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1.
Mol Ther Oncolytics ; 23: 65-81, 2021 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-34632051

RESUMO

Isocitrate dehydrogenase (IDH) mutations increase (R)-2-hydroxyglutarate (R-2HG) production; however, functional mechanisms of R-2HG in regulating cholangiocarcinoma (CCA) development remain to be further investigated. We first applied the CRISPR-Cas9 gene-editing system to create IDH1R132H-mutated CCA cells. Interestingly, our data showed that R-2HG could function through downregulating estrogen receptor alpha (ERα) and Yes-associated protein 1 (YAP1) pathways to decrease CCA growth. Detailed mechanistic studies revealed that R-2HG could target and degrade the fat mass and obesity-associated protein (FTO), the first identified mRNA demethylase. This reduced FTO can increase the N 6-methyladenosine (m6A) to methylate the mRNA of ERα, and consequently decrease protein translation of the ERα. Further mechanistic studies revealed that ERα could transcriptionally suppress miR-16-5p expression, which could then increase YAP1 expression due to the reduced miR-16-5p binding to the 3' UTR of YAP1. Furthermore, data from the pre-clinical animal model with implantation of IDH1R132H QBC939 cells demonstrated that R-2HG generated by the IDH1 mutation could downregulate ERα and YAP1 to suppress CCA tumor growth. Taken together, our new findings suggested that IDH1 mutation-induced R-2HG could suppress CCA growth via regulating the FTO/m6A-methylated ERα/miR16-5p/YAP1 signaling pathway. Upregulating R-2HG or downregulating the ERα signal by short hairpin RNA ERα (shERα) or antiestrogen could be effective strategies to inhibit CCA.

2.
J Cancer ; 12(22): 6706-6714, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34659560

RESUMO

Background: Bladder urothelial carcinoma (BC) is a common malignant tumor with a high incidence. This study aims to explore the role of miR-25 in BC tumorigenesis. Material and Methods: The expression of miR-25 and PTEN were detected in clinical BC tissues. BC cell lines T24 and 5637 were used to transfect miR-25 mimics or inhibitors. Luciferase reporter gene detection confirmed the correlation between miR-25 and PTEN. CCK-8 method and flow cytometry were used to detect cell viability and apoptosis. Cell migration and invasion ability were examined by transwell assays. Western blotting detects the protein levels of PTEN, ß-catenin, GSK-3ß and p-GSK-3ß. Results: MiR-25 and PTEN expression are found to be negatively correlated in BC tissues. Further research confirmed that PTEN is a direct target of miR-25. In addition, the overexpression of miR-25 down-regulates the expression of PTEN, induces cell survival and inhibits apoptosis, while the knockout of miR-25 leads to the opposite result. miR-25 also inhibits the phosphorylation of GSK-3ß and ß-catenin without changing the total level of GSK-3ß. In vivo experiments confirmed that miR-25 plays an oncogene's role by regulating the PTEN and Wnt/ß-catenin signaling pathways. Conclusion: Our research shows that miR-25 has a negative regulatory effect on the expression of PTEN in clinical specimens and in vitro. miR-25 can promote the proliferation of BC cells and induce cell invasion. Therefore, miR-25 may be used as a biomarker to predict the progression of BC.

3.
Cell Death Discov ; 7(1): 254, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545064

RESUMO

Parkinson's disease (PD) is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra and diminished dopamine content in the striatum. Recent reports show that 7,8-dihydroxyflavone (DHF), a TrkB agonist, attenuates the α-synuclein deposition and ameliorates motor deficits. However, the underlying mechanism is unclear. In this study, we investigated whether autophagy is involved in the clearance of α-synuclein and the signaling pathway through which DHF exerts therapeutic effects. We found that the administration of DHF (5 mg/kg/day, i.p.) prevented the loss of dopaminergic neurons and improved motor functions in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD, whereas these protective effects of DHF were completely blocked by autophagy inhibitor chloroquine (CQ). Further in vitro studies showed that autophagy was inhibited in N2A cells treated with 1-methyl-4-phenylpyridinium (MPP+), as reflected by a significant decrease in the expressions of autophagy marker proteins (Beclin1 and LC3II) and an increase in the expression of autophagic flux marker p62. DHF restored the impaired autophagy to control level in MPP+-treated N2A cells by inhibiting the ERK-LKB1-AMPK signaling pathway. Taken together, these results demonstrate that DHF exerts therapeutic effects in MPTP/MPP+-induced neurotoxicity by inhibiting the ERK-LKB1-AMPK signaling pathway and subsequently improving impaired autophagy.

4.
Semin Dial ; 2021 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-34550635

RESUMO

BACKGROUND: Studies suggested the association between blood flow rate (BFR) and mortality might be beyond dialysis adequacy. This study aimed to explore if BFR is an independent predictor of clinical outcomes in Chinese hemodialysis (HD) patients. METHODS: This study included data from patients in China Dialysis Outcomes and Practice Patterns Study (DOPPS) Phase 5. Patients with a record of BFR were included, and demographic data, comorbidities, hospitalization, and death records were collected. Associations between BFR and all-cause mortality and hospitalization were analyzed using Cox regression models. RESULTS: One thousand four hundred twelve (98.9%) patients were included. Most patients were with BFR < 300 ml/min. After full adjustment, each 10-ml/min increase of BFR was associated with a 6.4% decrease in all-cause mortality risk (HR: 0.936, 95% CI: 0.880-0.996) but not first hospitalization (HR: 0.987, 95% CI: 0.949-1.027). The impact of BFR on mortality may be more prominent in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl. CONCLUSION: Increased BFR is independently associated with a lower risk of all-cause mortality within the range of BFR 200-300 ml/min. And this effect is more pronounced in patients who were male gender, nondiabetic, albumin < 4.0 g/dl, and hemoglobin ≥ 9.0 g/dl.

5.
Gastroenterology ; 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34478742

RESUMO

BACKGROUNDS & AIMS: Increased permeability is implicated in the pathogenesis of intestinal disease. In vitro and in vivo studies have linked down-regulation of the scaffolding protein ZO-1, encoded by the TJP1 gene, to increased tight junction permeability. This has not, however, been tested in vivo. Here, we assessed the contributions of ZO-1 to epithelial barrier function and mucosal homeostasis. METHODS: Public Gene Expression Omnibus data sets and biopsy specimens from patients with inflammatory bowel disease (IBD) and healthy control individuals were analyzed. Tjp1f/f;vil-CreTg mice with intestinal epithelial-specific ZO-1 knockout (ZO-1KO.IEC) mice and Tjp1f/f mice littermates without Cre expression were studied using chemical and immune-mediated models of disease as well as colonic stem cell cultures. RESULTS: ZO-1 transcript and protein expression were reduced in biopsy specimens from patients with IBD. Despite mildly increased intestinal permeability, ZO-1KO.IEC mice were healthy and did not develop spontaneous disease. ZO-1KO.IEC mice were hypersensitive to mucosal insults and displayed defective repair. Furthermore, ZO-1-deficient colonic epithelia failed to up-regulate proliferation in response to damage in vivo or Wnt signaling in vitro. ZO-1 was associated with centrioles in interphase cells and mitotic spindle poles during division. In the absence of ZO-1, mitotic spindles failed to correctly orient, resulting in mitotic catastrophe and abortive proliferation. ZO-1 is, therefore, critical for up-regulation of epithelial proliferation and successful completion of mitosis. CONCLUSIONS: ZO-1 makes critical, tight junction-independent contributions to Wnt signaling and mitotic spindle orientation. As a result, ZO-1 is essential for mucosal repair. We speculate that ZO-1 down-regulation may be one cause of ineffective mucosal healing in patients with IBD.

6.
Medicine (Baltimore) ; 100(38): e27328, 2021 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-34559152

RESUMO

ABSTRACT: This study compares the efficacy of retroperitoneoscopic ureterolithotomy (RPUL) and ureteroscopic lithotripsy (URL) in the treatment of upper ureteral calculi.The clinical data of 150 patients with upper ureteral calculi who underwent RPUL and 136 patients who underwent URL between January 2014 and October 2019 were retrospectively analyzed. The operation time, postoperative hospital stay, operation success rate, stone clearance rate, and surgical complications were evaluated between the two groups.For the RPUL and URL groups, respectively, the average operation time was 74.5 ±â€Š24.6 minutes and 54.5 ±â€Š13.2 minutes; the postoperative hospital stay was 5.8 ±â€Š1.4 days and 3.2 ±â€Š1.2 days; the operation success rate was 96.0% (144/150) and 85.3% (116/136); the incidence rate of complications was 3.5% (5/144) and 17.5% (18/103); and the stone clearance rate was 100% (144/144) and 88.8% (103/116), which were all statistically significant (P < .05).Both RPUL and URL had the advantages of low trauma and fast recovery rate for patients with upper ureteral calculi. However, patients who underwent RPUL showed higher success and fewer complication rate. RPUL might be a safe and effective laparoscopic method for the treatment of patients with upper ureteral calculi.


Assuntos
Laparoscopia/estatística & dados numéricos , Litotripsia a Laser/estatística & dados numéricos , Ureterolitíase/cirurgia , Ureteroscopia/estatística & dados numéricos , Adulto , Idoso , Feminino , Humanos , Laparoscopia/métodos , Lasers de Estado Sólido/uso terapêutico , Masculino , Pessoa de Meia-Idade , Espaço Retroperitoneal/cirurgia , Estudos Retrospectivos , Ureteroscopia/métodos
7.
Front Oncol ; 11: 719863, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34490118

RESUMO

Objective: As a result of the inconsistency between reports, a meta-analysis was designed to appraise the clinical implications of long non-coding RNAs (lncRNAs) in exosomes for the diagnosis of bladder cancer. Methods: The PubMed, EMBASE, and Cochrane library databases were searched to identify the relevant literature on lncRNAs in exosomes for bladder cancer diagnosis from database inception to May 2021. The literature was screened according to the inclusion and exclusion criteria, and the Quality Assessment of Diagnostic Accuracy Studies-2 entry tool was applied to evaluate the quality of the literature, and the sources of heterogeneity were explored using meta-regression and subgroup analysis. Stata 14.0 and RevMan 5.3 software were used for statistical analysis. Results: A total of 23 studies described in 10 articles were included, with a total of 1883 patients with bladder cancer and 1721 patients in the non-cancerous control group. The exosome-derived lncRNAs performed better in the diagnosis of bladder cancer with a pooled sensitivity of 0.74 (95% CI, 0.69-0.77), specificity of 0.76 (95% CI, 0.72-0.80), and area under the curve of 0.83. The heterogeneity between studies was partly as a result of differences in specimen type, number of lncRNAs, lncRNA expression form, and reference gene type. Subgroup analysis showed that the detection efficacy based on the combination of multiple lncRNAs (0.86, 95% CI, 0.82-0.88) was higher than that based on a single lncRNA (0.81, 95% CI, 0.78-0.85), and exosomal lncRNAs with blood as the detection sample had a high diagnostic efficacy (0.86, 95% CI, 0.82-0.86). Conclusions: Exosome-derived lncRNAs hold great promise as non-invasive diagnostic biomarkers of bladder cancer. However, their clinical value needs to be examined in further comprehensive prospective studies.

8.
ACS Omega ; 6(34): 22011-22019, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34497895

RESUMO

Objective: To determine the possibility of early diagnosis and prognosis of ovarian cancer (OC) via detecting miR-181a in circulating tumor cells (CTCs) of OC and to solve clinical difficulties in OC tissue sample collection. Methods: EpCAM liposome magnetic beads (Ep-LMBs) were prepared by the reverse-phase evaporation method, and the performance of EpCAM was characterized. The cytotoxicity assay was detected by the MTT assay, and CTC capture efficiency was determined using OC cell lines. Blood and tissue samples were collected from 30 patients with OC and 30 normal ovarian tissue samples were selected. Expression of miR-181a in CTCs and tissue samples was measured by real-time fluorescence quantitative PCR (RT-qPCR) with U6 as an internal reference. Expression of miR-181a was interfered in OC cells and its relative expression was measured. Results: Ep-LMBs were successfully prepared with high stability. Cellular assays showed that these Ep-LMBs could capture up to 80% of OC cells. RT-qPCR showed that the expression of miR-181a was increased in OC tissues compared with that in normal ovarian tissues, and the relative expressions of miR-181a in cancerous tissues and CTCs were comparable. Correlation analysis with clinical characteristics revealed that miR-181a expression was correlated with the stage and metastasis of OC and the difference was statistically significant. Conclusion: MiR-181a may be involved in the development and progression of OC as an oncogene. Detection of miR-181a in Ep-LMB-captured CTCs is an effective and feasible alternative method for early diagnosis and prognostic evaluation of OC other than tissue tests.

9.
Immunopharmacol Immunotoxicol ; 43(5): 594-598, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34402367

RESUMO

BACKGROUND: Angiogenesis and inflammation exhibit a mutually reinforcing relationship in many human diseases. Vascular endothelial growth factor (VEGF) is one of the most important proangiogenic mediators. Conbercept is a novel VEGF inhibitor. METHOD: Type II collagen-induced rat rheumatoid arthritis (CIA) model was established to evaluate the anti-chronic inflammation activities of Conbercept. ELISA was used to measure the concentrations of immune factors in the blood of arthritis rats. The xylene-induced ear edema was conducted to evaluate the effect of Conbercept on acute inflammation. RESULT AND DISCUSSION: Our results showed that Conbercept significantly reduced the paw edema volume and the arthritis index in CIA rats. Furthermore, we found that Conbercept decreased the serum levels of vascular endothelial growth factor (VEGF), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) in CIA rats. Xylene-induced ear edema is a widely used method to study acute inflammation. Conbercept significantly inhibited xylene-induced ear edema. CONCLUSION: All results indicate that Conbercept exhibits significant inhibition of acute and chronic inflammation.

10.
PeerJ ; 9: e11694, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414022

RESUMO

Background: Accurate diagnosis of major depressive disorder (MDD) remains difficult, and one of the key challenges in diagnosing MDD is the lack of reliable diagnostic biomarkers. The objective of this study was to explore gene networks and identify potential biomarkers for MDD. Methods: In the present study, we performed a comprehensive analysis of the mRNA expression profiles using blood samples of four patients with MDD and four controls by RNA sequencing. Differentially expressed genes (DEGs) were screened, and functional and pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery. All DEGs were inputted to the STRING database to build a PPI network, and the top 10 hub genes were screened using the cytoHubba plugin of the Cytoscape software. The relative expression of 10 key genes was identified by quantitative real-time polymerase chain reaction (qRT-PCR) of blood samples from 50 MDD patients and 50 controls. Plasma levels of SQSTM1 and TNFα were measured using an enzyme-linked immunosorbent assay in blood samples of 44 MDD patients and 44 controls. A sucrose preference test was used to evaluate depression-like behavior in chronic unpredictable mild stress (CUMS) model rats. Immunofluorescence assay and western blotting were performed to study the expression of proteins in the brain samples of CUMS model rats. Results: We identified 247 DEGs that were closely associated with MDD. Gene ontology analyses suggested that the DEGs were mainly enriched in negative regulation of transcription by RNA polymerase II promoter, cytoplasm, and protein binding. Moreover, Kyoto Encyclopedia of Genes and Genomes pathway analysis suggested that the DEGs were significantly enriched in the MAPK signaling pathway. Ten hub genes were screened through the PPI network, and qRT-PCR assay revealed that one and six genes were downregulated and upregulated, respectively; however, SMARCA2, PPP3CB, and RAB5C were not detected. Pathway enrichment analysis for the 10 genes showed that the mTOR signaling pathway was also enriched. A strong positive correlation was observed between SQSTM1 and TNFα protein levels in patients with MDD. LC3 II and SQSTM1 protein levels were increased in the CUMS rat model; however, p-mTOR protein levels were decreased. The sucrose preference values decreased in the CUMS rat model. Conclusions: We identified 247 DEGs and constructed an MDD-specific network; thereafter, 10 hub genes were selected for further analysis. Our results provide novel insights into the pathogenesis of MDD. Moreover, SQSTM1, which is related to autophagy and inflammatory reactions, may play a key role in MDD. SQSTM1 may be used as a promising therapeutic target in MDD; additionally, more molecular mechanisms have been suggested that should be focused on in future in vivo and in vitro studies.

11.
Kidney Dis (Basel) ; 7(4): 315-322, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34395546

RESUMO

Background: Hemodialysis (HD) patients usually have impaired physical function compared with the general population. Self-reported physical function is a simple method to implement in daily dialysis care. This study aimed to examine the association of self-reported physical function with clinical outcomes of HD patients. Methods: The Dialysis Outcomes and Practice Patterns Study (DOPPS) is a prospective cohort study. Data on 1,427 HD patients in China DOPPS5 were analyzed. Self-reported physical function was characterized by 2 items of "moderate activities limited level" and "climbing stairs limited level." Demographic data, comorbidities, hospitalization, and death records were collected from patients' records. Associations between physical function and outcomes were analyzed using COX regression models. Results: Compared to "limited a lot" in moderate activities, "limited a little" and "not limited at all" groups were associated with lower all-cause mortality after adjusted for covariates (HR: 0.652, 95% CI: 0.435-0.977, and HR: 0.472, 95% CI: 0.241-0.927, respectively). And, not limited in moderate activities was associated with lower risk of hospitalization than the "limited a lot" group after adjusted for covariates (HR: 0.747, 95% CI: 0.570-0.978). Meanwhile, compared to "limited a lot" in climbing stairs, "limited a little" and "not limited at all" groups were associated with lower all-cause mortality (HR: 0.574, 95% CI: 0.380-0.865 and HR: 0.472, 95% CI: 0.293-0.762, respectively) but not hospitalization after fully adjusted. Conclusion: Higher limited levels in self-reported physical function were associated with higher risk of all-cause mortality and hospitalization in HD patients.

12.
Int. braz. j. urol ; 47(4): 843-855, Jul.-Aug. 2021. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1286781

RESUMO

ABSTRACT Objective: Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic inflammatory disease that can cause bladder pain and accompanying symptoms, such as long-term urinary frequency and urgency. IC/BPS can be ulcerative or non-ulcerative. The aim of this study was to explore the core genes involved in the pathogenesis of ulcerative IC, and thus the potential biomarkers for clinical treatment. Materials and Methods: First, the gene expression dataset GSE11783 was downloaded using the Gene Expression Omnibus (GEO) database and analyzed using the limma package in R to identify differentially expressed genes (DEGs). Then, the Database for Annotation, Visualization and Integrated Discovery (DAVID) was used for Gene Ontology (GO) functional analysis, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) was used for pathway enrichment analysis. Finally, the protein-protein interaction (PPI) network was constructed, and key modules and hub genes were determined using the STRING and Cytoscape software. The resulting key modules were then analyzed for tissue-specific gene expression using BioGPS. Results: A total of 216 up-regulated DEGs and 267 down-regulated genes were identified, and three key modules and nine hub genes were obtained. Conclusion: The core genes (CXCL8, CXCL1, IL6) obtained in this study may be potential biomarkers of interstitial cystitis with guiding significance for clinical treatment.

13.
Artigo em Inglês | MEDLINE | ID: mdl-34233920

RESUMO

Advances in our understanding of uremic retention solutes, and improvements in hemodialysis membranes and other techniques designed to remove uremic retention solutes, offer opportunities to readdress the definition and classification of uremic toxins. A consensus conference was held to develop recommendations for an updated definition and classification scheme on the basis of a holistic approach that incorporates physicochemical characteristics and dialytic removal patterns of uremic retention solutes and their linkage to clinical symptoms and outcomes. The major focus is on the removal of uremic retention solutes by hemodialysis. The identification of representative biomarkers for different classes of uremic retention solutes and their correlation to clinical symptoms and outcomes may facilitate personalized and targeted dialysis prescriptions to improve quality of life, morbidity, and mortality. Recommendations for areas of future research were also formulated, aimed at improving understanding of uremic solutes and improving outcomes in patients with CKD.

14.
Oncol Res ; 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34215350

RESUMO

Identifying prognostic indicators of clear cell renal cell carcinoma (ccRCC) and elucidating the mechanisms underlying ccRCC progression are crucial for improving ccRCC patient prognosis. This study investigated the clinical significance and biological role of Ring finger protein 43 ( RNF43) in ccRCC. Two independent cohorts of patients with ccRCC were employed to determine the prognostic significance of RNF43 by immunohistochemistry and statistical analyses. In vitro and in vivo experiments, RNA-seq, and other techniques were used to determine the biological role of RNF43 in ccRCC and related molecular mechanisms. RNF43 expression was commonly decreased in ccRCC specimens, and low expression of RNF43 indicated a higher TNM stage, SSIGN score, and WHO/ISUP grade and short survival in patients with ccRCC. Additionally, RNF43 overexpression suppressed the proliferation, migration, and targeted drug resistance of ccRCC cells, while the knockdown of RNF43 enhanced these characteristics of ccRCC. RNF43 knockdown activated YAP signaling by decreasing YAP phosphorylation by p-LATS1/2 and increasing the transcription and nuclear distribution of YAP. By contrast, RNF43 overexpression showed the opposite effects. Decreasing YAP abolished the effect of RNF43 knockdown in promoting the malignant features of ccRCC. Additionally, restoring RNF43 expression suppressed the resistance of the targeted drug pazopanib in in vivo orthotopic ccRCC. Furthermore, combining the expression of RNF43 andYAP with TNM stage or the SSIGN score exhibited greater accuracy than any of these indicators alone in assessing the postoperative prognosis of ccRCC patients. In summary, our study identified a novel tumor suppressor, RNF43, which is also a prognostic indicator and potential target for ccRCC potential target for ccRCC.

15.
Cancer Cell Int ; 21(1): 366, 2021 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-34246267

RESUMO

BACKGROUND: Peroxiredoxins (PRDXs) are an antioxidant enzymes protein family involved in several biological functions such as differentiation, cell growth. In addition, previous studies report that PRDXs play critical roles in the occurrence and development of carcinomas. However, few studies have conducted systematic analysis of PRDXs in cancers. Therefore, the present study sought to explore the molecular characteristics and potential clinical significance of PRDX family members in pan cancer and further validate the function of PRDX6 in bladder urothelial carcinoma (BLCA). METHODS: A comprehensive analysis of PRDXs in 33 types of cancer was performed based on the TCGA database. This involved an analysis of mRNA expression profiles, genetic alterations, methylation, prognostic values, potential biological pathways and target drugs. Moreover, both the gain and loss of function strategies were used to assess the importance and mechanism of PRDX6 in the cell cycle of BLCA. RESULT: Analysis showed abnormal expression of PRDX1-6 in several types of cancer compared to normal tissues. Univariate Cox proportional hazard regression analysis showed that expression levels of PRDX1, PRDX4 and PRDX6 were mostly associated with poor survival of OS, DSS and PFI, and PRDX2 and PRDX3 with favorable survival. In addition, the expression of PRDX genes were positively correlated with CNV and negatively with methylation. Moreover, analysis based on PharmacoDB dataset showed that the augmented levels of PRDX1, PRDX3 and PRDX6 were significantly correlated with EGFR/VEGFR inhibitor drugs. Furthermore, knocking down of PRDX6 inhibited growth of cancer cells through the JAK2-STAT3 in bladder cell lines. CONCLUSIONS: PRDXs are potential biomarkers and therapeutic targets for several carcinomas, especially for BLCA. In addition, PRDX6 could regulate proliferation of cancer cell via JAK2-STAT3 pathway and involve into the process of cell cycle in BLCA.

16.
Artigo em Inglês | MEDLINE | ID: mdl-34238199

RESUMO

BACKGROUND: Demethylincisterol A3 (DTA3) has been identified as an SHP2 inhibitor and suppresses the growth of many cancer cells. 5-Fluorouracil (5-FU) is widely used for the clinical treatment of various cancers. However, the combined effects of 5-FU and DTA3 on cervical cancer cells remain unknown. OBJECTIVE: This study evaluates the mechanism of the combined effects of 5-FU and DTA3 in cervical cancer cells. METHODS: The synergistic cytotoxic effects of 5-FU and DTA3 in cervical cancer cells were calculated. Apoptosis was analysed by flow cytometry. Western blot analyses were used to examine the related signalling pathways. RESULTS: DTA3 and 5-FU synergized to induce apoptosis and repress proliferation of cervical cancer cells by downregulating the activation of PI3K/AKT and NF-κB signalling pathway. We provided evidence that the upregulation of SHP2 expression by transfection significantly inhibited the cytotoxicity of 5-FU and DTA3. SHP2 knockdown enhanced the antiproliferation activity of 5-FU, indicating targeting SHP2 sensitized cervical cancer cells to 5-FU. CONCLUSION: Our study demonstrates that SHP2 inhibitor DTA3 and 5-FU have a synergistic cytotoxic effect on cervical cancer cells. The synergistic combination of SHP2 inhibitor and 5-FU may present a promising strategy for the treatment of cervical cancer.

17.
Am J Pathol ; 191(8): 1431-1441, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34294192

RESUMO

Glomeruli instance segmentation from pathologic images is a fundamental step in the automatic analysis of renal biopsies. Glomerular histologic manifestations vary widely among diseases and cases, and several special staining methods are necessary for pathologic diagnosis. A robust model is needed to segment and classify glomeruli with different staining methods and apply in cases with various glomerular pathologic changes. Herein, pathologic images from renal biopsy slides stained with three basic special staining methods were used to build the data sets. The snapshot group included 1970 glomeruli from 516 patients, and the whole-slide image group included 8665 glomeruli from 148 patients. Cascade Mask region-based convolutional neural net architecture was trained to detect, classify, and segment glomeruli into three categories: i) GN, structural normal; ii) global sclerosis; and iii) glomerular with other lesions. In the snapshot group, total glomeruli, GN, global sclerosis, and glomerular with other lesions achieved an F1 score of 0.914, 0.896, 0.681, and 0.756, respectively, which were comparable with those in the whole-slide image group (0.940, 0.839, 0.806, and 0.753, respectively). Among the three categories, GN achieved the best instance segmentation effect in both groups, as determined by average precision, average recall, F1 score, and Mask mean Intersection over Union. The present model segments and classifies multistained glomeruli with efficiency and robustness. It can be applied as the first step for more detailed glomerular histologic analysis.


Assuntos
Aprendizado Profundo , Interpretação de Imagem Assistida por Computador/métodos , Nefropatias/diagnóstico , Glomérulos Renais/patologia , Biópsia , Humanos , Nefropatias/patologia , Coloração e Rotulagem
18.
Sci Total Environ ; 783: 146898, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34088152

RESUMO

Di-n-butylphthalate (DBP) has been listed as an environmental priority pollutant in China due to its distinct biotoxicity. Epidemiological studies have shown that exposure to DBP is closely related to a series of congenital and acquired defects in the male reproductive system. The oxidative stress injury caused by DBP plays an important role in these defects. Previous studies have demonstrated that the Keap1/Nrf2 antioxidative pathway plays a protective role in DBP-induced oxidative stress injury. However, the further molecular regulation mechanism of the activation of Nrf2 pathway remains unclear. Here, we demonstrate that DBP caused testicular oxidative stress injury and Nrf2 pathway was activated in response to the injury in vivo and in vitro. Moreover, we validated that reduced level of USP15 attenuates DBP-induced oxidative stress injury through restraining the ubiquitylation and degradation of Nrf2. Notably, USP15 is confirmed as a target of miR-135b-5p and miR-135b-5p mediated inhibition of USP15 is involved in the DBP-induced oxidative stress injury. Collectively, these findings indicated that decreased level of USP15 functions a significant protective effect on the oxidative stress injury of testis caused by DBP via regulating the Keap1/Nrf2 signaling pathway.


Assuntos
Endopeptidases/genética , Proteína 1 Associada a ECH Semelhante a Kelch , Fator 2 Relacionado a NF-E2 , Estresse Oxidativo , Transdução de Sinais , Testículo , Animais , Proteína 1 Associada a ECH Semelhante a Kelch/genética , Proteína 1 Associada a ECH Semelhante a Kelch/metabolismo , Masculino , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Ratos Sprague-Dawley , Testículo/metabolismo , Testículo/patologia
19.
Medicine (Baltimore) ; 100(26): e26360, 2021 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-34190153

RESUMO

BACKGROUND: To describe the outcome of the patients with cerebral venous sinus thrombosis (CVST) during pregnancy and postpartum treated with anticoagulant therapy. METHODS: This is a retrospective cohort study and patients with CVST were collected from October 2009 to March 2018. Patients were divided into pregnancy-related (occurred during pregnancy and postpartum) group and non-pregnancy-related. Recovery rate at 12 months after anticoagulant therapy, adverse events, characteristics of patients with poor outcomes were statistically analyzed. RESULTS: Fifty-eight pregnancy-related CVST patients (17 pregnancy and 41 postpartum) as study group and 76 non-pregnancy-related CVST women as control group were enrolled. Study group was statistically different to control group in several baseline variables. More pregnancy-related patients had modified rankin scale (mRS) = 5 (15.5% vs 11.8%, P = 8.1×10-3) before anticoagulant therapy. At 12 months heparinization, difference in recovery rate was not statistically significant (80% vs 87.5%, P = .29) between 2 groups. No differences were found of adverse events between 2 groups. Patients with poor outcomes had less sigmoid sinus thrombosis (16.7% vs 61.5%, P = .14), more coma (41.2% vs 17.2%, P = 5.2×10-7), more mRS = 4 (33.3% vs 19.2%, P = 1.63 × 10-4), more mRS = 5 (66.7% vs 9.6%, P = 1.63 × 10-4) before treatment. CONCLUSION: Pregnancy-related CVST patients had severer condition before treatment, but can achieve comparable recovery rate at 12 months after anticoagulant therapy with non-pregnancy-related women. Pregnancy-related patients with poor prognosis had less sinus sigmoid occlusion, more coma, high mRS at admission.


Assuntos
Anticoagulantes/uso terapêutico , Complicações Hematológicas na Gravidez/tratamento farmacológico , Transtornos Puerperais/tratamento farmacológico , Trombose dos Seios Intracranianos/tratamento farmacológico , Anticoagulantes/efeitos adversos , Feminino , Heparina de Baixo Peso Molecular/efeitos adversos , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Gravidez , Resultado da Gravidez , Estudos Retrospectivos , Resultado do Tratamento
20.
Neuropsychiatr Dis Treat ; 17: 2041-2051, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34188474

RESUMO

Background: To investigate the clinical characteristics, iron metabolism and neuroinflammation in Parkinson's disease (PD) patients with excessive daytime sleepiness (EDS). Methods: We studied 379 patients with PD and 30 age-matched controls. All subjects were evaluated by Epworth sleepiness scale (ESS) and a series of rating scales and were divided into PD-EDS and PD-NEDS groups according to ESS score. The concentrations of iron and iron-related proteins and inflammatory cytokines in both cerebrospinal fluid (CSF) and serum were examined. Results: 1. The occurrence rate of EDS in total PD patients was 16.09%. 2. PD-EDS group had significantly severer disease stages, more severe motor and non-motor features of the disease. 3. In CSF, the concentrations of iron and IL-1ß in the PD-EDS group were significantly higher and ferritin concentration was prominently lower when compared with the PD-NEDS group and the control group; ESS score was significantly associated with high concentrations of iron and IL-1ß and low concentration of ferritin in the PD group. Iron concentration was positively correlated with IL-1ß concentration in the PD-EDS group. 4. In serum, no changes were observed in iron and iron-related proteins and inflammatory cytokines among the three groups. Conclusion: EDS was a common symptom in PD patients. PD patients with EDS had more severe motor and some non-motor symptoms. Overloaded iron-relevant inflammation in the brain might be an underlying mechanism of PD-EDS.

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