biomarkers for screening oral squamous cell carcinoma (OSCC) and to explore the underlying mechanisms of OSCC pathogenesis. MATERIALS AND METHODS: Differentially expressed miRNAs were obtained from salivary exosomes of four healthy controls and four OSCC patients using miRNA microarray analysis. The expression of miR-24-3p in the salivary exosomes was then verified by qRT-PCR. The diagnostic power was assessed by receiver operating characteristic (ROC) analysis. Cell proliferation was measured using CCK-8 cell viability assay and colony formation assay. The target gene of miR-24-3p was confirmed by dual luciferase reporter assay. RESULTS: A total of 109 miRNAs were found to be more than 2-fold altered in the salivary of patients and healthy individuals by miRNA microarray. qRT-PCR analysis further confirmed a significant increase of miR-24-3p in the salivary exosomes from 45 preoperative OSCC patients compared to 10 normal controls. ROC analysis showed that miR-24-3p has excellent diagnostic accuracy for OSCC (area under the ROC curve [AUC] = 0.738; P = 0.02). Similarly, we found that miR-24-3p expressed a higher level in OSCC neoplastic tissues, suggesting that circulating miR-24-3p may originate from tumor cells. Furthermore, exogenous exosomal miR-24-3p increased proliferation of recipient malignant cells. Additionally, overexpression of miR-24-3p promoted the proliferation of OSCC cells and regulated the expression of cell cycle-related genes. Dual luciferase reporter assay indicated that miR-24-3p can interact with PER1 directly. CONCLUSIONS: Salivary exosomal miR-24-3p is a potential novel diagnostic biomarker for OSCC, and miR-24-3p can maintain the proliferation of OSCC cells through targeting PER1.

7.
Steroids ; 155: 108558, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31866544

RESUMO

Two new hydroperoxy steroids, namely, xidaosteroids A and B (1 and 2), along with five known related compounds 3-7, were isolated from the South China Sea gorgonian Rumphella sp.. Their structures were established by extensive spectroscopic analyses and comparison of the spectral data with those reported in the literature. In bioassay, compound 3 showed weak cytotoxicities against SNU-398 and Capan-1 cells.

8.
J Clin Gastroenterol ; 2019 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-31789771

RESUMO

BACKGROUND: Serum hepatitis B e antigen (HBeAg) status is associated with the progression of chronic hepatitis B (CHB). The authors aimed to investigate the relationship between HBeAg status and liver pathology in CHB patients. METHODS: A total of 683 treatment-naive CHB patients who had undergone liver biopsy were retrospectively enrolled from 2 medical centers. Propensity score-matching (PSM) method was performed to adjust the imbalance of baseline confounders between HBeAg-positive and HBeAg-negative CHB patients. RESULTS: HBeAg-negative CHB patients (n=338) exhibited more advanced liver fibrosis than HBeAg-positive CHB patients (n=345) before PSM (P<0.001). However, there were no significant differences in the distribution of inflammation grades between HBeAg-positive and HBeAg-negative CHB patients (P=0.051). Of these 683 CHB patients, 123 patients were included in each group after PSM. HBeAg-negative CHB patients still showed significantly advanced liver fibrosis as compared with HBeAg-positive CHB patients (P=0.03) after PSM. Furthermore, the distribution of liver inflammation grades in the HBeAg-negative CHB patients was also more severe than patients with HBeAg-positive (P=0.037). HBeAg-negative status was identified as an independent risk factor of significant liver fibrosis (P=0.011) by multivariate analysis. CONCLUSIONS: HBeAg negativity is associated with more advanced liver fibrosis in CHB patients.

9.
Opt Express ; 27(21): 30893-30908, 2019 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-31684331

RESUMO

When an emitter is close to a plasmonic nanoantenna, besides coupling to the dipolar antenna mode, the emitter also considerably couples to a superposition of the high-order modes, referred to as a pseudomode. We comprehensively investigate the differences between the dipolar mode channel and the pseudomode channel in a representative system where a dipole emitter couples to a silver nanorod. The two channels are shown to be distinct in their mechanisms, characteristics (including chromatic dispersion and field distribution), and dependences on system parameters (including emitter-antenna distance, antenna geometry, and material loss). The study provides physical insight and reveals important design rules for controlling the competition between the two channels.

10.
Ann Med ; 51(7-8): 360-370, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31599180

RESUMO

Aim: This meta-analysis study aimed to compare the efficacy and safety of TEVAR versus OCSR for TBAD patients.Methods: We systematically searched PubMed, EmBase, and the Cochrane library to identify studies compared the effectiveness of TEVAR and OCSR in TBAD patients from the inception up to July 2019. The summary results were calculated using a random-effects model.Results: The electronic search identified 1,894 studies, and 18 studies with 9,664 TBAD patients were included. We noted patients received TEVAR were associated with a reduced risk of in-hospital mortality, acute renal failure, respiratory failure, and bleeding as compared with OCSR, whereas no significant differences between groups for the risk of stroke, myocardial infarction, paraplegia, mesenteric ischaemia/infarction, reinterventions, sepsis, and spinal cord ischaemia.Conclusions: The findings of this meta-analysis study suggested that TEVAR resulted in more short-term survival benefits. Moreover, the reduced risk of acute renal failure, respiratory failure and bleeding was detected in TEVAR group. The treatment effects of TEVAR versus OCSR on specific complications should be further verified by a study with high-level of evidence.Key messageComprehensive collected studies investigated the treatment effectiveness between TEVAR and OCSR for TBAD patientsTEVAR resulted in more survival benefits, in addition to lower risk of acute renal failure, respiratory failure and bleedingThe results of stratified analyses according to patients' characteristics were conducted.

11.
J Med Chem ; 62(18): 8642-8663, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31490070

RESUMO

BRD4 has recently emerged as a promising drug target. Therefore, identifying novel inhibitors with distinct properties could enrich their use in anticancer treatment. Guided by the cocrystal structure of hit compound 4 harboring a five-membered-ring linker motif, we quickly identified lead compound 7, which exhibited good antitumor effects in an MM.1S xenograft model by oral administration. Encouraged by its high potency and interesting scaffold, we performed further lead optimization to generate a novel potent series of bromodomain and extra-terminal (BET) inhibitors with a (1,2,4-triazol-5-yl)-3,4-dihydroquinoxalin-2(1H)-one structure. Among them, compound 19 was found to have the best balance of activity, stability, and antitumor efficacy. After confirming its low brain penetration, we conducted comprehensive preclinical studies, including a multiple-species pharmacokinetics profile, extensive cellular mechanism studies, hERG assay, and in vivo antitumor growth effect testing, and we found that compound 19 is a potential BET protein drug candidate for the treatment of cancer.

13.
Cell Death Dis ; 10(8): 557, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324754

RESUMO

The bromodomain and extra terminal domain (BET) family members, including BRD2, BRD3, and BRD4, act as epigenetic readers to regulate gene expression. Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme that participates in tumor immune escape primarily by catalyzing tryptophan to L-kynurenine. Here, we report that IDO1 is a new target gene of the BET family. RNA profiling showed that compound 9, a new BET inhibitor, reduced IDO1 mRNA up to seven times in Ty-82 cells. IDO1 differentially expressed in tumor cells and its expression could be induced with interferon gamma (IFN-γ). BET inhibitors (ABBV-075, JQ1, and OTX015) inhibited both constitutive and IFN-γ-inducible expression of IDO1. Similarly, reduction of BRD2, BRD3, or BRD4 decreased IDO1 expression. All these BET family members bound to the IDO1 promoter via the acetylated histone H3. JQ1 led to their release and reduced enrichment of RNA polymerase II (Pol II) on the promoter. IFN-γ increased the binding of BRD2, BRD3, BRD4, and Pol II on the IDO1 promoter by increasing the acetylation of histone H3, which could be prevented by JQ1 partially or even completely. Furthermore, both JQ1 and OTX015 decreased the production of L-kynurenine. The combination of BET inhibitors with the IDO1 inhibitor further reduced L-kynurenine, though only marginally. Importantly, the BET inhibitor ABBV-075 significantly inhibited the growth of human Ty-82 xenografts in nude mice and reduced both protein and mRNA levels of IDO1 in the xenografts. This finding lays a basis for the potential combination of BET inhibitors and IDO1 inhibitors for the treatment of IDO1-expressing cancers.

14.
Clin Cancer Res ; 25(20): 6180-6194, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31350312

RESUMO

PURPOSE: Multiple negative regulators restrict the ability of T cells to attack tumors. This work demonstrates the role of PI3K-interacting protein 1 (Pik3ip1) in restraining T-cell responses and antitumor immunity. EXPERIMENTAL DESIGN: An anti-Pik3ip1 mAb was generated to identify the Pik3ip1 expression pattern of hematopoietic cells. Pik3ip1 -/- mice and a Pik3ip1 fusion protein were generated to investigate the effect of Pik3ip1 on T-cell-mediated antitumor immunity in MC38 and B16-F10 tumor models. Immunoblotting and confocal microscopy were used to identify inhibitory effects of Pik3ip1 on T-cell receptor (TCR) signaling. Pik3ip1 expression was quantified, and its impact on T-cell function in human tumors was measured. RESULTS: We demonstrated that Pik3ip1 was predominantly expressed on T cells and served as an essential rheostat for T-cell-mediated immunity. A Pik3ip1 genetic deficiency led to enhanced T-cell responsiveness upon immunization with a neoantigen. Pik3ip1 -/- mice exhibited a marked increase in antitumor immunity and were resistant to tumor growth. Furthermore, Pik3ip1 extracellular domain fusion protein enhanced MC38 tumor growth was observed. Mechanistically, we found that Pik3ip1 inhibited TCR signaling by mediating the degradation of SLP76 through Pik3ip1 oligomerization via its extracellular region. Consistent with the results from the mouse models, PIK3IP1 expression correlated with T-cell dysfunction in human tumors. CONCLUSIONS: Our data reveal a critical role for Pik3ip1 as a novel inhibitory immune regulator of T-cell responses and provide a potential molecular target for cancer immunotherapy.

15.
Invest New Drugs ; 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31267379

RESUMO

The bromodomain and extra-terminal domain (BET) family of proteins, especially bromodomain-containing protein 4 (BRD4), has emerged as exciting anti-tumor targets due to their important roles in epigenetic regulation. Therefore, the discovery of BET inhibitors with promising anti-tumor efficacy will provide a novel approach to epigenetic anticancer therapy. Recently, we discovered the new BET inhibitor compound 171, which is derived from a polo-like kinase 1 (PLK1)-BRD4 dual inhibitor based on our previous research. Compound 171 was found to maintain BET inhibition ability without PLK1 inhibition, and there was no selectivity among BET family members. The in vitro and in vivo results both indicated that the overall anti-tumor activity of compound 171 was improved compared with the (+)-JQ-1 or OTX-015 BET inhibitors. Furthermore, we found that compound 171 could regulate the expression of cell cycle-regulating proteins including c-Myc and p21 and induce cell cycle arrest in the G0/G1 phase. However, compound 171 only has a quite limited effect on apoptosis, in considering that apoptosis was only observed at doses greater than 50 µM. To determine the mechanisms underlying cell death, proliferation activity assay was conducted. The results showed that compound 171 induced clear anti-proliferative effects at doses that no obvious apoptosis was induced, which indicated that the cell cycle arresting effect contributed mostly to its anti-tumor activity. The result of this study revealed the anti-tumor mechanism of compound 171, and laid a foundation for the combination therapy in clinical practice, if compound 171 or its series compounds become drug candidates in the future.

16.
Steroids ; 149: 108425, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31202682

RESUMO

Two new highly oxygenated ergostane-type sterols (1, 2) together with one known related compound sinugrandisterol A (3) were isolated from the soft coral Sinularia sp. collected from the water area near the Xisha Islands, South China Sea. Their structures were elucidated on the basis of detailed spectroscopic analysis, chemical transformations, and by comparison with those reported in literature. In bioassays, compounds 1 and 2 showed in vitro antiproliferative activity against a panel of cancer cell lines, including MDA-MB-436, A549, Hep3B, HT-29 and H157. Morphological observation and Hoechst 33,258 staining assays showed that compound 1-treated H157 cells displayed apoptosis characteristics. Moreover, western blot assays suggested that 1 could increase the expression of Bax and down-regulate expression of Bcl-2.

17.
Environ Technol ; : 1-7, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31046643

RESUMO

The Ag/ZnO microplates, composed by various nanoparticles, were facilely synthesized by calcination of the precursor obtained by ion exchanging between zinc carbonate hydroxide [Zn2(OH)2CO3] and silver nitrate (AgNO3) in a short time. The structures of ZnO and Ag/ZnO were characterized carefully by a series of methods and so on. Especially, the results from the UV-Vis-NIR diffuse reflectance and PL spectra confirmed that the presence of metallic Ag led to the fact that the adsorption of visible light and an increase of separation of electrons and holes in the Ag/ZnO composite. The photocatalytic activities of the Ag/ZnO were 1.5 and nearly 5 times higher that of ZnO for removal of RhB and MB, respectively. We proposed a possible mechanism to explain the enhanced photocatalytic degradation over Ag/ZnO under UV light irradiation. Finally, this work could provide a simple example for the synthesis of metal-semiconductor composite as well as their applications.

18.
J Oral Pathol Med ; 48(6): 477-482, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31077446

RESUMO

BACKGROUND: Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC. METHODS: Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme-linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial-mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays. RESULTS: We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E-cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC. CONCLUSIONS: CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.


Assuntos
Carcinoma de Células Escamosas/patologia , Quimiocina CCL2/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias Bucais/patologia , Antígenos CD , Caderinas , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Humanos , Neoplasias Bucais/metabolismo
19.
Eur J Gastroenterol Hepatol ; 31(12): 1527-1532, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31107736

RESUMO

BACKGROUND: Red blood cell distribution width (RDW) was reported to be associated with the severity of liver diseases. We aimed to investigate the association between RDW and severity of liver inflammation in autoimmune hepatitis (AIH). PATIENTS AND METHODS: Ninety-two consecutive AIH patients who underwent liver biopsy during 2016-2017 were included. Liver histology was evaluated using the Scheuer scoring system. Logistic regression analysis was used to analyze the risk factors for significant inflammation. The diagnostic accuracy was evaluated by the area under the receiver operating characteristic curve. RESULTS: The RDW level was higher in AIH patients with significant inflammation (14.6%, interquartile range: 13.2-16.3%) than in patients with mild inflammation (13.2%, interquartile range: 12.6-13.8%). The RDW level was correlated positively with the grades of liver inflammation (r=0.356, P < 0.001). The area under the receiver operating characteristic curve of RDW in predicting significant inflammation was 0.739 (95% confidential interval: 0.634-0.843, P < 0.001), with 67.80% sensitivity and 75.76% specificity. The diagnostic performance of RDW for significant inflammation was better than alanine aminotransferase (P = 0.003) and immunoglobulin G (P = 0.049). RDW (odds ratio = 1.702, P = 0.001) was identified as an independent predictor for significant inflammation by logistic multivariable analysis. CONCLUSION: The RDW level was correlated positively with the severity of liver inflammation in AIH patients. RDW can be a promising indicator for predicting significant liver inflammation in AIH.

20.
EBioMedicine ; 44: 275-288, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097406

RESUMO

BACKGROUND: R-spondins (Rspo) and leucine-rich repeat-containing G-protein-coupled receptors (LGR) play important roles in development, stem cells survival, and tumorigenicity by activating Wnt signaling pathway. Whether R-spondins-LGR signaling affects the progression of squamous cell carcinoma (SCC) remain unknown. This study aims to uncover the role of R-spodin2/LGR4 in tongue SCC (TSCC). METHODS: The expression of Rspo2 in TSCC specimens and its correlation with TSCC clinical outcome were evaluated. Levels of Rspo2 or LGR4 were altered by pharmacological and genetic approaches, and the effects on TSCC progression were assessed. FINDINGS: Aberrantly high levels of Rspo2 were detected in TSCC specimens. Its levels were closely related with lymph node metastasis, clinical stage and survival rate in patients with tongue SCC. Exogenous Rspo2 or overexpression of Rspo2 promoted growth, migration and invasion, epithelial-mesenchymal transition (EMT) and stem-like properties in SCC both in vivo and in vitro. Silence of Rspo2 abolished these phenotypes. LGR4 was functionally upregulated by Rspo2 in TSCC. Overexpression of Rspo2 increased, whereas Rspo2 silencing decreased the expression of LGR4, leading to subsequent phosphorylation of LRP6 and nuclear translocation of ß-catenin in TSCC cell lines. This nuclear translocation of ß-catenin was associated with a significant alteration in TCF-1, a downstream nuclear transcription factor of ß-catenin, as well as its target genes: CD44, CyclinD1 and c-Myc. INTERPRETATION: Rspo2-LGR4 system regulates growth, migration and invasion, EMT and stem-like properties of TSCC via Wnt/ß-catenin signaling pathway.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Transição Epitelial-Mesenquimal , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Neoplásicas/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Neoplasias da Língua/metabolismo , Neoplasias da Língua/patologia , Via de Sinalização Wnt , Adulto , Idoso , Animais , Biomarcadores Tumorais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/patologia , Modelos de Riscos Proporcionais , Neoplasias da Língua/genética , Neoplasias da Língua/mortalidade
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