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1.
FASEB J ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31944405

RESUMO

Mangrove-derived actinobacteria strains are well-known for producing novel secondary metabolites. The polycyclic tetramate macrolactam (PTM), ikarugamycin (IKA) isolated from Streptomyces xiamenensis 318, exhibits antiproliferative activities against pancreatic ductal adenocarcinoma (PDAC) in vitro. However, the protein target for bioactive IKA is unclear. In this study, whole transcriptome-based profiling revealed that the glycolysis pathway is significantly affected by IKA. Metabolomic studies demonstrated that IKA treatment induces a significant drop in glucose-6-phosphate and a slight increase in intracellular glucose level. Analysis of glucose consumption, lactate production, and the extracellular acidification rate confirmed the inhibitory role of IKA on the glycolytic flux in PDAC cells. Surface plasmon resonance (SPR) experiments and docking studies identified the key enzyme of glycolysis, hexokinase 2 (HK2), as a molecular target of IKA. Moreover, IKA reduced tumor size without overt cytotoxicity in mice with PDAC xenografts and increased chemotherapy response to gemcitabine in PDAC cells in vitro. Taken together, IKA can block glycolysis in pancreatic cancer by targeting HK2, which may be a potential drug candidate for PDAC treatment.

2.
Ann Transl Med ; 7(20): 534, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807516

RESUMO

Background: The aim of the study was to evaluate whether the preemptive renal replacement therapy (RRT) might improve outcomes in post-cardiotomy cardiogenic shock (PCCS) patients. Methods: In Period A (September 2014-April 2016), patients with PCCS received RRT, depending on conventional indications or bedside attendings. In Period B (May 2016-November 2017), the preemptive RRT strategy was implemented in all PCCS patients in our intensive care unit. The goal-directed RRT was applied for the RRT patients. The hospital mortality and renal recovery were compared between the two periods. Results: A total of 155 patients (76 patients in Period A and 79 patients in Period B) were ultimately enrolled in this study. There were no significant differences in demographic characteristics and intraoperative and postoperative parameters between the two groups. The duration between surgery and RRT initiation was significantly shorter in Period B than in Period A [23 (17, 66) vs. 47 (20, 127) h, P<0.01]. The hospital mortality in Period B was significantly lower than that in Period A (38.0% vs. 59.2%, P<0.01). There were fewer patients with no renal recovery in Period B (4.1% vs. 19.4%, P=0.026). Patients in Period B displayed a significantly shorter time to completely renal recovery (12±15 vs. 25±15 d, P<0.05). Conclusions: Among PCCS patients, preemptive RRT compared with conventional initiation of RRT reduced mortality in hospital and also led to faster and more frequent recovery of renal function. Our preliminary study supposed that preemptive initiation of RRT might be an effective approach to PCCS with acute kidney injury (AKI).

3.
Brain Res ; : 146553, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31734396

RESUMO

The mechanisms of secondary brain injury after traumatic brain injury (TBI) are complex and are the result of multiple factors. Protecting the blood-brain barrier (BBB) and ameliorating cerebral edema are two key factors for improving the prognosis of TBI patients. The BBB is regulated by the hedgehog pathway through Scube2 and Shh protein. Matrix metalloproteinase-9 (MMP-9) influences the transport system and enzyme system of vascular endothelial cells, possibly via the hedgehog pathway. The present study aimed to investigate the role and mechanism of MMP-9 in TBI via the hedgehog pathway. Eighty male Sprague-Dawley rats were used to establish a murine model of TBI. Subsequently, the effect of SB-3CT-a specific inhibitor of MMP-9-was assessed via Western blotting, real-time PCR, immunofluorescence, apoptotic assays, and neurological scoring. The results showed that, compared with those of the sham-operation group, the mRNA and protein levels of MMP-9 were significantly increased after TBI, while the expressions of Scube2 and Shh were decreased. Application of SB-3CT at 24 h after TBI significantly reduced neuronal apoptosis and BBB permeability, while increasing expressions of Scube2 and Shh. In conclusion, these findings demonstrate an influence of TBI-induced MMP-9 upregulation in the induction of post-traumatic nerve and BBB injury, which may be partially mediated by Scube2 and Shh via the hedgehog pathway.

4.
Cell Death Differ ; 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31685978

RESUMO

Cancer cells reprogram their energy metabolic system from the mitochondrial oxidative phosphorylation (OXPHOS) pathway to a glucose-dependent aerobic glycolysis pathway. This metabolic reprogramming phenomenon is known as the Warburg effect, a significant hallmark of cancer. However, the detailed mechanisms underlying this event or triggering this reprogramming remain largely unclear. Here, we found that histone H2B monoubiquitination (H2Bub1) negatively regulates the Warburg effect and tumorigenesis in human lung cancer cells (H1299 and A549 cell lines) likely through controlling the expression of multiple mitochondrial respiratory genes, which are essential for OXPHOS. Moreover, our work also suggested that pyruvate kinase M2 (PKM2), the rate-limiting enzyme of glycolysis, can directly interact with H2B in vivo and in vitro and negatively regulate the level of H2Bub1. The inhibition of cell proliferation and nude mice xenograft of human lung cancer cells induced by PKM2 knockdown can be partially rescued through lowering H2Bub1 levels, which indicates that the oncogenic function of PKM2 is achieved, at least partially, through the control of H2Bub1. Furthermore, PKM2 and H2Bub1 levels are negatively correlated in cancer specimens. Therefore, these findings not only provide a novel mechanism triggering the Warburg effect that is mediated through an epigenetic pathway (H2Bub1) but also reveal a novel metabolic regulator (PKM2) for the epigenetic mark H2Bub1. Thus, the PKM2-H2Bub1 axis may become a promising cancer therapeutic target.

5.
Zhongguo Zhong Yao Za Zhi ; 44(13): 2799-2805, 2019 Jul.
Artigo em Chinês | MEDLINE | ID: mdl-31359693

RESUMO

To establish and validate the design space of the Digeda-4 flavored decoction( DGD-4D) extraction process by using the quality by design( Qb D) concept. With DGD-4D decoction pieces as a model drug,with the transfer rate of aesculin,picroside I,picroside Ⅱ,geniposide and the yield of extract as critical quality attributes( CQAs),the single factor experiment design was used to determine the level of each factor; the Plackett-Burman experiment design was used to select the critical process parameters( CPPs);and the Box-Behnken experiment design was used to optimize the extraction process. The design space of the DGD-4D extraction process was established,and finally,four experimental points were selected to verify the established model. The single factor experiment determined the levels of each factor,including soaking time 60 min and 30 min,water adding volume 12 times and 8 times,extraction time 90 min and 30 min,number of extraction times 3 times and 1 time,as well as extraction temperature 100 ℃ and 90 ℃.By Plackett-Burman experimental design,the DGD-4D water addition,extraction time and number of extraction times were determined to be CPPs. The Box-Behnken experimental variance analysis showed that P of the regression model was less than 0. 01 and the misstated value was more than 0. 01,indicating that the model had good predictive ability,and the operation space of CPPs in the DGD-4D extraction process was determined as follows: the amount of water addition was 10-12 times; extraction time 50-80 min; and number of extraction times was 3 times. The design space of DGD-4D extraction process based on the concept of Qb D is conducive to improving the stability of product quality and laying a foundation for the future development of DGD-4D.


Assuntos
Química Farmacêutica/métodos , Medicamentos de Ervas Chinesas/química , Projetos de Pesquisa
6.
J Exp Clin Cancer Res ; 38(1): 214, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118109

RESUMO

BACKGROUND: Gastric cancer is one of the deadliest malignant tumours, with a high incidence in China, and is regulated by aberrantly overexpressed oncogenes. However, existing therapies are insufficient to meet patients' needs; thus, the identification of additional therapeutic targets and exploration of the underlying mechanism are urgently needed. GPAA1 is the subunit of the GPI transamidase that transfers the GPI anchor to proteins within the ER. The functional impacts of increased expression levels of GPAA1 in human cancers are not well understood. METHODS: Data mining was performed to determine the pattern of GPAA1 expression and the reason for its overexpression in tumour and adjacent normal tissues. In vitro and in vivo experiments evaluating proliferation and metastasis were performed using cells with stable deletion or overexpression of GPAA1. A tissue microarray established by the Ren Ji Hospital was utilized to analyse the expression profile of GPAA1 and its correlation with prognosis. Western blotting, an in situ proximity ligation assay, and co-immunoprecipitation (co-IP) were performed to reveal the mechanism of GPAA1 in gastric cancer. RESULTS: GPAA1 was a markedly upregulated oncogene in gastric cancer due to chromosomal amplification. GPAA1 overexpression was confirmed in specimens from the Ren Ji cohort and was associated with ERBB2 expression, predicting unsatisfactory patient outcomes. Aberrantly upregulated GPAA1 dramatically contributed to cancer growth and metastasis in in vitro and in vivo studies. Mechanistically, GPAA1 enhanced the levels of metastasis-associated GPI-anchored proteins to increase tumour metastasis and intensified lipid raft formation, which consequently promoted the interaction between EGFR and ERBB2 as well as downstream pro-proliferative signalling. CONCLUSIONS: GPAA1 facilitates the expression of cancer-related GPI-anchored proteins and supplies a more robust platform-the lipid raft-to promote EGFR-ERBB2 dimerization, which further contributes to tumour growth and metastasis and to cancer progression. GPAA1 could be a promising diagnostic biomarker and therapeutic target for gastric cancer.

7.
Biochem Biophys Res Commun ; 514(3): 632-638, 2019 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-31076106

RESUMO

Acetyl-CoA synthetase 2 (ACSS2) generates acetyl-CoA from acetate is important for histone acetylation and gene expression. ACSS2 fulfills distinct functions depending on its cellular location in tumor cells. The role and cellular localization of ACSS2 in hepatocellular carcinoma (HCC) remains to be studied. Herein, we identified that the alternative transcription start site selection of ACSS2 was significantly different between HCC and corresponding adjacent tissues. Alternative transcription start site selection produced two different ACSS2 transcripts, ACSS2-S1 and ACSS2-S2. The two isoforms of ACSS2 had different subcellular localization and different functions. Overexpression of ACSS2-S2 promoted cell proliferation and invasion, but ACSS2-S1 did not. The ACSS2-S1 was mainly present in cytoplasm, and ACSS2-S2 was distributed in both nucleus and cytoplasm. Finally, we demonstrated that alternative transcription start site selection of ACSS2 correlates ribosome biogenesis in HCC. Our findings reveal an oncogenic role of ACSS2-S2 in HCC progression via increase of ribosome biogenesis, and suggest ACSS2-S2 might be a potential therapeutic target against the HCC.

8.
J Thorac Dis ; 11(2): 495-504, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30962993

RESUMO

Background: To evaluate the effect of inhaled nitric oxide (iNO) therapy on oxygenation and clinical outcomes in patients with refractory hypoxemia after surgical reconstruction for acute type A aortic dissection (TAAD). Methods: A before-and-after interventional study was conducted in patients with refractory hypoxemia after surgical reconstruction for TAAD. Postoperative refractory hypoxemia was defined as a persistent PaO2/FiO2 ratio ≤100 mmHg despite conventional therapy. From January to November 2016, conventional treatment was carried out for refractory hypoxemia. From December 2016 to October 2017, on the basis of conventional therapy, we explored the use of iNO to treat refractory hypoxemia. Results: Fifty-three TAAD patients with refractory hypoxemia were enrolled in this study. Twenty-seven patients received conventional treatment (conventional group), while the remaining 26 patients received iNO therapy. The PaO2/FiO2 ratio was significantly higher in the iNO group after treatment than in the conventional group when analyzed over the entire 72 hours. The duration of invasive mechanical ventilation was significantly reduced in the iNO group (69.19 vs. 104.56 hours; P=0.003). Other outcomes, such as mortality (3.85% vs. 7.41%, P=1.000), intensive care unit (ICU) duration (9.88 vs. 12.36 days, P=0.059) and hospital stay (16.88 vs. 20.76 days, P=0.060), were not significantly different between the two groups. Conclusions: iNO therapy might play an ameliorative role in patients with refractory hypoxemia after surgical reconstruction for TAAD. This therapy may lead to sustained improvement in oxygenation and reduce the duration of invasive mechanical ventilation.

9.
Cardiovasc Ultrasound ; 17(1): 5, 2019 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-30944001

RESUMO

BACKGROUND: Three-dimensional color flow Doppler (3DCF) is a new convenient technique for cardiac output (CO) measurement. However, to date, no one has evaluated the accuracy of 3DCF echocardiography for CO measurement after cardiac surgery. Therefore, this single-center, prospective study was designed to evaluate the reliability of three-dimensional color flow and two-dimensional pulse wave Doppler (2D-PWD) transthoracic echocardiography for estimating cardiac output after cardiac surgery. METHODS: Post-cardiac surgical patients with a good acoustic window and a low dose or no dose of vasoactive drugs (norepinephrine < 0.05 µg/kg/min) were enrolled for CO estimation. Three different methods (third generation FloTrac/Vigileo™ [FT/V] system as the reference method, 3DCF, and 2D-PWD) were used to estimate CO before and after interventions (baseline, after volume expansion, and after a dobutamine test). RESULTS: A total of 20 patients were enrolled in this study, and 59 pairs of CO measurements were collected (one pair was not included because of increasing drainage after the dobutamine test). Pearson's coefficients were 0.260 between the CO-FT/V and CO-PWD measurements and 0.729 between the CO-FT/V and CO-3DCF measurements. Bland-Altman analysis showed the bias between the absolute values of CO-FT/V and CO-PWD measurements was - 0.6 L/min with limits of agreement between - 3.3 L/min and 2.2 L/min, with a percentage error (PE) of 61.3%. The bias between CO-FT/V and CO-3DCF was - 0.14 L/min with limits of agreement between - 1.42 L /min and 1.14 L/min, with a PE of 29.9%. Four-quadrant plot analysis showed the concordance rate between ΔCO-PWD and ΔCO-3FT/V was 93.3%. CONCLUSIONS: In a comparison with the FT/V system, 3DCF transthoracic echocardiography could accurately estimate CO in post-cardiac surgical patients, and the two methods could be considered interchangeable. Although 2D-PWD echocardiography was not as accurate as the 3D technique, its ability to track directional changes was reliable.

10.
Gut ; 68(11): 1994-2006, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30826748

RESUMO

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death worldwide. Neurotransmitter-initiated signalling pathway is profoundly implicated in tumour initiation and progression. Here, we investigated whether dysregulated neurotransmitter receptors play a role during pancreatic tumourigenesis. METHODS: The Cancer Genome Atlas and Gene Expression Omnibus datasets were used to identify differentially expressed neurotransmitter receptors. The expression pattern of gamma-aminobutyric acid type A receptor pi subunit (GABRP) in human and mouse PDAC tissues and cells was studied by immunohistochemistry and western blot analysis. The in vivo implications of GABRP in PDAC were tested by subcutaneous xenograft model and lung metastasis model. Bioinformatics analysis, transwell experiment and orthotopic xenograft model were used to identify the in vitro and in vivo effects of GABRP on macrophages in PDAC. ELISA, co-immunoprecipitation, proximity ligation assay, electrophysiology, promoter luciferase activity and quantitative real-time PCR analyses were used to identify molecular mechanism. RESULTS: GABRP expression was remarkably increased in PDAC tissues and associated with poor prognosis, contributed to tumour growth and metastasis. GABRP was correlated with macrophage infiltration in PDAC and pharmacological deletion of macrophages largely abrogated the oncogenic functions of GABRP in PDAC. Mechanistically, GABRP interacted with KCNN4 to induce Ca2+ entry, which leads to activation of nuclear factor κB signalling and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression. CONCLUSIONS: Overexpressed GABRP exhibits an immunomodulatory role in PDAC in a neurotransmitter-independent manner. Targeting GABRP or its interaction partner KCNN4 may be an effective therapeutic strategy for PDAC.


Assuntos
Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Receptores de GABA-A/metabolismo , Ácido gama-Aminobutírico/metabolismo , Animais , Quimiocinas/metabolismo , Modelos Animais de Doenças , Humanos , Canais de Potássio Ativados por Cálcio de Condutância Intermediária/metabolismo , Macrófagos/fisiologia , Camundongos , Transdução de Sinais/fisiologia
11.
Sci Total Environ ; 653: 758-764, 2019 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-30759601

RESUMO

This study investigated the water resource potential for bioenergy production from sweet sorghum (Sorghum bicolor (L.)) in Northern China according to the distribution of water resources, climate conditions and the total water consumption of bioenergy based on sweet sorghum, which consisted of blue water, green water and grey water. At a case study site in Inner Mongolia, simulation with a plant phenological model was used to determine whether sweet sorghum could reach the harvestable stage for sugar juice production. The blue water in the agricultural phase was estimated according to the potential crop evapotranspiration (ETc), the drought sensitivity of sweet sorghum in different stages and the precipitation during the growing season. The results showed that the irrigation water was significantly different among the districts, ranging from 730 to 5500 m3/ha and 2060 to 6680 m3/ha for early-maturing and late-maturing varieties, respectively. To avoid the water pressure level to be exacerbated and the severe reallocation of water resources resulting in negative effects on other sectors, the maximal annual water withdrawal was set to not surpass the upper threshold of water stress level of 40%. That makes the maximum area for the production of sweet sorghum cannot exceed 1.95 × 104 ha, representing only 0.24% of the total marginal land area in Inner Mongolia. However, the economic benefits of bioenergy production from sweet sorghum would be negative due to the high labour input. Therefore, not only the availability of marginal land, the climate conditions and local water resources but also the improvement of mechanisation and agricultural production techniques should be considered to attain the sustainable development of bioenergy production and address global energy and environmental crises.


Assuntos
Irrigação Agrícola , Biocombustíveis/análise , Sorghum/crescimento & desenvolvimento , Recursos Hídricos/provisão & distribução , Biomassa , China
12.
Clin Cancer Res ; 25(4): 1318-1330, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30420446

RESUMO

PURPOSE: Extensive research has reported that the tumor microenvironment components play crucial roles in tumor progression. Thus, blocking the supports of tumor microenvironment is a promising approach to prevent cancer progression. We aimed to determine whether blocking extracellular ATP-P2RY2 axis could be a potential therapeutic approach for PDAC treatment. EXPERIMENTAL DESIGN: Expression of P2RY2 was determined in 264 human PDAC samples and correlated to patient survival. P2RY2 was inhibited in human PDAC cell lines by antagonist and shRNA, respectively, and cell viability, clonogenicity, and glycolysis were determined. RNA sequencing of PDAC cell line was applied to reveal underlying molecular mechanisms. Multiple PDAC mouse models were used to assess the effects of the P2RY2 inhibition on PDAC progression. RESULTS: P2RY2 was upregulated and associated with poor prognosis in PDAC. Activated P2RY2 by increased extracellular ATP in tumor microenvironment promoted PDAC growth and glycolysis. Further studies showed that the agonist-activated P2RY2 triggered PI3K/AKT-mTOR signaling by crosstalk with PDGFR mediated by Yes1, resulting in elevated expression of c-Myc and HIF1α, which subsequently enhanced cancer cell glycolysis. Genetic and pharmacologic inhibition of P2RY2 impaired tumor cell growth in subcutaneous and orthotopic xenograft model, as well as delayed tumor progression in inflammation-driven PDAC model. In addition, synergy was observed when AR-C118925XX, the selective antagonist of P2RY2 receptor, and gemcitabine were combined, resulting in prolonged survival of xenografted PDAC mice. CONCLUSIONS: These findings reveal the roles of the P2RY2 in PDAC metabolic reprogramming, suggesting that P2RY2 might be a potential metabolic therapeutic target for PDAC.

13.
Oncol Rep ; 41(2): 1101-1112, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30535456

RESUMO

Ovarian cancer is one of the three most deadly gynecological cancers, with the highest mortality rate. As the main cause of death, metastasis is considered to be a crucial factor that reduces the survival time of ovarian carcinoma patients. YWHAZ (also known as 14­3­3ζ) influences diverse vital cellular processes such as metabolism, signal transduction, apoptosis and cell cycle regulation. In the present study, we determined that YWHAZ is upregulated in ovarian cancers in contrast to normal tissues by immunohistochemical staining. High YWHAZ expression was found to be associated with TNM stage and metastasis­free prognosis of ovarian cancer patients. Silencing of YWHAZ inhibited the proliferation and facilitated serum starvation­induced apoptosis of ovarian cancer cells. Cell migration was also suppressed by YWHAZ silencing. Furthermore, using an in vivo metastatic model, we found that YWHAZ silence also inhibited ovarian cancer metastasis in vivo. Notably, glycolysis was clearly inhibited in YWHAZ­silenced ovarian cancer cells as determined by lactate production assay and Seahorse XF analysis. YWHAZ also regulated the PI3K/Akt1/vimentin signaling pathway in ovarian cancer cells as detected by western blot analysis. Taken together, our results demonstrated that YWHAZ plays an important role in the progression of ovarian cancer and can be used as a potential target for the diagnosis and treatment of epithelial ovarian cancer.


Assuntos
Proteínas 14-3-3/metabolismo , Glicólise , Neoplasias Ovarianas/patologia , Proteínas 14-3-3/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Progressão da Doença , Feminino , Técnicas de Silenciamento de Genes , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Ovarianas/mortalidade , Prognóstico , RNA Interferente Pequeno/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
14.
EBioMedicine ; 40: 276-289, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30594556

RESUMO

BACKGROUND: Endometrial cancer is one of the most common gynecological malignancies and has exhibited an increasing incidence rate in recent years. Cancer stem cells (CSCs), which are responsible for tumor growth and chemoresistance, have been confirmed in endometrial cancer. However, it is still challenging to identify endometrial cancer stem cells to then target for therapy. METHODS: Flow cytometry was used to identify the endometrial cancer stem cells. Sphere formation assay, western blotting, qRT-PCR assay, cell viability assay, xenograft assay and immunohistochemistry staining analysis were utilized to evaluate the effect of SPARC-related modular calcium binding 2 (SMOC-2) on the cells proliferation and drug resistance. Cell viability assay, qRT-PCR assay, immunofluorescence staining, Co-IP assay and luciferase reporter gene assay were performed to explore the possible molecular mechanism by which SMOC-2 activates WNT/ß-catenin pathway. FINDINGS: We found the expression of SPARC-related modular calcium binding 2 (SMOC-2), a member of SPARC family, was higher in endometrial CSCs than that in non-CSCs. SMOC-2 was also more highly expressed in spheres than in monolayer cultures. The silencing of SMOC-2 suppressed cell sphere ability; reduced the expression of the stemness-associated genes SOX2, OCT4 and NANOG; and enhanced chemosensitivity in endometrial cancer cells. By co-culture IP assay, we demonstrated that SMOC-2 directly interacted with WNT receptors (Fzd6 and LRP6), enhanced ligand-receptor interaction with canonical WNT ligands (Wnt3a and Wnt10b), and finally, activated the WNT/ß-catenin pathway in endometrial cancer. SMOC-2 expression was closely correlated with CSC markers CD133 and CD44 expression in endometrial cancer tissue. INTERPRETATION: Taken together, we conclude that SMOC-2 might be a novel endometrial cancer stem cell signature gene and therapeutic target for endometrial cancer. FUND: National Natural Science Foundation of China, Scientific and Technological Innovation Act Program of Shanghai Science and Technology Commission, Scientific and Technological Innovation Act Program of Fengxian Science and Technology Commission, Natural Science Foundation of Shanghai.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias do Endométrio/genética , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Animais , Biomarcadores , Linhagem Celular Tumoral , Sobrevivência Celular/genética , Modelos Animais de Doenças , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Humanos , Camundongos , Gradação de Tumores , Estadiamento de Neoplasias , Paclitaxel/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
BMC Dev Biol ; 18(1): 20, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30458702

RESUMO

BACKGROUND: Histone modifications are critical in regulating neuronal processes. However, the impacts of individual histone modifications on learning and memory are elusive. Here, we investigated the contributions of histone H3 lysine modifications to learning and memory in Drosophila by using histone lysine-to-alanine mutants. RESULTS: Behavioural analysis indicated that compared to the H3WT group, mutants overexpressing H3K23A displayed impaired courtship learning. Chromatin immunoprecipitation analysis of H3K23A mutants showed that H3K23 acetylation (H3K23ac) levels were decreased on learning-related genes. Knockdown of CREB-binding protein (CBP) decreased H3K23ac levels, attenuated the expression of learning-related genes, led to a courtship learning defect and altered development of the mushroom bodies. A decline in courtship learning ability was observed in both larvae and adult treatments with ICG-001. Furthermore, treatment of Drosophila overexpressing mutated H3K23A with a CBP inhibitor did not aggravate the learning defect. CONCLUSIONS: H3K23ac, catalysed by the acetyltransferases dCBP, contributes to Drosophila learning, likely by controlling the expression of specific genes. This is a novel epigenetic regulatory mechanism underlying neuronal behaviours.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Histonas/metabolismo , Lisina/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Acetilação , Animais , Corte , Feminino , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Histonas/genética , Aprendizagem , Masculino , Mutação , Neurônios/metabolismo
16.
Gastroenterology ; 155(4): 1233-1249.e22, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30009820

RESUMO

BACKGROUND & AIMS: Agents designed to block or alter cytokinesis can kill or stop proliferation of cancer cells. We aimed to identify cytokinesis-related proteins that are overexpressed in hepatocellular carcinoma (HCC) cells and might be targeted to slow liver tumor growth. METHODS: Using the Oncomine database, we compared the gene expression patterns in 16 cancer microarray datasets and assessed gene enrichment sets using gene ontology. We performed immunohistochemical analysis of an HCC tissue microarray and identified changes in protein levels that are associated with patient survival times. Candidate genes were overexpressed or knocked down with small hairpin RNAs in SMMC7721, MHCC97H, or HCCLM3 cell lines; we analyzed their proliferation, viability, and clone-formation ability and their growth as subcutaneous or orthotopic xenograft tumors in mice. We performed microarray analyses to identify alterations in signaling pathways and immunoblot and immunofluorescence assays to detect and localize proteins in tissues. Yeast 2-hybrid screens and mass spectrometry combined with co-immunoprecipitation experiments were used to identify binding proteins. Protein interactions were validated with co-immunoprecipitation and proximity ligation assays. Chromatin immunoprecipitation, promoter luciferase activity, and quantitative real-time polymerase chain reaction analyses were used to identify factors that regulate transcription of specific genes. RESULTS: The genes that were most frequently overexpressed in different types of cancer cells were involved in cell division processes. We identified 3 cytokinesis-regulatory proteins among the 10 genes most frequently overexpressed by all cancer cell types. Rac GTPase activating protein 1 (RACGAP1) was the cytokinesis-regulatory protein that was most highly overexpressed in multiple cancers. Increased expression of RACGAP1 in tumor tissues was associated with shorter survival times of patients with cancer. Knockdown of RACGAP1 in HCC cells induced cytokinesis failure and cell apoptosis. In microarray analyses, we found knockdown of RACGAP1 in SMMC7721 cells to reduce expression of genes regulated by yes-associated protein (YAP) and WW domain containing transcription regulator 1 (WWTR1 or TAZ). RACGAP1 reduced activation of the Hippo pathway in HCC cells by increasing activity of RhoA and polymerization of filamentous actin. Knockdown of YAP reduced phosphorylation of RACGAP1 and redistribution at the anaphase central spindle. We found transcription of the translocated promoter region, nuclear basket protein (TPR) to be regulated by YAP and coordinately expressed with RACGAP1 to promote proliferation of HCC cells. TPR redistributed upon nuclear envelope breakdown and formed complexes with RACGAP1 during mitosis. Knockdown of TPR in HCC cells reduced phosphorylation of RACGAP1 by aurora kinase B and impaired their redistribution at the central spindle during cytokinesis. STAT3 activated transcription of RACGAP in HCC cells. CONCLUSIONS: In an analysis of gene expression patterns of multiple tumor types, we found RACGAP1 to be frequently overexpressed, which is associated with shorter survival times of patients. RACGAP1 promotes proliferation of HCC cells by reducing activation of the Hippo and YAP pathways and promoting cytokinesis in coordination with TPR.


Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Citocinese , Proteínas Ativadoras de GTPase/metabolismo , Neoplasias Hepáticas/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células A549 , Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Apoptose , Biomarcadores Tumorais/genética , Feminino , Proteínas Ativadoras de GTPase/genética , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Células HCT116 , Células Hep G2 , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Complexo de Proteínas Formadoras de Poros Nucleares/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Interferência de RNA , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição , Carga Tumoral , Regulação para Cima , Proteína rhoA de Ligação ao GTP/genética , Proteína rhoA de Ligação ao GTP/metabolismo
17.
J Immunol Res ; 2018: 4602570, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951557

RESUMO

Integrin subunit alpha 9 (ITGA9) mediates cell-cell and cell-matrix adhesion, cell migration, and invasion through binding different kinds of extracellular matrix (ECM) components. However, its potential role and underlying molecular mechanisms remain unclear in hepatocellular carcinoma (HCC). Here, we found that ITGA9 expression was obviously decreased in patients with HCC, which was negatively correlated with HCC growth and metastasis. ITGA9 overexpression significantly inhibited cell proliferation and migration in vitro as well as tumor growth and metastasis in vivo. Our data demonstrated that the inhibitory effect of ITGA9 on HCC cell motility was associated with reduced phosphorylation of focal adhesion kinase (FAK) and c-Src tyrosine kinase (Src), disrupted focal adhesion reorganization, and decreased Rac1 and RhoA activity. Our data suggest ITGA9, as a suppressor of HCC, prevents tumor cell migration and invasiveness through FAK/Src-Rac1/RhoA signaling.


Assuntos
Carcinoma Hepatocelular/metabolismo , Cadeias alfa de Integrinas/metabolismo , Neoplasias Hepáticas/metabolismo , Transdução de Sinais , Proteínas rho de Ligação ao GTP/metabolismo , Adulto , Idoso , Animais , Biomarcadores , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Modelos Animais de Doenças , Feminino , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Xenoenxertos , Humanos , Imuno-Histoquímica , Cadeias alfa de Integrinas/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Fosforilação
18.
J Cell Sci ; 131(12)2018 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-29760279

RESUMO

Dysregulation of the homeostatic balance of histone H3 di- and tri-methyl lysine 27 (H3K27me2/3) levels caused by the mis-sense mutation of histone H3 (H3K27M) is reported to be associated with various types of cancers. In this study, we found that reduction in H3K27me2/3 caused by H3.1K27M, a mutation of H3 variants found in patients with diffuse intrinsic pontine glioma (DIPG), dramatically attenuated the presence of 53BP1 (also known as TP53BP1) foci and the capability of non-homologous end joining (NHEJ) in human dermal fibroblasts. H3.1K27M mutant cells showed increased rates of genomic insertions/deletions and copy number variations, as well as an increase in p53-dependent apoptosis. We further showed that both hypo-H3K27me2/3 and H3.1K27M interacted with FANCD2, a central player in the choice of DNA repair pathway. H3.1K27M triggered the accumulation of FANCD2 on chromatin, suggesting an interaction between H3.1K27M and FANCD2. Interestingly, knockdown of FANCD2 in H3.1K27M cells recovered the number of 53BP1-positive foci, NHEJ efficiency and apoptosis rate. Although these findings in HDF cells may differ from the endogenous regulation of the H3.1K27M mutant in the specific tumor context of DIPG, our results suggest a new model by which H3K27me2/3 facilitates NHEJ and the maintenance of genome stability.This article has an associated First Person interview with the first author of the paper.


Assuntos
Cromatina/metabolismo , Reparo do DNA por Junção de Extremidades , Enzimas Reparadoras do DNA/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/metabolismo , Histonas/metabolismo , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/metabolismo , Linhagem Celular , Cromatina/genética , Reparo do DNA , Enzimas Reparadoras do DNA/genética , Proteínas de Ligação a DNA/genética , Proteína do Grupo de Complementação D2 da Anemia de Fanconi/genética , Fibroblastos , Instabilidade Genômica , Glioma/genética , Glioma/metabolismo , Células HEK293 , Histonas/genética , Humanos , Metilação , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/genética , Proteína 1 de Ligação à Proteína Supressora de Tumor p53/metabolismo
19.
J Thorac Dis ; 10(2): 920-929, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29607165

RESUMO

Background: To evaluate the effect of restriction of soybean-based intravenous fat emulsions (IVFEs) in clinical outcomes in cardiac surgical patients. Methods: This was a before-and-after interventional study comparing the clinical outcomes regarding the intervention of IVFEs restriction. Before August 2015, parenteral nutrition (PN) using a soy-based lipid emulsion was routinely implemented if patients failed to meet >60% of energy requirements in 48 h post cardiac surgery (Period A). Beginning in August 2015, a lipid restriction strategy was implemented in our cardiac surgery intensive care unit (CSICU) unless enteral route could not be established within 7 days (Period B). The ICU and hospital mortality, nosocomial infections during ICU stay, length of ICU and hospital stay, ICU and hospital cost, mechanical ventilation time and postoperative complications were compared between two periods. Results: A total of 761 patients (370 patients in Period A and 391 patients in Period B) were ultimately enrolled in this study. There were no significant differences in demographic characteristics and intraoperative and postoperative parameters between the two groups. After the implementation of IVFEs restriction, the overall ICU mortality and hospital mortality were similar between two groups. Nosocomial infection rate was significantly reduced (3.84% vs. 7.84%, P=0.021). The mean length of ICU stay (3.15 vs. 3.74 days, P<0.001) and hospital stay (12.14 vs. 13.24 days, P<0.001) were significantly lower. The mean in-hospital cost (133,368 vs. 139,383 Yuan, P=0.037) was found to be reduced after implementation of IVFEs restriction. The duration of mechanical ventilation was shorter in the latter period (35.23±10.43 vs. 47.63±12.54 hours, P=0.011). IVFEs restriction was also associated with reduced cholestasis (2.81% vs. 6.76%, P=0.013). Conclusions: The implementation of soybean-based IVFEs restriction in cardiac surgical patients was associated with reduced postoperative nosocomial infection rate. It also led to reductions in the length of ICU/hospital stay, hospital costs and mechanical ventilation time and a lower incidence of cholestasis. Further studies are required to validate the conclusions.

20.
Neural Regen Res ; 13(3): 456-462, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29623930

RESUMO

Acute brain injury caused by subarachnoid hemorrhage is the major cause of poor prognosis. The pathology of subarachnoid hemorrhage likely involves major morphological changes in the microcirculation. However, previous studies primarily used fixed tissue or delayed injury models. Therefore, in the present study, we used in vivo imaging to observe the dynamic changes in cerebral microcirculation after subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by perforation of the bifurcation of the middle cerebral and anterior cerebral arteries in male C57/BL6 mice. The diameter of pial arterioles and venules was measured by in vivo fluorescence microscopy at different time points within 180 minutes after subarachnoid hemorrhage. Cerebral blood flow was examined and leukocyte adhesion/albumin extravasation was determined at different time points before and after subarachnoid hemorrhage. Cerebral pial microcirculation was abnormal and cerebral blood flow was reduced after subarachnoid hemorrhage. Acute vasoconstriction occurred predominantly in the arterioles instead of the venules. A progressive increase in the number of adherent leukocytes in venules and substantial albumin extravasation were observed between 10 and 180 minutes after subarachnoid hemorrhage. These results show that major changes in microcirculation occur in the early stage of subarachnoid hemorrhage. Our findings may promote the development of novel therapeutic strategies for the early treatment of subarachnoid hemorrhage.

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