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1.
BMC Infect Dis ; 20(1): 542, 2020 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-32711473

RESUMO

BACKGROUND: To evaluate whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) can be used as an early predictor of ventilator-associated pneumonia (VAP). METHODS: Ventilated neonatal patients admitted into the neonatology department between January 2017 and January 2018 were divided into VAP (n = 30) and non-VAP (n = 30) groups. Serum sTREM, procalcitonin (PCT), C-reactive protein and interleukin-6 levels were measured at 0, 24, 72, and 120 h after initiation of mechanical ventilation (MV). Correlations between blood biomarker concentrations and VAP occurrence were analyzed. Predictive factors for VAP were identified by logistic regression analysis and Hosmer-Lemeshow test, and the predictive value of sTREM-1 and biomarker combinations for VAP was determined by receiver operating characteristic curve analysis. RESULTS: The serum sTREM-1 concentration was significantly higher in the VAP group than in the non-VAP group after 72 and 120 h of MV (72 h: 289.5 (179.6-427.0) vs 202.9 (154.8-279.6) pg/ml, P < 0.001; 120 h: 183.9 (119.8-232.1) vs 141.3 (99.8-179.1) pg/ml, P = 0.042). The area under the curve (AUC) for sTREM-1 at 72 h was 0.902 with a sensitivity of 90% and specificity of 77% for the optimal cut-off value of 165.05 pg/ml. Addition of PCT to sTERM-1 at 72 h further improved the predictive value, with this combination having an AUC of 0.971 (95% confidence interval: 0.938-1.000), sensitivity of 0.96, specificity of 0.88, and Youden index of 0.84. CONCLUSION: sTREM-1 is a reliable predictor of VAP in neonates, and combined measurement of serum levels of sTREM-1 and PCT after 72 h of MV provided the most accurate prediction of VAP in neonatal patients.

2.
Mol Med Rep ; 22(2): 1440-1448, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32627010

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the main causes of death and nervous system damage in neonates. The aim of the present study was to investigate the effect of the Toll­like receptor 4 (TLR4) antagonist TAK­242 on HIE. The Rice­Vannucci method was used for ligation of the left common carotid artery, followed by hypoxic treatment for 2.5 h to establish a neonatal HIE rat model. Rats were intraperitoneally injected with 7.5 ml/kg TAK­242 after hypoxia­ischemia. It was demonstrated that TAK­242 significantly reduced the infarct volume and cerebral edema content of neonatal rats after HIE, alleviating neuronal damage and neurobehavioral function deficits. Furthermore, TAK­242 decreased the protein expression levels of TLR4, MyD88, TIR­domain­containing adapter­inducing interferon­ß (TRIF), NF­κB, tumor necrosis factor α (TNF­α) and interleukin­1ß in the hippocampus. The present results suggested that TAK­242 may exert a neuroprotective effect after HIE by inhibiting the TLR4/MyD88/TRIF/NF­κB signaling pathway, and reducing the release of downstream inflammatory cytokines.

3.
Artigo em Inglês | MEDLINE | ID: mdl-32666578

RESUMO

Rapid synthesis of marine ladder polyethers from polyepoxide precursors (in analogy with the biosynthetic pathway hypothesized by Nakanishi) is hampered by the fact that the exo -selective epoxide-opening cyclization cascade that gives THF-type polyethers is preferred over the endo -selective cascade that gives the desired products. We found that perfluoro- tert -butanol (PFTB) cooperates with 1-ethyl-3-methylimidazolium tetrafluoroborate ([EMIM]BF 4 ) can promote endo -selective epoxide-opening cyclization reactions of trisubstituted epoxy alcohols. Starting from readily accessible homochiral polyepoxy alcohols with a methyl group at all the endo -cyclization sites, we were able to construct polyethers up to five consecutive fused 6-, 7-, and/or 8-membered rings in one step. Notably, molecules with the 7/7/6/6 and 7/7/6/7/6 polyether frameworks of hemibrevetoxin B and brevenal, respectively, could be synthesized in 40% and 17% chemical yields.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32485859

RESUMO

The COVID-19 pandemic might lead to more mental health problems. However, few studies have examined sleep problems, depression, and posttraumatic symptoms among the general adult population during the COVID-19 outbreak, and little is known about coping behaviors. This survey was conducted online in China from February 1st to February 10th, 2020. Quota sampling was used to recruit 2993 Chinese citizens aged ≥18 years old. Mental health problems were assessed with the Post-Traumatic Stress Disorders (PTSD) Checklist for the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), the Center for Epidemiological Studies Depression inventory, and the Pittsburgh Sleep Quality Index. Exposure to COVID-19 was measured with questions about residence at outbreak, personal exposure, media exposure, and impact on livelihood. General coping style was measured by the brief Coping Style Questionnaire (SCSQ). Respondents were also asked 12 additional questions about COVID-19 specific coping behaviors. Direct exposure to COVID-19 instead of the specific location of (temporary) residence within or outside the epicenter (Wuhan) of the pandemic seems important (standardized beta: 0.05, 95% confidence interval (CI): 0.02-0.09). Less mental health problems were also associated with less intense exposure through the media (standardized beta: -0.07, 95% CI: -0.10--0.03). Perceived negative impact of the pandemic on livelihood showed a large effect size in predicting mental health problems (standardized beta: 0.15, 95% CI: 0.10-0.19). More use of cognitive and prosocial coping behaviors were associated with less mental health problems (standardized beta: -0.30, 95% CI: -0.34--0.27). Our study suggests that the mental health consequences of the lockdown impact on livelihood should not be underestimated. Building on cognitive coping behaviors reappraisal or cognitive behavioral treatments may be most promising.


Assuntos
Adaptação Psicológica , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Pneumonia Viral/epidemiologia , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático , China/epidemiologia , Depressão/epidemiologia , Surtos de Doenças , Feminino , Humanos , Funções Verossimilhança , Masculino , Saúde Mental , Pessoa de Meia-Idade , Pandemias , Transtornos do Sono-Vigília/epidemiologia , Transtornos de Estresse Pós-Traumáticos , Inquéritos e Questionários , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-32572674

RESUMO

PURPOSE: Changes in DNA methylation modifications have been associated with male infertility. With the development of assisted reproductive technologies (ARTs), abnormal DNA methylation in sperm, especially in imprinted genes, may impact the health of offspring and requires an in-depth study. METHODS: In this study, we collected abnormal human semen samples, including asthenospermic, oligospermic, oligoasthenospermic and deformed sperm, and investigated the methylation of imprinted genes by reduced representation bisulfite sequencing (RRBS) and bisulfite amplicon sequencing on the Illumina platform. RESULTS: The differentially methylated regions (DMRs) of imprinted genes, including H19, GNAS, MEG8 and SNRPN, were different in the abnormal semen groups. MEG8 DMR methylation in the asthenospermic group was significantly increased. Furthermore, higher methylation levels of MEG8, GNAS and SNRPN DMR in the oligospermic and oligoasthenospermic groups and a decrease in the H19 DMR methylation level in the oligospermic group were observed. However, the methylation levels of these regions varied greatly among the different semen samples and among individual sperm within the same semen sample. The SNP rs2525883 genotype in the H19 DMR affected DNA methylation. Moreover, DNA methylation levels differed in the abnormal semen groups in the non-imprinted genomic regions, including repetitive sequence DNA transposons and long/short interspersed nuclear elements (LINEs and SINEs). CONCLUSION: Our study established that imprinted gene DMRs, such as H19, GNAS, SNRPN and MEG8, were differentially methylated in the abnormal semen groups with obvious inter- and intra-sample heterogeneities. These results suggest that special attention needs to be paid to possible epigenetic risks during reproduction.

6.
Ying Yong Sheng Tai Xue Bao ; 31(4): 1267-1277, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32530202

RESUMO

Habitat quality is an important index to evaluate regional ecological security. Revealing its spatial and temporal responses to urbanization is conducive to the in-depth implementation of new urbanization. Based on land use data, we analyzed the spatio-temporal characteristics of Changchun's landscape pattern, habitat quality and its sample zone from the grid scale with comprehensive utilization of spatial analysis and ecological model analysis. We further discussed the responses of habitat quality during urbanization. The results showed that the low values of patch density (PD), edge density (ED) and Shannon diversity index (SHDI) were distributed in the western plains, while the high aggregation index (AI) showed a patchy distribution in eastern and southern of the city. During 2000-2015, the habitat quality of Changchun showed a trend of degradation and significant spatial heterogeneity, showing a distribution of "high in the east, and low in the west". The expansion of construction land and the transportation infrastructure played a leading role in the degradation of regional habitat quality. The changes of habitat quality differed significantly in different zones. The overall variation of water belt was relatively small, while the variation frequency and amplitude of mountain, urban expansion, and traffic belt were relatively high. Natural factors including slope and elevation basically shaped the overall distribution pattern of habitat quality in Changchun, while urbanization factors including population density, GDP and night light index showed significant negative correlation with habitat quality. To alleviate the ecological pressure of urbanization and promote habitat quality, we proposed differentiated development strategies, such as preventing deforestation in the Dahei Mountains, using ecological strategies to restore habitat degradation areas, improving land use efficiency in built-up urban areas, promoting "smart growth" in urban areas, setting red line of farmland in hilly areas, and strengthening ecological infrastructure construction.


Assuntos
Ecossistema , Urbanização , China , Cidades , Conservação dos Recursos Naturais
7.
J Exp Med ; 217(8)2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32453420

RESUMO

CDC-like kinase 3 (CLK3) is a dual specificity kinase that functions on substrates containing serine/threonine and tyrosine. But its role in human cancer remains unknown. Herein, we demonstrated that CLK3 was significantly up-regulated in cholangiocarcinoma (CCA) and identified a recurrent Q607R somatic substitution that represented a gain-of-function mutation in the CLK3 kinase domain. Gene ontology term enrichment suggested that high CLK3 expression in CCA patients mainly was associated with nucleotide metabolism reprogramming, which was further confirmed by comparing metabolic profiling of CCA cells. CLK3 directly phosphorylated USP13 at Y708, which promoted its binding to c-Myc, thereby preventing Fbxl14-mediated c-Myc ubiquitination and activating the transcription of purine metabolic genes. Notably, the CCA-associated CLK3-Q607R mutant induced USP13-Y708 phosphorylation and enhanced the activity of c-Myc. In turn, c-Myc transcriptionally up-regulated CLK3. Finally, we identified tacrine hydrochloride as a potential drug to inhibit aberrant CLK3-induced CCA. These findings demonstrate that CLK3 plays a crucial role in CCA purine metabolism, suggesting a potential therapeutic utility.

8.
Ital J Pediatr ; 46(1): 67, 2020 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-32448169

RESUMO

BACKGROUND: A prompt diagnosis of HIE remains a challenge clinically. This study aimed to identify potential biomarkers of neonatal hypoxic-ischemic encephalopathy (HIE) via a novel proteomic approach, the isobaric tags for absolute and relative quantification (iTRAQ) method. METHODS: Blood samples were collected from neonates with mild (n = 4), moderate (n = 4), or severe (n = 4) HIE who were admitted to the neonatal intensive care unit of Children's Hospital of Soochow University between Oct 2015 and Oct 2017. iTRAQ was performed in HIE patients and healthy controls (n = 4). Bioinformatics analyses including Gene Ontology and KEGG pathway enrichment analysis were performed to evaluate the potential features and capabilities of the identified differentially expressed proteins. RESULTS: A total of 51 commonly differentially expressed proteins were identified among the comparisons between mild, moderate, and severe HIE as well as healthy controls. Haptoglobin (HP) and S100A8 were most significantly up-regulated in patients with HIE and further validated via real-time PCR and western blotting. The differentially expressed proteins represented multiple biological processes, cellular components and molecular functions and were markedly enriched in complement and coagulation cascades. CONCLUSIONS: HP and S100A8 may serve as a potential biomarker for neonatal HIE and reflects the severity of HIE. The complement and coagulation cascades play crucial roles in the development of neonatal HIE.

9.
Exp Lung Res ; 46(7): 226-233, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32410473

RESUMO

Introduction: GPRC5a plays an important role in many types of cancers with intriguing dual functions. GPRC5a acts as oncogene or tumor suppressor in different types of cancer. It is interesting to illustrate why GPRC5a functions differently.Methods: Data mining method were used to analyze the potential prognostic value of GPRC5a expression for Non-Small Cell Lung Cancer (NSCLC) lung cancer patients. Then we used cell models to further investigate the effect of p53 mutation on GPRC5a expression and the thereafter cell biological behaviors.Results: Our results present here showed High mRNA-level expression of GPRC5a was associated with worse overall survival about lung cancer patients; mutation of p53 gene could result in up regulation of GPRC5a expression and promotion of cell proliferation in lung cancer cells. Our results not only demonstrate the role of GPRC5a as a tumor suppressor in lung cancer, but also revealed the tumor suppressive factor p53 regulated tightly on GPRC5a and cell growth of NSCLC cancer.Conclusions: Our results demonstrated that p53 upregulated GPRC5a expression in NSCLC cells, and the loss of p53 expression in NSCLC may be one of the mechanisms leading to the decreased GPRC5a expression in NSCLC.

10.
J Affect Disord ; 274: 85-92, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469837

RESUMO

BACKGROUND: The specific impacts of attitudes toward aging on depressive symptoms have not been widely reported in previous studies in China. OBJECTIVES: The aim is to examine the associations between attitudes toward aging, perceived social support, and depressive symptoms among older adults stratified by rural and urban dwelling. METHODS: This study used a cross-sectional data including 7209 participants, among which 64.6% were urban adults and 35.4% were rural adults. Several multiple liner regression models were used to analysis the data. Three social support types were analyzed as moderators of the relationship between the attitudes toward aging and depressive symptoms. RESULTS: Positive attitudes toward aging (ß=-0.139, P<0.001), negative attitudes toward aging (ß=0.284, P<0.001) were significantly associated with lower depressive symptoms among older Chinese adults. Support from family (ß=-0.087, P<0.001), friends (ß=-0.047, P<0.01) and the government (ß=-0.035, P<0.01) were all significantly associated with urban older adults' levels of depressive symptoms. Only family support (ß=-0.109, P<0.001) was associated with lower depressive symptoms among rural older adults'. In addition, family support buffered the effect of negative attitudes toward aging on depressive symptoms for all the older adults, while the moderation effects of support from friends and government only worked for urban elderly. LIMITATIONS: A cross-sectional design is limited to establish causal associations. CONCLUSIONS: Addressing depression among older adults should focus on improving attitudes toward aging and expanding the availability of social support. Moreover, deeper reforms are needed to address inequalities between urban and rural areas in China.

11.
EMBO Rep ; 21(7): e48035, 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32410369

RESUMO

Negative regulation of immunoreceptor signaling is required for preventing hyperimmune activation and maintaining immune homeostasis. The roles of p38IP in immunoreceptor signaling remain unclear. Here, we show that p38IP suppresses T-cell receptor (TCR)/LPS-activated NF-κB and p38 by targeting TAK1 kinase and that p38IP protein levels are downregulated in human PBMCs from rheumatoid arthritis (RA) patients, inversely correlating with the enhanced activity of NF-κB and p38. Mechanistically, p38IP interacts with TAK1 to disassemble the TAK1-TAB (TAK1-binding protein) complex. p38IP overexpression decreases TCR-induced binding of K63-linked polyubiquitin (polyUb) chains to TAK1 but increases that to TAB2, and p38IP knockdown shows the opposite effects, indicating unanchored K63-linked polyUb chain transfer from TAB2 to TAK1. p38IP dynamically interacts with TAK1 upon stimulation, because of the polyUb chain transfer and the higher binding affinity of TAK1 and p38IP for polyUb-bound TAB2 and TAK1, respectively. Moreover, p38IP scaffolds the deubiquitinase USP4 to deubiquitinate TAK1 once TAK1 is activated. These findings reveal a novel role and the mechanisms of p38IP in controlling TCR/LPS signaling and suggest that p38IP might participate in RA pathogenesis.

12.
Biochem Biophys Res Commun ; 528(1): 1-6, 2020 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-32448507

RESUMO

A common, yet often neglectable, feature of neonatal hypoxic-ischemic brain damage (HIBD) is circadian rhythm disorders resulted from pineal gland dysfunction. Our previous work demonstrated that miRNAs play an important role in regulating key circadian genes in the pineal gland post HIBD [5,21]. In current study, we sought out to extend our investigation by profiling expression changes of pineal long non-coding RNAs (lncRNAs) upon neonatal HIBD using RNA-Seq. After validating lncRNA changes, we showed that one lncRNA: TCONS_00044595 is highly enriched in the pineal gland and exhibits a circadian expression pattern. Next, we performed bioinformatic analysis to predict the lncRNA-miRNA regulatory network and identified 168 miRNAs that potentially targetlncRNA TCONS_00044595. We further validated the bona fide interaction between one candidate miRNA: miR-182, a known factor to regulate pineal Clock expression, and lncRNA TCONS_00044595. Finally, we showed that suppression of lncRNA TCONS_00044595 alleviated the CLOCK activation both in the cultured pinealocytes under OGD conditions and in the pineal gland post HIBD in vivo. Our study thus shed light into novel mechanisms of pathophysiology of pineal dysfunction post neonatal HIBD.

13.
BMC Pediatr ; 20(1): 261, 2020 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-32471377

RESUMO

BACKGROUND: This study aimed to describe the causative organisms of neonatal late-onset sepsis (LOS) and their antimicrobial resistance in Suzhou, Southeast China over a 7-year period. METHODS: We performed a retrospective study on neonates with LOS from Jan1, 2011 to Dec 31, 2017. The demographic, clinical, and laboratory data of neonates with LOS were analyzed. Logistic regression was used to investigate the risk factors with mortality. RESULTS: During the study period, 202 neonates with LOS were finally identified. The most common pathogens were Escherichia coli (29.2%), followed by Klebsiella pneumoniae (19.3%), and Coagulase-negative Staphylococcus (CoNS) (16.8%). Nearly 90% of the K. pneumoniae were resistant to cefazolin and 71.8% to ceftazidime. Thirty-four patients (16.8%) died. Multivariable logistic regression showed that significant predictors of mortality were birth weight < 1500 g, respiratory distress and convulsions. CONCLUSIONS: Gram-negative organisms have an important role in LOS in our region, with high levels of resistance to third-generation cephalosporins. These data may help in the selection of antibiotics for empirical treatment of neonates with sepsis.

14.
J Vis Exp ; (157)2020 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-32225145

RESUMO

Pneumothorax (PTX) represents accumulation of the air in the pleural space. A large or tension pneumothorax can collapse the lung and cause hemodynamic compromise, a life-threatening disorder. Traditionally, neonatal pneumothorax diagnosis has been based on clinical images, auscultation, transillumination, and chest X-ray findings. This approach may potentially lead to a delay in both diagnosis and treatment. The use of lung US in diagnosis of PTX together with US-guided thoracentesis results in earlier and more precise management. The recommendations presented in this publication are aimed at improving the application of lung US in guiding neonatal PTX diagnosis and management.

15.
Int J Radiat Oncol Biol Phys ; 107(4): 779-792, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32259569

RESUMO

PURPOSE: Acquired hematopoietic failure is commonly caused by therapeutic and accidental exposure of the bone marrow (BM) to toxic agents. Efficient recovery from BM failure is dictated not only by the intrinsic sensitivity and proliferation capacity of the hematopoietic stem and progenitor cells but also by the BM environment niche. Identification of genetic factors that improve recovery from hematopoietic failure is essential. Vertebrate SETD4 is a poorly characterized and putatively nonhistone methyltransferase. This study aims to identify the roles of SETD4 in BM recovery. METHODS AND MATERIALS: An inducible SETD4 knockout mouse model (Setd4flox/flox;Rosa26-CreERT2+) was used. Adult sex-matched littermates were treated with tamoxifen to induce Setd4 deletion or oil as the control. Tamoxifen-treated Setd4wt/wt;Rosa26-CreERT2+ mice were included as another control. Those mice were irradiated to induce hematopoietic syndrome and analyzed to identify the roles and mechanisms of Setd4 in of BM recovery. RESULTS: Loss of Setd4 in adult mice improved the survival of whole-body irradiation-induced BM failure. This was associated with improved recoveries of long-term and short-term hematopoietic stem cells (HSCs) and early progenitor cells. BM transplantation analyses surprisingly showed that the improved recovery was not due to radiation resistance of the Setd4-deficient HSCs but that Setd4-deficient HSCs were actually more sensitive to radiation. However, the Setd4-deficient mice were better recipients for allogeneic HSC transplantation. Furthermore, there was enhanced splenic erythropoiesis in Setd4-deficient mice. CONCLUSION: These findings not only revealed a previously unrecognized role of Setd4 as a unique modulator of hematopoiesis but also underscored the critical role of the BM niche in recovery from hematopoietic failure. Our study also implicated Setd4 as a potential target for therapeutic inhibition to improve the conditioning of the BM niche before allogeneic transplantation.

16.
Am J Pathol ; 190(6): 1175-1187, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32201259

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and nonalcoholic fatty liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin-dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histologic features of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intracellular distribution of high-mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC and offers a novel mouse model for future investigations of nonviral or nonalcoholic causes of HCC development.


Assuntos
Proteína BRCA2/genética , Carcinoma Hepatocelular/genética , Proteínas de Ciclo Celular/genética , Neoplasias Hepáticas/genética , Linfoma de Células B/genética , Animais , Proteína BRCA2/metabolismo , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Proteínas de Ciclo Celular/metabolismo , Heterozigoto , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linfoma de Células B/metabolismo , Linfoma de Células B/patologia , Camundongos , Camundongos Knockout , Mosaicismo
17.
Autophagy ; : 1-20, 2020 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-32186433

RESUMO

Although the treatment of brain tumors by targeting kinase-regulated macroautophagy/autophagy, is under investigation, the precise mechanism underlying autophagy initiation and its significance in glioblastoma (GBM) remains to be defined. Here, we report that PAK1 (p21 [RAC1] activated kinase 1) is significantly upregulated and promotes GBM development. The Cancer Genome Atlas analysis suggests that the oncogenic role of PAK1 in GBM is mainly associated with autophagy. Subsequent experiments demonstrate that PAK1 indeed serves as a positive modulator for hypoxia-induced autophagy in GBM. Mechanistically, hypoxia induces ELP3-mediated PAK1 acetylation at K420, which suppresses the dimerization of PAK1 and enhances its activity, thereby leading to subsequent PAK1-mediated ATG5 (autophagy related 5) phosphorylation at the T101 residue. This event not only protects ATG5 from ubiquitination-dependent degradation but also increases the affinity between the ATG12-ATG5 complex and ATG16L1 (autophagy related 16 like 1). Consequently, ELP3-dependent PAK1 (K420) acetylation and PAK1-mediated ATG5 (T101) phosphorylation are required for hypoxia-induced autophagy and brain tumorigenesis by promoting autophagosome formation. Silencing PAK1 with shRNA or small molecule inhibitor FRAX597 potentially blocks autophagy and GBM growth. Furthermore, SIRT1-mediated PAK1-deacetylation at K420 hinders autophagy and GBM growth. Clinically, the levels of PAK1 (K420) acetylation significantly correlate with the expression of ATG5 (T101) phosphorylation in GBM patients. Together, this report uncovers that the acetylation modification and kinase activity of PAK1 plays an instrumental role in hypoxia-induced autophagy initiation and maintaining GBM growth. Therefore, PAK1 and its regulator in the autophagy pathway might represent potential therapeutic targets for GBM treatment.Abbreviations: 3-MA: 3-methyladenine; Ac-CoA: acetyl coenzyme A; ATG5: autophagy related 5; ATG16L1, autophagy related 16 like 1; BafA1: bafilomycin A1; CDC42: cell division cycle 42; CGGA: Chinese Glioma Genome Atlas; CHX, cycloheximide; ELP3: elongator acetyltransferase complex subunit 3; GBM, glioblastoma; HBSS: Hanks balanced salts solution; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MAP2K1: mitogen-activated protein kinase kinase 1; MAPK14, mitogen-activated protein kinase 14; PAK1: p21 (RAC1) activated kinase 1; PDK1: pyruvate dehydrogenase kinase 1; PGK1, phosphoglycerate kinase 1; PTMs: post-translational modifications; RAC1: Rac family small GTPase 1; SQSTM1: sequestosome 1; TCGA, The Cancer Genome Atlas.

18.
Theranostics ; 10(3): 1046-1059, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31938050

RESUMO

Resistance to the chemotherapeutic drug 5'-azacytidine (5'-AZA) is a major obstacle in the treatment of patients with acute myeloid leukemia (AML). The uridine-cytidine kinase 1 (UCK1) has an established role in activating 5'-AZA and its protein level is significantly downregulated in patients resistant to the drug. However, the underlying molecular mechanism for the reduced UCK1 expression remains to be elucidated. Methods: Using mass spectrometry and molecular biochemistry analyses, we identified specific enzymes mediating UCK1 degradation. Human AML cell lines and murine AML model were used to characterize the effects of these enzymes on 5'-AZA resistance. Results: We demonstrated that the ubiquitin E3 ligase KLHL2 interacted with UCK1 and mediated its polyubiquitination at the K81 residue and degradation. We showed that deubiquitinase USP28 antagonized KLHL2-mediated polyubiquitylation of UCK1. We also provided evidence that ATM-mediated phosphorylation of USP28 resulted in its disassociation from KLHL2 and UCK1 destabilization. Conversely, UCK1 phosphorylation by 5'-AZA-activated ATM enhanced the KLHL2-UCK1 complex formation. Importantly, silencing KLHL2 or USP28 overexpression not only inhibited AML cell proliferation but also sensitized AML cells to 5'-AZA-induced apoptosis in vitro and in vivo. These results were no longer observed in USP28-deficient cells. Conclusions: Our study revealed a novel mechanism by which the KLHL2/USP28/ATM axis mediates resistance of AML cells to 5'-AZA by regulating UCK1 ubiquitination and phosphorylation. These results have direct clinical implications and provide a rationale for the combination drug treatment of AML patients.

19.
EMBO J ; 39(5): e102541, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31975428

RESUMO

UHMK1 is a nuclear serine/threonine kinase recently implicated in carcinogenesis. However, the functions and action mechanisms of UHMK1 in the pathogenesis of human gastric cancer (GC) are unclear. Here, we observed that UHMK1 was markedly upregulated in GC. UHMK1 silencing strongly inhibited GC aggressiveness. Interestingly, UHMK1-induced GC progression was mediated primarily via enhancing de novo purine synthesis because inhibiting purine synthesis reversed the effects of UHMK1 overexpression. Mechanistically, UHMK1 activated ATF4, an important transcription factor in nucleotide synthesis, by phosphorylating NCOA3 at Ser (S) 1062 and Thr (T) 1067. This event significantly enhanced the binding of NCOA3 to ATF4 and the expression of purine metabolism-associated target genes. Conversely, deficient phosphorylation of NCOA3 at S1062/T1067 significantly abrogated the function of UHMK1 in GC development. Clinically, Helicobacter pylori and GC-associated UHMK1 mutation induced NCOA3-S1062/T1067 phosphorylation and enhanced the activity of ATF4 and UHMK1. Importantly, the level of UHMK1 was significantly correlated with the level of phospho-NCOA3 (S1062/T1067) in human GC specimens. Collectively, these results show that the UHMK1-activated de novo purine synthesis pathway significantly promotes GC development.

20.
Biochem Biophys Res Commun ; 521(4): 933-938, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31718799

RESUMO

Neonatal hypoxic-ischemic encephalopathy (HIE) often leads to neonatal death or severe, irreversible neurological deficits. Pathologically, the occurrence of massive cell death and subsequent inflammation suggested that pyroptosis, an inflammation associated programed cell death, might play a role in HIE. Here, by measuring changes of key molecules in pyroptosis pathway in HIE patients, we discovered that their elevation levels tightly correlate with the severity of HIE. Next, we demonstrated that application of MCC950, a small molecule to inhibit NLRP3 inflammasome and thus pyroptosis, substantially alleviated pyroptosis and the injury severity in rats with neonatal hypoxic-ischemic brain damage (HIBD). Mechanistically, we showed that NLRP-3/caspase-1/GSDMD axis is required for microglia pyroptosis and activation. Our data demonstrated that microglia mediated pyroptosis played a crucial role in neonatal HIE, which shed lights into the development of intervention avenues targeting pyroptosis to treat HIE and traumatic brain injuries.

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