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1.
Cardiol Young ; : 1-4, 2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33616030

RESUMO

OBJECTIVE: The aim of this study was to evaluate the safety and efficacy of the Cardi-O-Fix plug used for the treatment of muscular ventricular septal defects. METHODS: We retrospectively reviewed the medical records of five patients with muscular ventricular septal defects who underwent transcatheter closure using the Cardi-O-Fix Plug, from November 2017 to August 2019. The median age was 5.1 years (range: 3.2-6.5). Their median body weight was 18.1 kg (range: 13.4-21.8). All the patients underwent detailed two-dimensional Doppler and colour flow imaging by transthoracic echocardiography. The left ventricular median defect size of the muscular ventricular septal defects was 5.6 mm (range: 5.3-7.0). The right ventricular median defect size of the muscular ventricular septal defects was 3.9 mm (range: 3.3-4.7). All the procedures were performed on beating hearts. RESULTS: All the patients underwent successful device implantation with no displacement or detachment, they have complete echocardiographic closure at the 1-year follow-up. There were no occluder-related arrhythmia, chordae tendineae rupture, tricuspid insufficiency, aortic regurgitation, haemolysis, or embolisation. CONCLUSIONS: Application of the Cardi-O-Fix plug appears to be a feasible, safe, and effective treatment option for patients with muscular ventricular septal defects. Longer follow-up periods are warranted to prove the conclusion for long-term outcomes.

2.
Biochim Biophys Acta Gen Subj ; 1865(6): 129859, 2021 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-33581251

RESUMO

BACKGROUND: Giardia lamblia differentiates into resistant cysts as an established model for dormancy. Myeloid leukemia factor (MLF) proteins are important regulators of cell differentiation. Giardia possesses a MLF homolog which was up-regulated during encystation and localized to unknown cytosolic vesicles named MLF vesicles (MLFVs). METHODS: We used double staining for visualization of potential factors with role in protein metabolism pathway and a strategy that employed a deletion mutant, CDK2m3, to test the protein degradation pathway. We also explored whether autophagy or proteasomal degradation are regulators of Giardia encystation by treatment with MG132, rapamycin, or chloroquine. RESULTS: Double staining of MLF and ISCU or CWP1 revealed no overlap between their vesicles. The aberrant CDK2m3 colocalized with MLFVs and formed complexes with MLF. MG132 increased the number of CDK2m3-localized vesicles and its protein level. We further found that MLF colocalized and interacted with a FYVE protein and an ATG8-like (ATG8L) protein, which were up-regulated during encystation and their expression induced Giardia encystation. The addition of MG132, rapamycin, or chloroquine, increased their levels and the number of their vesicles, and inhibited the cyst formation. MLF and FYVE were detected in exosomes released from culture. CONCLUSIONS: The MLFVs are not mitosomes or encystation-specific vesicles, but are related with degradative pathway for CDK2m3. MLF, FYVE, and ATG8L play a positive role in encystation and function in protein clearance pathway, which is important for encystation and coordinated with Exosomes. GENERAL SIGNIFICANCE: MLF, FYVE, and ATG8L may be involved an encystation-induced protein metabolism during Giardia differentiation.

3.
Hum Vaccin Immunother ; : 1-8, 2021 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-33577390

RESUMO

Background: The first Chinese domestic 13-valent pneumococcal conjugate vaccine (WoAnxin®, PCV-13) is available for children aged 2 months to 5 years and is more economical than import vaccine with equal safety and immunogenicity. However, the cost-effectiveness of this new PCV-13 for children <5 years in mainland China is not clear. Methods: In the present study, we developed a Markov model under societal perspective to evaluate the incremental cost-effectiveness ratios (ICERs) of five birth cohorts of 100,000 Chinese infants across four alternative vaccination programs:1) no vaccination; 2) vaccinate 4 doses of new PCV-13 for children aged 2 to 6 months; 3) vaccinate 3 doses of new PCV-13 for children aged 7 to 11 months; 4) vaccinate 2 doses of new PCV-13 for children aged 12 to 23 months; 5) vaccinate 1 dose of new PCV-13 for children aged 2 to 5 years. We conducted one-way and probability sensitivity analysis to determine the uncertainty of the model findings. Results: We found that with awillingness-to-pay (WTP) threshold of three-times Chinese per-capita gross domestic product (GDP) all vaccination programs were cost-effective compared to no vaccination and children aged 2 to 5 years received 1 dose of new PCV-13 would incur the lowest additional cost of US$2417 per quality-adjusted-life-years (QALYs) compare with other vaccination programs ($15394/QALYs for 4 doses program, $9292/QALYs for 3 doses program, $4445/QALYs for 2 doses program). Conclusions: According to our results, China should give priority to incorporating new PCV-13 into its national immunization program.

4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(1): 98-103, 2021 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-33554804

RESUMO

OBJECTIVE: To evaluate the prognostic value of GELTAMO-IPI for patients with diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 238 newly diagnosed DLBCL patients treated in Shanxi Cancer Hospital from September 2011 to March 2016 were collected retrospectively, the risk stratification and prognostic evaluation of the patients were analyzed according to GELTAMO-IPI. Progression-free survival (PFS) and overall survival (OS) of the patients were analyzed by the Kaplan-Meier method, COX regression analysis was used to compare the risk of death and progress in each risk group. Harrell's C statistics was used to compare the prognostic stratification ability of each model. RESULTS: The 3-year OS rate statistics showed that both IPI and GELTAMO-IPI could distinguish low risk group and Low-intermediate risk group, but the prognosis stratification ability of IPI was better (IPI: HR=5.085, P<0.05; GELTAMO-IPI; HR=4.639, P>0.05). GELTAMO-IPI could distinguish High-intermediate risk group from high risk group (GELTAMO-IPI: HR=2.966, P<0.05; 3 years OS rate was 34.5%), but the ability of IPI to identify high risk groups was weak (3 years OS>50%). The results of Harrell's C statistics showed the C-index of IPI and GELTAMO-IPI was 0.687 and 0.721 (P<0.001); the C-index of the predicted PFS was 0.672 and 0.700 (P<0.001). It was suggested that the prognostic stratification ability of GELTAM0-IPI be superior to that of IPI, R-IPI, NCCN-IPI. CONCLUSION: GELTAMO-IPI can make a clear distinction between DLBCL patients with different prognosis, especially for high-risk patients, and the prognostic stratification ability of GELTAMO-IPI is significantly better than that of IPI.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Prognóstico , Estudos Retrospectivos , Fatores de Risco
6.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33573049

RESUMO

The capacity to synthesize a protective cyst wall is critical for infectivity of Giardia lamblia. It is of interest to know the mechanism of coordinated synthesis of three cyst wall proteins (CWPs) during encystation, a differentiation process. Multiprotein bridging factor 1 (MBF1) gene family is a group of transcription coactivators that bridge various transcription factors. They are involved in cell growth and differentiation in yeast and animals, or in stress response in fungi and plants. We asked whether Giardia has MBF1-like genes and whether their products influence gene expression. BLAST searches of the Giardia genome database identified one gene encoding a putative MBF1 protein with a helix-turn-helix domain. We found that it can specifically bind to the AT-rich initiator promoters of the encystation-induced cwp1-3 and myb2 genes. MBF1 localized to cell nuclei and cytoplasm with higher expression during encystation. In addition, overexpression of MBF1 induced cwp1-3 and myb2 gene expression and cyst generation. Mutation of the helixes in the helix-turn-helix domain reduced cwp1-3 and myb2 gene expression and cyst generation. Chromatin immunoprecipitation assays confirmed the binding of MBF1 to the promoters with its binding sites in vivo. We also found that MBF1 can interact with E2F1, Pax2, WRKY, and Myb2 transcription factors that coordinately up-regulate the cwp genes during encystation. Using a CRISPR/Cas9 system for targeted disruption of mbf1 gene, we found a downregulation of cwp1-3 and myb2 genes and decrease of cyst generation. Our results suggest that MBF1 is functionally conserved and positively regulates Giardia cyst differentiation.

7.
J Matern Fetal Neonatal Med ; : 1-7, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588678

RESUMO

OBJECTIVE: To compare cesarean delivery (CD) rates in referral and non-referral hospitals in Maternal Safety Collaboration in Jiangsu province, China. METHODS: Sixteen participants (4 referral hospitals, 12 non-referral hospitals) from Drum Tower Hospital Collaboration for Maternal Safety reported CD rates in 2019 using ten-group classification system and maternal/neonatal morbidity and mortality. RESULTS: A total of 22,676 CDs were performed among 52,499 deliveries and the average CD rate was 43.2% (range 34.8-69.6%). CD rate in non-referral hospitals (44.7%) was significantly higher than it was in referral hospitals (40.4%, p < .001). Term singleton cephalic nulliparous women with spontaneous labor (Group 1) or induced labor (Group 2a) had higher CD rates if they were cared in non-referral hospitals compared with those in referral hospitals (Group 1: 11.8% vs. 4.4%, p < .001; Group 2a: 29.1% vs. 21.3%, p < .001). In non-referral hospitals, CD rate in Group 5 and the proportion of Group 5 to the overall population were also significantly higher than those in referral hospitals (98.5% vs. 92.5%, p < .001; and 21.0% vs. 14.5%, p < .001). CONCLUSION: To decrease the CD rate, we need to take efforts in decreasing unnecessary operations for term singleton cephalic nulliparous women and increasing the rate of trial of labor after CD.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33596171

RESUMO

Future activity anticipation is a challenging problem in egocentric vision. As a standard future activity anticipation paradigm, recursive sequence prediction suffers from the accumulation of errors. To address this problem, we propose a simple and effective Self-Regulated Learning framework, which aims to regulate the intermediate representation consecutively to produce representation that (a) emphasizes the novel information in the frame of the current time-stamp in contrast to previously observed content, and (b) reflects its correlation with previously observed frames. The former is achieved by minimizing a contrastive loss, and the latter can be achieved by a dynamic reweighing mechanism to attend to informative frames in the observed content with a similarity comparison between feature of the current frame and observed frames. The learned final video representation can be further enhanced by multi-task learning which performs joint feature learning on the target activity labels and the automatically detected action and object class tokens. SRL sharply outperforms existing state-of-the-art in most cases on two egocentric video datasets and two third-person video datasets. Its effectiveness is also verified by the experimental fact that the action and object concepts that support the activity semantics can be accurately identified.

9.
Free Radic Biol Med ; 165: 368-384, 2021 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-33460768

RESUMO

Emerging evidences implicate the contribution of ROS to T cell activation and signaling. The tyrosine kinase, ζ-chain-associated protein of 70 kDa (ZAP70), is essential for T cell development and activation. However, it remains elusive whether a direct redox regulation affects ZAP70 activity upon TCR stimulation. Here, we show that deficiency of non-selenocysteine containing phospholipid hydroperoxide glutathione peroxidase (NPGPx), a redox sensor, results in T cell hyperproliferation and elevated cytokine productions. T cell-specific NPGPx-knockout mice reveal enhanced T-dependent humoral responses and are susceptible to experimental autoimmune encephalomyelitis (EAE). Through proteomic approaches, ZAP70 is identified as the key interacting protein of NPGPx through disulfide bonding. NPGPx is activated by ROS generated from TCR stimulation, and modulates ZAP70 activity through redox switching to reduce ZAP70 recruitment to TCR/CD3 complex in membrane lipid raft, therefore subduing TCR responses. These results reveal a delicate redox mechanism that NPGPx serves as a modulator to curb ZAP70 functions in maintaining T cell homeostasis.

10.
Transl Res ; 2021 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-33400994

RESUMO

The gonadotropin-releasing hormone (GnRH) signaling pathway controls reproductive functions and cancer growth and progression. However, few studies investigated roles of genetic variants of GnRH pathway genes in survival of patients with non-small cell lung cancer (NSCLC). Therefore, we first evaluated associations between 22,528 single-nucleotide polymorphisms (SNPs) in 101 GnRH pathway genes and survival of 1185 NSCLC patients using a dataset from Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial. We found 572 SNPs to be significantly associated with overall survival (OS) of NSCLC (P ≤ 0.05, Bayesian false discovery probability ≤0.80). We then validated these SNPs in another dataset with 984 NSCLC patients from the Harvard Lung Cancer Susceptibility Study. Finally, two independent SNPs (HBEGF rs4150236G>A and ITPR3 rs116454384C>T) remained significantly associated with NSCLC OS in the combined analysis with hazards ratios of 0.84 (95% confidence interval = 0.76-0.92, P = 0.0003) and 0.85 (0.78-0.94, 0.0012), respectively; their genetic score (the number of protective genotypes) was associated with a better OS and disease-specific survival (Ptrend = 0.0002 and 0.0001, respectively). Further expression quantitative trail loci analysis showed a significant correlation between ITPR3 rs116454384 T allele and an increased mRNA expression level in both whole blood and normal lung tissue, and high ITPR3 mRNA expression levels in tumors were associated with a better survival of NSCLC patients. Because ITPR3 mutations were rare in tumors, ITPR3 rs116454384C>T likely had an effect on cancer progression by regulating the gene expression. Therefore, genetic variants of HBEGF rs4150236G>A and ITPR3 rs116454384C>T may be predictors for NSCLC survival, but HBEGF rs4150236G>A functional relevance remains to be determined.

11.
JAMA Netw Open ; 4(1): e2034569, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33502483

RESUMO

Importance: Acute respiratory distress syndrome (ARDS) confers high mortality risk among critically ill patients. Identification of biomarkers associated with ARDS risk may guide clinical diagnosis and prognosis. Objective: To systematically evaluate the association of blood metabolites with ARDS risk and survival. Design, Setting, and Participants: In this cohort study, data from the Molecular Epidemiology of ARDS (MEARDS) study, a prospective cohort of 403 patients with ARDS and 1227 non-ARDS controls, were analyzed. Patients were recruited in intensive care units (ICUs) at Massachusetts General Hospital and Beth Israel Deaconess Medical Center, both in Boston, Massachusetts, from January 1, 1998, to December 31, 2014. Data analysis was performed from December 9, 2018, to January 4, 2019. Main Outcomes and Measures: Participants were followed up daily for ARDS development defined by Berlin criteria, requiring fulfillment of chest radiograph and oxygenation criteria on the same calendar day during invasive ventilatory assistance. A 2-stage study design was used to explore novel metabolites associated with ARDS risk and survival. Results: Of the 1630 participants from MEARDS who were admitted to the ICU , 403 (24.7%) were diagnosed with ARDS (mean [SD] age, 63.0 [17.0] years; 251 [62.3%] male) and 1227 (75.3%) were at-risk but did not have ARDS (mean [SD] age, 62.3 [16.9] years; 753 [61.4%] male). Mendelian randomization suggested that genetically regulated serum mannose was associated with ARDS risk (odds ratio [OR], 0.64; 95% CI, 0.53-0.78; P = 7.46 × 10-6) in the discovery stage. In the functional validation stage incorporating 83 participants with ARDS and matched at-risk participants in the control group from the ICU, the protective association of mannose with ARDS risk was validated (OR, 0.67; 95% CI, 0.46-0.97; P = .03). Furthermore, serum mannose was associated with 28-day (OR, 0.25; 95% CI, 0.11-0.56; P = 6.95 × 10-4) and 60-day (OR, 0.36; 95% CI, 0.19-0.71; P = 3.12 × 10-3) mortality and 28-day (hazard ratio, 0.49; 95% CI, 0.32-0.74; P = 6.41 × 10-4) and 60-day (hazard ratio, 0.55; 95% CI, 0.37-0.80; P = 2.11 × 10-3) survival. Conclusions and Relevance: In this study, genetically regulated serum mannose appeared to be associated with ARDS risk and outcome, and increased serum mannose at admission was associated with reduced ARDS risk and better survival. These findings could inform prevention and clinical intervention in ARDS cases, which have increased with the expansion of the coronavirus disease 2019 pandemic.


Assuntos
Manose/sangue , /mortalidade , APACHE , Idoso , Estado Terminal , Feminino , Humanos , Unidades de Terapia Intensiva , Modelos Logísticos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco
12.
Neuroimage ; 229: 117749, 2021 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-33454416

RESUMO

BACKGROUND: First-degree relatives of people with dementia (FH+) are at increased risk of developing Alzheimer's disease (AD). Here, we investigate "estimated years to onset of dementia" (EYO) as a surrogate marker of preclinical disease progression and assess its associations with multi-modal neuroimaging biomarkers. METHODS: 89 FH+ participants in the PREVENT-Dementia study underwent longitudinal MR imaging over 2 years. EYO was calculated as the difference between the parental age of dementia diagnosis and the current age of the participant (mean EYO = 23.9 years). MPRAGE, ASL and DWI data were processed using Freesurfer, FSL-BASIL and DTI-TK. White matter lesion maps were segmented from FLAIR scans. The SPM Sandwich Estimator Toolbox was used to test for the main effects of EYO and interactions between EYO, Time, and APOE-ε4+. Threshold free cluster enhancement and family wise error rate correction (TFCE FWER) was performed on voxelwise statistical maps. RESULTS: There were no significant effects of EYO on regional grey matter atrophy or white matter hyperintensities. However, a shorter EYO was associated with lower white matter Fractional Anisotropy and elevated Mean/Radial Diffusivity, particularly in the corpus callosum (TFCEFWERp < 0.05). The influence of EYO on white matter deficits were significantly stronger compared to that of normal ageing. APOE-ε4 carriers exhibited hyperperfusion with nearer proximity to estimated onset in temporo-parietal regions. There were no interactions between EYO and time, suggesting that EYO was not associated with accelerated imaging changes in this sample. CONCLUSIONS: Amongst cognitively normal midlife adults with a family history of dementia, a shorter hypothetical proximity to dementia onset may be associated with incipient brain abnormalities, characterised by white matter disruptions and perfusion abnormalities, particularly amongst APOE-ε4 carriers. Our findings also confer biological validity to the construct of EYO as a potential stage marker of preclinical progression in the context of sporadic dementia. Further clinical follow-up of our longitudinal sample would provide critical validation of these findings.

13.
J Neurol ; 2021 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-33423129

RESUMO

BACKGROUND: Structural brain changes associated with Alzheimer's disease (AD) can occur decades before the onset of symptoms. The Cardiovascular Risk Factors, Aging, and Dementia (CAIDE) score has been suggested to be associated with accelerated brain atrophy in middle-aged subjects but the regional specificity of atrophic areas remains to be elucidated. METHODS: 3T T1-weighted magnetic resonance imaging scans of 160 cognitively healthy middle-aged participants (mean age = 52) in the PREVENT-Dementia cohort, from baseline and from follow-up after 2 years, were examined. Images were preprocessed using Computational Anatomy Toolbox 12. Voxel-based morphometry was performed in FSL 6.0.1 to identify areas of grey matter (GM) volume differences both cross-sectionally and longitudinally between subjects with high and low baseline CAIDE score (CAIDE score was dichotomized at cohort-median). A GM percentage of change map was created for each subject for evaluation of atrophy over 2 years. Analyses were adjusted for age, gender, education and total intracranial volume. RESULTS: Compared to subjects with CAIDE score ≤ 6 (low risk), subjects with CAIDE score > 6 (high risk) showed lower GM volume in the temporal, occipital, and fusiform cortex and lingual gyrus at baseline, and greater percentage of GM loss over 2 years in the supramarginal gyrus, angular gyrus, precuneus, lateral occipital cortex, superior parietal lobule and cingulate gyrus (corrected P < 0.05). CONCLUSION: This study demonstrated accelerated GM atrophy concentrated in several AD signature cortical regions in healthy middle-aged subjects with high CAIDE scores.

14.
Eur J Pharmacol ; 895: 173888, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33493484

RESUMO

To explore the potential targets underlying the effect of rosuvastatin on heart failure (HF) by utilizing a network pharmacology approach and experiments to identify the results. PharmMapper and other databases were mined for information relevant to the prediction of rosuvastatin targets and HF-related targets. Then, the rosuvastatin-HF target gene networks were created in Cytoscape software. Eventually, the targets and enriched pathways were examined by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Furthermore, we constructed an HF animal model and used rosuvastatin to treat them, identifying the changes in heart function and related protein expression. We further used different cells to explore the mechanisms of rosuvastatin. Thirty-five intersection targets indicated the therapeutic targets linked to HF. GO analysis showed that 481 biological processes, 4 cellular components and 23 molecular functions were identified. KEGG analysis showed 13 significant treatment pathways. In animal experiments, rosuvastatin significantly improved the cardiac function of post-myocardial infarction mice and prevented the development of HF after myocardial infarction by inhibiting IL-1Β expression. Cell experiments showed that rosuvastatin could reduce the expression of IL-1B in HUVEC and THP-1 cells. The therapeutic mechanism of rosuvastatin against HF may be closely related to the inhibition of the expression of apoptosis-related proteins, inflammatory factors, and fibrosis-related genes. However, IL-1Β is one of the most important target genes.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33432473

RESUMO

PURPOSE: The use of transvenous implantable cardioverter defibrillators (TV-ICDs) is associated with multiple risks related to the presence of the defibrillator leads within the venous system and right side of the heart, including endocarditis, venous occlusion, tricuspid regurgitation, and potential lead failure. The emergence of subcutaneous ICDs (S-ICDs) may potentially overcome the aforementioned disadvantages. However, evidence validating the safety of S-ICDs relative to TV-ICDs is limited. The present study aimed to synthesize and analyze available data from published studies to comprehensively compare transvenous and subcutaneous ICDs. METHODS: Different databases were searched for full-text publications with a direct comparison of TV- and S-ICDs. Fixed effect models were applied to pooled data, and no study-to-study heterogeneity was detected. RESULTS: Data from 7 studies totaling 1666 patients were pooled together. Compared to S-ICDs, the risk of suffering device-related complications was higher in patients with TV-ICDs (OR = 1.71; 95% CI: 1.23-2.38). The number of patients with an S-ICD who suffered inappropriate shocks (IS) was not significantly different than patients with a TV-ICD (OR = 0.92; 95% CI: 0.65-1.30). Subgroup analysis indicated that the TV-ICD group had a higher risk of IS due to supraventricular oversensing (OR = 3.29; 95% CI: 1.92-5.63) while T-wave oversensing tending to cause IS in the S-ICD group (OR = 0.09; 95% CI: 0.03-0.23). The risk of device-related infection in the S-ICD group was not any lower than that in the TV-ICD group (OR = 1.57; 95% CI: 0.67-3.68). The survival rate without any complications during a 1-year follow-up period was similar between the 2 groups (HR = 1.23; 95% CI: 0.81-1.86), although it was assumed that the trend leaned toward more complications in patients with a TV-ICD. CONCLUSION: The present study verified the safety of S-ICDs based on pooled data. Although there were no differences between TV- and S-ICDs in the short term, fewer adverse events were found in patients with S-ICDs during long-term follow-up.

16.
Artigo em Inglês | MEDLINE | ID: mdl-33403398

RESUMO

Bone is the most common late metastasis of breast cancer. Bone metastasis causes not only severe bone pain, but also bone-related diseases such as pathological fractures, which are closely related to osteoclasts. The effects of demethoxycurcumin (DMC) on osteoclast biology has not been investigated. In this study, we explored the effects of DMC on MDA-MB-231 cells, MCF-7 cells, and osteoclasts induced by RANKL in vitro, as well as the protective effect on bone destruction of tumor bone metastasis in vivo. DMC showed inhibitory effect on the migration and promotes the apoptosis of MDA-MB-231 and MCF-7 cells. At the same time, DMC inhibited osteoclast maturation and mature osteoclast bone resorption in a dose-dependent manner, and suppressed the expression of osteoclast marker genes TRAP, CTSK, MMP9, V-ATPase-d2 and DC-STAMP significantly. Biochemical data showed that DMC inhibited tumor cells and osteoclasts by inhibiting the early activation of ERK and JNK MAPK pathway. Consistent with the results in vitro, we confirmed that DMC protects bone destruction caused by tumor metastasis in vivo. In short, our study confirmed that DMC could be used as a potential drug for the treatment of tumor bone destruction.

17.
Talanta ; 221: 121607, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33076137

RESUMO

Drug-induced liver injury (DILI) has been a hot issue of public health, owing to its unpredictability and serious harm to public health. Peroxynitrite (ONOO-) is an important biomarker for the assessment and diagnosis of DILI. In this article, based on a kind of rhodamine analogue with a near-infrared (NIR) emission (610 nm-800 nm) and a two-photon absorption cross section (54 GM), a two-photon excited NIR fluorescence probe (NIR-ONOO) for ONOO- was developed. With a high selectivity and a high sensitivity to ONOO-, NIR-ONOO has a linear range for detection of ONOO- from 5.0 × 10-8 to 1.0 × 10-5 M, a good detection limit (15 nM) and a large fluorescence enhancement (340-fold). In addition, NIR-ONOO has been used to monitor ONOO- in cells with satisfactory results. Because of its two-photon excied NIR emission, NIR-ONOO also showed excellent performances for imaging ONOO- including low autofluorescence, stable and persistent fluorescence, and a deep penetration (204 µm). Finally, NIR-ONOO was successfully employed to image ONOO- in inflammatory mouse, drug-induced hepatotoxicity in cells and its remediation. All the results indicated that NIR-ONOO is a powerful chemical tool to image ONOO- and assay drug-induced hepatotoxicity.

18.
Neurosci Lett ; 745: 135596, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33359735

RESUMO

BACKGROUND: Schizophrenia (SCZ) is a highly heritable mental disorder with a substantial disease burden. Machine learning (ML) method can be used to identify individuals with SCZ on the basis of blood gene expression data with high accuracy. METHODS: This study aimed to differentiate patients with SCZ from healthy individuals by using the messenger RNA expression level in peripheral blood of 48 patients with SCZ and 50 controls via ML algorithms, namely, artificial neural networks, extreme gradient boosting, support vector machine (SVM), decision tree, and random forest. The expression of six mRNAs was detected using quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: The relative expression levels of GNAI1 (P < 0.001), PRKCA (P < 0.001), and PRKCB (P = 0.021) increased in the SCZ group, whereas those of FYN (P < 0.001), LYN (P = 0.022), and YWHAZ (P < 0.001) decreased in the SCZ group. We generated models with various combinations of genes based on five ML algorithms. The SVM model with six factors (GNAI1, FYN, PRKCA, YWHAZ, PRKCB, and LYN genes) was the best model for distinguishing patients with SCZ from healthy individuals (AUC = 0.993, sensitivity = 1.000, specificity = 0.895, and Youden index = 0.895). CONCLUSIONS: This study suggested that the combination of genes using the ML method is better than the use of a single gene to discriminate patients with SCZ from healthy individuals. The combination of GNAI1, FYN, PRKCA, YWHAZ, PRKCB, and LYN under the SVM model can be used as a diagnostic biomarker for SCZ.

19.
Neuroreport ; 32(2): 125-134, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33323836

RESUMO

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can damage dopaminergic neurons in the substantia nigra in many mammals with biochemical and cellular changes that are relatively similar to those observed in Parkinson's disease. Our study examined whether MPTP-treated echolocation bats can cause changes in bat echolocation system. By considering ultrasound spectrums, auditory brainstem-evoked potentials and flight trajectories of normal bats, we observed that the vocal, auditory, orientation and movement functions of MPTP-treated bats were significantly impaired, and they exhibited various symptoms resembling those in patients with Parkinson's disease. Our immunohistochemistry and western blot analyses further indicated that expression of vocal-related FOXP2 in the superior colliculus, auditory-related otoferlin in the inferior colliculus, dopamine synthesis-related aromatic l-amino acid decarboxylase in the substantia nigra and dopamine receptor in the striatum was significantly decreased. Furthermore, protein expression related to inflammation, oxidative stress and apoptosis in the substantia nigra was significantly increased in MPTP-treated bats. These results indicate that inflammation, oxidative stress and apoptosis may be instrumental in dopaminergic neurodegeneration in the substantia nigra. The vocal, auditory and orientation and movement dysfunctions of MPTP-treated bats are relatively consistent with symptoms of Parkinson's disease.

20.
Stem Cell Res ; 49: 102099, 2020 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-33296812

RESUMO

SIPA1, a GTPase activating protein that negatively regulates Ras-related protein (Rap), is a potential modulator of tumor metastasis and recurrence. In this study, we first showed that SIPA1 facilitated the stemness features of breast cancer cells, such as of tumorsphere formation capability and the expression of stemness marker CD44. In addition, SIPA1 promoted the expression of four stemness-associated transcription factors through increasing the expression of SMAD2 and SMAD3 in vitro and in vivo. The stemness features were abolished by blocking the phosphorylation of SMAD3 with its specific inhibitor SIS3. Furthermore, SIPA1 decreased the breast cancer cell sensitivity to chemotherapy drugs. This effect was, however, competitively reversed by blocking the SMAD3 phosphorylation by SIS3 treatment in breast cancer cells. Taken together, SIPA1 promotes and sustains the stemness of breast cancer cells and their resistance to chemotherapy by increasing the expression of SMAD2 and SMAD3, and blocking SMAD3 phosphorylation could suppress the cancer cell stemness and increase the sensitivity to chemotherapy in breast cancer cells expressing a high level of SIPA1.

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