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1.
Artigo em Inglês | MEDLINE | ID: mdl-32224126

RESUMO

BACKGROUND: Translationally controlled tumor protein (TCTP), which has been verified to have a proinflammatory activity, plays an important role in allergy. However, it remains unclear whether TCTP has an impact on the acute rejection (AR) after liver transplantation. METHODS: Three protocols were used to delineate the role of TCTP in AR after liver transplantation. First, in rat orthotopic liver transplantation (OLT), the expression of TCTP was measured by enzyme-linked immunosorbent assay (ELISA), real-time PCR, Western blot and immunofluorescence assays. Second, in mixed lymphocyte reaction (MLR), the role of TCTP in lymphocyte proliferation was measured by carboxyfluorescein succinimidyl ester (CFSE) labeling and the impact of TCTP on inflammatory factor release was detected by cytokine arrays. Third, in human OLT, the level of serum TCTP was detected by ELISA, and the relationship between TCTP and model for early allograft function (MEAF) score was assessed by Spearman's correlation. RESULTS: In rat OLT, AR resulted in great harm to allografts, manifesting as deterioration of liver function, increasing inflammatory factors and infiltrating lymphocytes. Meanwhile, TCTP was overexpressed in serum and allografts. Higher level of TCTP was associated with higher rejection activity index (RAI). In an MLR protocol, TCTP knockdown inhibited the proliferation of mixed inflammatory cells and significantly suppressed the release of 15 cytokines and chemokines. In human OLT, the serum TCTP was up-regulated within a week after operation. Additionally, the increasing speed of serum TCTP positively correlated with MEAF scores (r = 0.449; P = 0.0088). CONCLUSIONS: Up-regulated TCTP positively affects AR after liver transplantation.

2.
Biomed Res Int ; 2020: 8709804, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32149142

RESUMO

Studies on the number and proportion of regulatory T cells (Tregs) in ankylosing spondylitis (AS) patients have been controversial, which has led to a disagreement regarding the role of Tregs in the pathogenesis of AS. To clarify this debate, we conducted a meta-analysis to verify the reported changes in Tregs during AS. We systematically searched the PubMed, Foreign Medical Retrieval System (FMRS), and China National Knowledge Infrastructure (CNKI) web of knowledge databases for eligible articles. A meta-analysis of studies that examined the proportion and number of Tregs among peripheral blood mononuclear cells (PBMCs) and CD4+ T cells was performed using Stata software. Further, subgroup analysis was performed based on Treg definition markers and disease activity to identify potential sources of heterogeneity. Forty-seven studies involving a total of 4373 participants were included in the meta-analysis. The Treg/PBMC and Treg/CD4+ T cell ratios were significantly lower in AS patients than those in healthy controls (HCs). A subgroup analysis indicated that patients defined by CD4+CD25+/high, CD4+CD25+CD127low/-, and CD4+CD25+FOXP3+ had much lower Treg/PBMC and Treg/CD4+ T cell ratios than HCs. Active AS patients also had a substantially lower proportion of Tregs/PBMCs and Treg/CD4+ T cells than HCs. The proportion of Tregs among both PBMCs and CD4+ T cells was significantly decreased in AS patients. Treg definition markers and disease activity may influence the proportion of Tregs measured among the PBMC and CD4+ T cell populations. Further study of the correlation between AS disease activity and the proportion of Tregs in peripheral blood is needed to determine the physiological role of this association. This study implies that loss of Tregs may play a role in the pathogenesis of AS and helps clarify the contradictory Treg results in AS patients. This trial is registered with PROSPERO (CRD42019147064).

3.
Phytopathology ; : PHYTO08190319R, 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32167850

RESUMO

Xanthomonads were detected by using the Xan-D(CCF) medium from the brassica seeds, and their pathogenicity was determined by plant inoculation tests. It was found that some seed lots were infested with Xanthomonas campestris pv. campestris, some with X. campestris pv. raphani, and some with nonpathogenic xanthomonads. The nonpathogenic xanthomonad strains were identified as X. campestris, and the multilocus sequence analysis showed that the nonpathogenic X. campestris strains were grouped together with pathogenic X. campestris, but not with nonpathogenic strains of X. arboricola. In addition, all isolated X. campestris pv. campestris and X. campestris pv. raphani strains were positive in the hrpF-PCR, but the nonpathogenic strains were negative. It was further found that nonpathogenic X. campestris strain nE1 does not contain the entire pathogenicity island (hrp gene cluster; type III secretion system) and all type III effector protein genes based on the whole genome sequence analyses. The nonpathogenic X. campestris strain nE1 could acquire the entire pathogenicity island from the endemic X. campestris pv. campestris and X. campestris pv. raphani strains by conjugation, but type III effector genes were not cotransferred. The studies showed that the nonpathogenic X. campestris strains indeed exist on the brassica seeds, but it could be differentiated by the PCR assays on the hrp and type III effector genes. Nevertheless, the nonpathogenic X. campestris strains cannot be ignored because they may be potential gene resources to increase genetic diversity in the endemic pathogenic X. campestris pv. campestris and X. campestris pv. raphani strains.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32170772

RESUMO

AIM: Alzheimer's disease (AD) is a chronic neurodegenerative disease. Various inflammatory processes account for the pathology of AD, and macrophages in particular have a distinct polarization phenotype related to M1/M2 classification. We aimed to investigate macrophage polarization patterns as an indicator of cognitive function in AD. METHODS: We recruited 54 non-demented individuals as control and 105 AD patients as experimental groups respectively. Percentages of macrophage (PM2K+ CD14+ and PM2K+ CD14- ) and macrophage polarization subsets (M1, M2a, M2b, and M2c) were assessed using flow cytometry. All AD patients were classified by dementia severity using clinical Dementia Rating scale (CDR) as CDR 0.5, 1 and ≧2. AD patients had cognitive function evaluation using Mini-Mental State Examination (MMSE) and Cognitive Assessment Screening Instrument (CASI). We compared the macrophage polarization patterns between control and patient groups. Cognitive function was evaluated in association with macrophage polarization patterns in AD patients. RESULTS: The percentages of PM2K+ CD14+ and PM2K+ CD14- macrophages were higher in AD patients than in controls. M2b macrophage subset decrement and M1 macrophage subset increment of PM2K+ CD14+ and PM2K+ CD14- macrophages were observed in AD patients compared with controls. Although percentages of macrophage subsets were not consistent with CDR staging, PM2K+ CD14+ M2b macrophage subset decrement was correlated with worse cognitive functioning by MMSE and CASI in AD patients. CONCLUSION: M2b macrophage subset decrement and M1 macrophage subset increment were noted in AD patients, while PM2K+ CD14+ M2b macrophage subset decrement indicated worse cognitive function in such patients. This article is protected by copyright. All rights reserved.

5.
Radiat Oncol ; 15(1): 65, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32169088

RESUMO

BACKGROUND AND PURPOSE: We evaluated the relationship between patient-, tumor-, and treatment-related features and radiation-induced lymphopenia (RIL) and evaluated the correlation between RIL and survival outcome in NPC patients to help improve the treatment strategy. METHODS: This retrospective study included 374 patients with stage II-IVa NPC who had been treated with definitive RT and were enrolled from 2004 to 2015; The associations between the G3-4 RIL (absolute lymphocyte count, ALC <  0.5 × 109 cells/L) during RT and patient-, tumor-, and treatment-related factors were assessed using Cox regression analyses. The correlation between ALC nadir and survival was examined using a Kaplan-Meier analysis, compared with the log-rank test, and confirmed by a Cox proportional hazards analysis. RESULTS: In the multivariate analysis, lower baseline ALC and intensity modulated radiation therapy (IMRT) (vs. 2 dimensional-conformal radiation therapy,2D-CRT) were identified as 2 independent factors that were associated with G3-4 RIL. In the multivariate survival analysis, patients with G3-4 ALC nadir had longer local recurrence-free survival durations (LRFS) (vs. G0-2 nadir, HR = 0.548, P = 0.005) and longer progression-free survival durations (PFS) (vs. G0-2 nadir, HR = 0.676, P = 0.022), while patients with G4 ALC nadir had a shorter distant-metastasis-free survival duration (DMFS) (vs. G0-2 nadir, hazard ratio [HR] = 2.567, P = 0.037). CONCLUSIONS: In the study, lymphopenia during RT were affected by baseline ALC and RT modality independently. Moreover, G3-4 ALC nadir was independently linked with longer PFS and LRFS durations, while G4 ALC nadir was independently linked with a shorter DMFS duration.

6.
Medicine (Baltimore) ; 99(10): e19324, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32150068

RESUMO

The surgical outcomes of patients with single ureteral stones who had undergone ureteroscopic Holmium laser lithotripsy as outpatients and compare them with those of patients who had received the same procedure as inpatients. Records were obtained from January 2012 to December 2016 for selected patients who had undergone the above mentioned procedure at our institution. Patients were excluded if their ECOG performance status was ≥2, presented with multiple stones or concomitant renal stones, had histories of cancer or congenital urinary system abnormalities, or had undergone urinary system reconstruction surgery. Patients could decide whether to receive the procedure as an outpatient or inpatient. All surgeries were performed by a single surgeon. Patients preoperative, operative, and postoperative data were recorded. The clinical results, such as urinary tract infection, analgesic requirement, rate of returning to the emergency room, stone clearance, surgical complications, and medical expenditure for the treatment courses were analyzed and compared between the 2 cohorts. In total, 303 patients met the inclusion criteria. Among them, 119 patients decided to receive ureteroscopic laser lithotripsy as outpatients, whereas 184 decided to be inpatients. The outpatient cohort was younger (P < .001), had smaller stone diameters (P < .001), and fewer comorbidity factors (P = .038). Patients with a history of stone manipulation favored receiving the procedure under admission (P < .001). After 1:1 propensity score matching, no significant differences were discovered between the cohorts with regard to operative time, rate of lithotripsy failure, and operative complications. Furthermore, rates of stone clearance, post-op urinary tract infection, analgesic requirement, and returning to the emergency room were comparable between the 2 groups. However, the medical expenditure was significantly lower in the outpatient cohort (P < .001). Our data revealed that outpatient ureteroscopic lithotripsy with a Holmium laser was more economical compared with the inpatient group and achieved favorable outcomes for patients with a single ureteral stone.


Assuntos
Litotripsia a Laser/tendências , Pacientes Ambulatoriais/estatística & dados numéricos , Cálculos Ureterais/complicações , Cálculos Ureterais/terapia , Adulto , Idoso , Feminino , Humanos , Litotripsia a Laser/métodos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Cálculos Ureterais/epidemiologia , Ureteroscopia/métodos , Ureteroscopia/tendências
7.
Circ Res ; 2020 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-32091972

RESUMO

Rationale: Drug-induced proarrhythmia is so tightly associated with prolongation of the QT interval that QT prolongation is an accepted surrogate marker for arrhythmia. But QT interval is too sensitive a marker and not selective, resulting in many useful drugs eliminated in drug discovery. Objective: To predict the impact of a drug from the drug chemistry on the cardiac rhythm. Methods and Results: In a new linkage, we connected atomistic scale information to protein, cell and tissue scales by predicting drug binding affinities and rates from simulation of ion channel and drug structure interactions and then used these values to model drug effects on the hERG channel. Model components were integrated into predictive models at the cell and tissue scales to expose fundamental arrhythmia vulnerability mechanisms and complex interactions underlying emergent behaviors. Human clinical data were used for model framework validation and showed excellent agreement, demonstrating feasibility of a new approach for cardiotoxicity prediction. Conclusions: We present a multiscale model framework to predict electro-toxicity in the heart from the atom to the rhythm. Novel mechanistic insights emerged at all scales of the system, from the specific nature of proarrhythmic drug interaction with the hERG channel, to the fundamental cellular and tissue level arrhythmia mechanisms. Applications of machine learning indicate necessary and sufficient parameters that predict arrhythmia vulnerability. We expect that the model framework may be expanded to make an impact in drug discovery, drug safety screening for a variety of compounds and targets, and in a variety of regulatory processes.

8.
Carbohydr Polym ; 233: 115632, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32059874

RESUMO

Atmospheric low-temperature plasma has been widely applied in surface modification of lignocellulose for manufacturing lightweight, strong composites. This study is aimed at elaborating the structural changes of cellulose after plasma treatment and further understanding the mechanism underlying plasma-induced oxidation of cellulose. Experiments suggested that atmospheric low-temperature plasma exhibits strong capacity to cleave covalent bonds, leading to oxidation and degradation of cellulose. Theoretical analysis revealed that cleavage of C4O covalent bond is the first-step reaction during plasma-induced oxidation due to its low bond dissociation energy (229.2 kJ mol-1). Subsequent pyranose ring-breaking reaction dominates dynamically and thermodynamically. Obtained outcomes are vital for fundamentally understanding the plasma-lignocellulose interaction. On that basis, plasma treatment for activation and oxidation of lignocellulose can be optimized and designed for improved efficiency. Wettability of lignocellulose can be thus improved in a short time, providing an opportunity to manufacture lignocellulose-based composites with enhanced efficiency and mechanical properties in future.

11.
Biochem Biophys Res Commun ; 524(4): 1003-1009, 2020 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-32063361

RESUMO

Colon cancer is one of the leading causes of cancer-related deaths and its five-year survival rate remains low in locally advanced or metastatic stages of colon cancer. Overexpression of high mobility group protein AT-hook2 (HMGA2) is associated with cancer progression, metastasis, and poor prognosis in many malignancies. Oxidative stress regulates cellular mechanisms and provides an environment that favors the cancer cells to survive and progress, yet, at the same time, oxidative stress can also be utilized as a cancer-damaging strategy. The molecular regulatory roles of HMGA2 in oxidative stress and their involvement in cancer progression are largely unknown. In this study, we investigated the involvement of HMGA2 in regulation of oxidative stress responses by luciferase reporter assays. Moreover, we utilized dicoumarol (DIC), a derivative of coumarin which has been suggested to be involved in oxidation regulation with anticancer effects, and demonstrated that DIC could induce apoptosis and inhibit cell migration of HMGA2 overexpressing colon cancer cells. Further investigation also evidenced that DIC can enhance the cancer inhibition effect of 5-FU in colony formation assays. Taken together, our data revealed novel insights into the molecular mechanisms underlying HMGA2 and highlighted the possibility of targeting the cellular antioxidant system for treating patients and preventing from cancer progression in HMGA2 overexpressing colon cancer cells.

12.
J Cancer Res Clin Oncol ; 146(3): 579-591, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32060643

RESUMO

PURPOSE: The WHO classification for IDH-mutant grade II and grade III astrocytoma may not be as prognostically meaningful as expected. We aimed to develop a novel classification system based on the DNA damage response signature. METHODS: We developed the gene signature of DNA damage response with 115 samples from The Cancer Genome Atlas (TCGA) database. The dataset from Chinese Glioma Genome Atlas (CGGA) database with 41 samples was used as the validation set. Lasso Cox regression model was applied for selection of the best signature. Gene set enrichment analysis (GSEA) and gene ontology (GO) analysis were implemented to reveal its biological phenotype. RESULTS: A two-gene DNA damage response signature (RAD18, MSH2) was developed using the lasso Cox regression model based on the TCGA dataset. Its prognostic efficiency was validated in the CGGA cohort. The result of Cox regression analysis showed that the signature has a better predictive accuracy than the WHO grade. The risk score was an independent prognostic factor for the overall survival of the IDH-mutant grade II and grade III astrocytoma. GSEA and GO analysis confirmed enhanced processes related to DNA damage response in high-risk group. CONCLUSION: We developed a two-gene signature which can effectively predict the prognosis of patients with IDH-mutant grade II and grade III astrocytoma. It suggests a novel classification of astrocytoma with better prognostic accuracy based on the expression of DNA damage response genes.


Assuntos
Astrocitoma/classificação , Astrocitoma/genética , Dano ao DNA/genética , Transcriptoma , Adulto , Astrocitoma/mortalidade , Feminino , Humanos , Isocitrato Desidrogenase/genética , Masculino , Pessoa de Meia-Idade , Prognóstico
13.
J Chem Inf Model ; 60(3): 1779-1790, 2020 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-32105478

RESUMO

Preclinical assessment of drug-induced proarrhythmicity is typically evaluated by the potency of the drug to block the potassium human ether-à-go-go-related gene (hERG) channels, which is currently quantified by the IC50. However, channel block depends on the experimental conditions. Our aim is to improve the evaluation of the blocking potency of drugs by designing experimental stimulation protocols to measure the IC50 that will help to decide whether the IC50 is representative enough. We used the state-of-the-art mathematical models of the cardiac electrophysiological activity to design three stimulation protocols that enhance the differences in the probabilities to occupy a certain conformational state of the channel and, therefore, the potential differences in the blocking effects of a compound. We simulated an extensive set of 144 in silico IKr blockers with different kinetics and affinities to conformational states of the channel and we also experimentally validated our key predictions. Our results show that the IC50 protocol dependency relied on the tested compounds. Some of them showed no differences or small differences on the IC50 value, which suggests that the IC50 could be a good indicator of the blocking potency in these cases. However, others provided highly protocol dependent IC50 values, which could differ by even 2 orders of magnitude. Moreover, the protocols yielding the maximum IC50 and minimum IC50 depended on the drug, which complicates the definition of a "standard" protocol to minimize the influence of the stimulation protocol on the IC50 measurement in safety pharmacology. As a conclusion, we propose the adoption of our three-protocol IC50 assay to estimate the potency to block hERG in vitro. If the IC50 values obtained for a compound are similar, then the IC50 could be used as an indicator of its blocking potency, otherwise kinetics and state-dependent binding properties should be accounted.

14.
Biomed Eng Online ; 19(1): 12, 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32070352

RESUMO

BACKGROUND: Bone defects are often combined with the risk of infection in the clinic, and artificial bone substitutes are often implanted to repair the defective bone. However, the implant materials are carriers for bacterial growth, and biofilm can form on the implant surface, which is difficult to eliminate using antibiotics and the host immune system. Magnesium (Mg) was previously reported to possess antibacterial potential. METHODS: In this study, Mg was incorporated into poly(lactide-co-glycolic acid) (PLGA) to fabricate a PLGA/Mg scaffold using a low-temperature rapid-prototyping technique. All scaffolds were divided into three groups: PLGA (P), PLGA/10 wt% Mg with low Mg content (PM-L) and PLGA/20 wt% Mg with high Mg content (PM-H). The degradation test of the scaffolds was conducted by immersing them into the trihydroxymethyl aminomethane-hydrochloric acid (Tris-HCl) buffer solution and measuring the change of pH values and concentrations of Mg ions. The antibacterial activity of the scaffolds was investigated by the spread plate method, tissue culture plate method, scanning electron microscopy and confocal laser scanning microscopy. Additionally, the cell attachment and proliferation of the scaffolds were evaluated by the cell counting kit-8 (CCK-8) assay using MC3T3-E1 cells. RESULTS: The Mg-incorporated scaffolds degraded and released Mg ions and caused an increase in the pH value. Both PM-L and PM-H inhibited bacterial growth and biofilm formation, and PM-H exhibited higher antibacterial activity than PM-L after incubation for 24 and 48 h. Cell tests revealed that PM-H exerted a suppressive effect on cell attachment and proliferation. CONCLUSIONS: These findings demonstrated that the PLGA/Mg scaffolds possessed favorable antibacterial activity, and a higher content of Mg (20%) exhibited higher antibacterial activity and inhibitory effects on cell attachment and proliferation than low Mg content (10%).

15.
Aging (Albany NY) ; 12(2): 1888-1898, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31991402

RESUMO

This study compared the surgical outcomes of the 120-W Thulium laser (Vela™ XL) enucleation of the prostate and bipolar transurethral resection of the prostate (TURP) in terms of efficacy, safety, and improvements of quality of life (QoL) in patients with benign prostate hyperplasia (BPH). Records were obtained from January 2014 to September 2018 for selected patients with symptomatic BPH who underwent 120-W Thulium laser (Vela™XL) prostate enucleation and bipolar TURP in our institution. All the patients selected met the surgical criteria for TURP and had received medical treatment for at least 3 months. Patients were excluded if their ECOG performance status was >1, if they had active malignant disease, of if they had a history of prostate surgery or reconstruction surgery of the urinary system. Patients decided which treatment option would be performed. Both the procedures were conducted by a single surgeon. Clinical outcomes such as changes in the International Prostate Symptom Score (IPSS) score, urodynamic parameters, drug consumption, pain scores, and QoL were evaluated. The rate of urinary tract infection, recatheterization, additional analgesic requirement, return to the emergency department for treatment, and other surgical complications was analyzed and compared between the two cohorts. A total of 276 patients met the inclusion criteria. Among them, 141 patients received bipolar TURP, where as 135 decided to receive laser vaporesection. No significant difference was observed in age, PSA level, prostate volume, and comorbidities between the two cohorts. Pre-operative (pre-op) urodynamic parameters were also identical, except that the laser surgery group had a higher rate of admission with a urinary catheter (24.4% vs. 14.2%, p=0.044). The operating time was longer in the laser surgery group (79.3 minutes vs. 62.4 minutes, p<0.001). However, enucleation using the Thulium laser was superior to bipolar TURP in terms of post-operative (post-op) pain status, including the numeric rating scale of pain, rate of additional narcotic use, and oral analgesic requirement. Compared with bipolar TURP, laser enucleation achieved a higher improvement in the QoL score at post-op follow-up at 2 weeks and 3 months. Nevertheless, the complication rate, changes in IPSS score, Qmax, and post-op medication-free survival were statistically identical in the two cohorts. Our data revealed that compared with bipolar TURP, 120-W Thulium laser (Vela™ XL) enucleation of the prostate achieved lower post-op pain and higher improvement in the short-term QoL of patients after surgery.

16.
Biomolecules ; 10(1)2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31936661

RESUMO

The main curative treatments for hepatocellular carcinoma (HCC) are surgical resection and liver transplantation, which only benefits 15% to 25% of patients. In addition, HCC is highly refractory and resistant to cytotoxic chemotherapy. Although several multi-kinase inhibitors, such as sorafenib, regorafenib, and lenvatinib, have been approved for treating advanced HCC, only a short increase of median overall survival in HCC patients was achieved. Therefore, there is an urgent need to design more effective strategies for advanced HCC patients. Human ribonucleotide reductase is responsible for the conversion of ribonucleoside diphosphate to 2'-deoxyribonucleoside diphosphate to maintain the homeostasis of nucleotide pools. In this study, mining the cancer genomics and proteomics data revealed that ribonucleotide reductase regulatory subunit M2 (RRM2) serves as a prognosis biomarker and a therapeutic target for HCC. The RNA sequencing (RNA-Seq) analysis and public microarray data mining found that RRM2 was a novel molecular target of sorafenib in HCC cells. In vitro experiments validated that sorafenib inhibits RRM2 expression in HCC cells, which is positively associated with the anticancer activity of sorafenib. Although both RRM2 knockdown and sorafenib induced autophagy in HCC cells, restoration of RRM2 expression did not rescue HCC cells from sorafenib-induced autophagy and growth inhibition. However, long-term colony formation assay indicated that RRM2 overexpression partially rescues HCC cells from the cytotoxicity of sorafenib. Therefore, this study identifies that RRM2 is a novel target of sorafenib, partially contributing to its anticancer activity in HCC cells.

17.
Redox Biol ; 30: 101413, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31896509

RESUMO

Drug resistance is the main obstacle in the improvement of chemotherapeutic efficacy in glioblastoma. Previously, we showed that dehydroepiandrosterone (DHEA), one kind of androgen/neurosteroid, potentiates glioblastoma to acquire resistance through attenuating DNA damage. Androgen receptor (AR) activated by DHEA or other types of androgen was reported to promote drug resistance in prostate cancer. However, in DHEA-enriched microenvironment, the role of AR in acquiring resistance of glioblastoma remains unknown. In this study, we found that AR expression is significantly correlated with poor prognosis, and AR obviously induced the resistance to temozolomide (TMZ) treatment. Herein, we observed that ALZ003, a curcumin analog, induces FBXL2-mediated AR ubiquitination, leading to degradation. Importantly, ALZ003 significantly inhibited the survival of TMZ-sensitive and -resistant glioblastoma in vitro and in vivo. The accumulation of reactive oxygen species (ROS), lipid peroxidation and suppression of glutathione peroxidase (GPX) 4, which are characteristics of ferroptosis, were observed in glioblastoma cell after treatment of ALZ003. Furthermore, overexpression of AR prevented ferroptosis in the presence of GPX4. To evaluate the therapeutic effect in vivo, we transplanted TMZ-sensitive or -resistant U87MG cells into mouse brain followed by intravenous administration with ALZ003. In addition to inhibiting the growth of glioblastoma, ALZ003 significantly extended the survival period of transplanted mice, and significantly decreased AR expression in the tumor area. Taken together, AR potentiates TMZ resistance for glioblastoma, and ALZ003-mediated AR ubiquitination might open a new insight into therapeutic strategy for TMZ resistant glioblastoma.

18.
J Cell Physiol ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31951022

RESUMO

Traumatic osteonecrosis of femoral head (TONFH) is a common orthopedic disease caused by physical injury in hip. However, the unclear pathogenesis mechanism of TONFH and lacking of simple noninvasive early diagnosis method cause the necessity of hip replacement for most patients with TONFH. In this study, we aimed to identify circulating microRNAs (miRNAs) by integrated bioinformatics analyses as potential biomarker of TONFH. mRNA expression profiles were downloaded from the Gene Expression Omnibus database. Then we combined two miRNA screen methods: Weighted gene co-expression network analysis and fold change based differentially expressed miRNAs analysis. As a result, we identified 14 key miRNAs as potential biomarkers for TONFH. Besides, 302 target genes of these miRNAs were obtained and the miRNA-mRNA interaction network was constructed. Furthermore, the results of Kyoto Encyclopedia of Gene and Genome pathway analysis, Gene Ontology function analysis, protein-protein interaction (PPI) network analysis and PPI network module analysis showed close correlation between these 14 key miRNAs and TONFH. Then we established receiver operating characteristic curves and identified 6-miRNA signature with highly diagnosis value including miR-93-5p (area under the curve [AUC] = 0.93), miR-1324 (AUC = 0.92), miR-4666a-3p (AUC = 0.92), miR-5011-3p (AUC = 0.92), and miR-320a (AUC = 0.89), miR-185-5p (AUC = 0.89). Finally, the results of quantitative real-time polymerase chain reaction confirmed the significantly higher expression of miR-93-5p and miR-320a in the serum of patients with ONFH. These circulating miRNAs could serve as candidate early diagnosis markers and potential treatment targets of TONFH.

19.
Biomed Res Int ; 2020: 1710452, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998781

RESUMO

Background: This study aims to investigate the coronary microcirculatory resistance and prognosis of patients with acute myocardial infarction (AMI) concomitant with hyperhomocysteinemia (HHcy) after an elective percutaneous coronary intervention (PCI). Methods: A total of 101 patients that underwent elective PCI between May 2015 and July 2018 due to AMI were consecutively enrolled in this study. Patients were divided into a HHcy group (53) and a normal Hcy group (control; 48) based on their plasma homocysteine concentration. The characteristics of coronary angiography, the index of microcirculatory resistance (IMR) of infarct-related vessels (IRV), changes in left ventricular end diastolic diameter (LVEDd) and left ventricular ejection fraction (LVEF) before and after PCI, and the incidence of major adverse cardiovascular events (MACE) three months after PCI were compared between these groups. Results: Compared to the results from the Hcy group, the HHcy group had a higher IMR. The HHcy group had significantly higher LVEDd and a lower LVEF than the Hcy group 3 months after PCI. Additionally, the incidence of MACE at three months after PCI was higher in the HHcy group than in the Hcy group. Pearson correlation analysis revealed a positive correlation with IMR in the HHcy group. Furthermore, there was a difference in the LVEDd measured at one day after PCI and at three months after PCI in the HHcy group. Conclusion: AMI patients concomitant with HHcy that undergo elective PCI are prone to coronary microcirculatory dysfunction and have a poor cardiac function and poor prognosis at three months after PCI.

20.
Inorg Chem ; 59(3): 2062-2069, 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-31951403

RESUMO

An organo-templated titanium-oxo sulfate of the formulation (H2nep)[TiO(SO4)2] (denoted as TiOS, nep = N-ethylpiperazine) was synthesized under solvent-free conditions. The framework of TiOS is assembled from the [TiO(SO4)2]n2n- infinite chains interconnected by the H2nep cations through H-bond networks. After thermal treatment under vacuum conditions, the organic template H2nep was partially decomposed and converted into N-doped carbon dots (N-CDs), resulting in the N-CDs@TiOS composite material with retained crystallinity of the parent TiOS. The thermolysis of organic templates generates meso-cavities in the framework, rendering N-CDs@TiOS with a mesoporous structure. Photoelectrochemical and photocatalytic experiments show that the presence of N-CDs substantially improved visible-light-driven photocatalytic activity of N-CDs@TiOS compared to that of TiOS. The template thermolysis strategy gives an effective approach to construct the CDs-sensitized Ti-based mesoporous open-framework materials for visible-light photocatalytic applications.

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