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1.
Cell Death Differ ; 2020 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-32015502

RESUMO

Angiogenesis plays crucial roles in maintaining the complex operation of central nervous system (CNS) development. The architecture of communication between neurogenesis and angiogenesis is essential to maintain normal brain development and function. Hence, any disruption of neuron-vascular communications may lead to the pathophysiology of cerebrovascular diseases and blood-brain barrier (BBB) dysfunction. Here we demonstrate that neural differentiation and communication are required for vascular development. Regarding the cellular and molecular mechanism, our results show that PRDM16 activity determines the production of mature neurons and their specific positions in the neocortex. In the cortical plate (CP), aberrant neurons fail to secrete modular calcium-binding protein 1 (SMOC1), an important neuronal signal that participates in neurovascular communication to regulate CNS angiogenesis. Neuronal SMOC1 interacts with TGFBR1 by activating the transcription factors phospho-Smad2/3 to convey intercellular signals to endothelial cells (ECs) in the TGF-ß-Smad signaling pathway. Together, our results highlight a crucial coordinated neurovascular development process orchestrated by PRDM16 and reveal the importance of intimate communication for building the neurovascular network during brain development.

2.
Plant Physiol ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32047049

RESUMO

Sugar content is an important trait of fleshy fruit, and elevating sucrose levels is a major goal in horticultural crop breeding. Here, we examined the sugar content in two varieties of the Ussurian pear (Pyrus ussuriensis), Nanguo (NG) and its bud sport (BNG), and we found that sucrose content was higher in BNG fruit than in NG fruit. We compared the transcriptomes of the two varieties using RNA-seq and identified a SWEET (Sugars Will Eventually be Exported Transporter) gene, PuSWEET15, expressed at higher levels in BNG fruit. Heterologous expression of PuSWEET15 in a SUSY7/ura yeast (Saccharomyces cerevisiae) strain showed that PuSWEET15 is an active sucrose transporter. Overexpression of PuSWEET15 in NG pear fruit increased sucrose content, while silencing of PuSWEET15 in BNG fruit decreased sucrose content. The WRKY transcription factor PuWRKY31 was also expressed more highly in BNG fruit than in NG fruit, and we found that PuWRKY31 bound to the PuSWEET15 promoter and induced its transcription. The histone acetylation level of the PuWRKY31 promoter was higher in BNG fruit, suggesting a mechanism by which sucrose levels can be elevated.

3.
Radiat Res ; 2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017668

RESUMO

New radiosensitizers are urgently needed for radiation therapy patients with localized hepatocellular carcinoma (HCC) that is refractory to radical surgery. We previously found that genistein, a major soy isoflavone, exerts radioprotective effects on L-02 normal liver cells at low concentrations. Here, we report that 5 µM genistein shows less harm to L-02 cells than HCC cells and that it significantly enhances the radiosensitivity of HCC cells by enhancing DNA damage, chromosomal aberrations and cell cycle arrest at G2/M phase and by exacerbating apoptosis. Mechanistically, genistein aggravates X-ray-induced decreases in the levels of phospho-Bad (Ser136) but enhances the levels of phospho-Chk2 (Thr68), phospho-ATM (Ser1981) and γ-H2AX. Microarray analysis indicated that downregulation of POU6F and CCNE2 expression and upregulation of FBXO32 and cyclin B1 expression might play vital roles in genistein-induced radiosensitivity. These findings suggest genistein as an interesting candidate for adjuvant radiotherapy for HCC and indicate that genistein causes less harm to normal cells than HCC cells by inducing G2/M arrest and apoptosis.

4.
Artigo em Inglês | MEDLINE | ID: mdl-32053828

RESUMO

Repetitive transcranial magnetic stimulation (rTMS) is a commonly used treatment for major depressive disorder (MDD). However, our understanding of the mechanism by which TMS exerts its antidepressant effect is minimal. Furthermore, we lack brain signals that can be used to predict and track clinical outcome. Such signals would allow for treatment stratification and optimization. Here, we performed a randomized, sham-controlled clinical trial and measured electrophysiological, neuroimaging, and clinical changes before and after rTMS. Patients (N = 36) were randomized to receive either active or sham rTMS to the left dorsolateral prefrontal cortex (dlPFC) for 20 consecutive weekdays. To capture the rTMS-driven changes in connectivity and causal excitability, resting fMRI and TMS/EEG were performed before and after the treatment. Baseline causal connectivity differences between depressed patients and healthy controls were also evaluated with concurrent TMS/fMRI. We found that active, but not sham rTMS elicited (1) an increase in dlPFC global connectivity, (2) induction of negative dlPFC-amygdala connectivity, and (3) local and distributed changes in TMS/EEG potentials. Global connectivity changes predicted clinical outcome, while both global connectivity and TMS/EEG changes tracked clinical outcome. In patients but not healthy participants, we observed a perturbed inhibitory effect of the dlPFC on the amygdala. Taken together, rTMS induced lasting connectivity and excitability changes from the site of stimulation, such that after active treatment, the dlPFC appeared better able to engage in top-down control of the amygdala. These measures of network functioning both predicted and tracked clinical outcome, potentially opening the door to treatment optimization.

5.
Nat Biotechnol ; 2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32042166

RESUMO

Antidepressants are widely prescribed, but their efficacy relative to placebo is modest, in part because the clinical diagnosis of major depression encompasses biologically heterogeneous conditions. Here, we sought to identify a neurobiological signature of response to antidepressant treatment as compared to placebo. We designed a latent-space machine-learning algorithm tailored for resting-state electroencephalography (EEG) and applied it to data from the largest imaging-coupled, placebo-controlled antidepressant study (n = 309). Symptom improvement was robustly predicted in a manner both specific for the antidepressant sertraline (versus placebo) and generalizable across different study sites and EEG equipment. This sertraline-predictive EEG signature generalized to two depression samples, wherein it reflected general antidepressant medication responsivity and related differentially to a repetitive transcranial magnetic stimulation treatment outcome. Furthermore, we found that the sertraline resting-state EEG signature indexed prefrontal neural responsivity, as measured by concurrent transcranial magnetic stimulation and EEG. Our findings advance the neurobiological understanding of antidepressant treatment through an EEG-tailored computational model and provide a clinical avenue for personalized treatment of depression.

7.
Int J Mol Sci ; 21(3)2020 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32050573

RESUMO

Salt stress inhibits normal plant growth and development by disrupting cellular water absorption and metabolism. Therefore, understanding plant salt tolerance mechanisms should provide a theoretical basis for developing salt-resistant varieties. Here, we cloned ThTrx5 from Tamarix hispida, a salt-resistant woody shrub, and generated ThTrx5-overexpressing transgenic Arabidopsis thaliana lines. Under NaCl stress, the germination rate of overexpressing ThTrx5 lines was significantly increased relative to that of the nontransgenic line; under salt stress, superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), and glutathione levels and root length and fresh weight values of transgenic ThTrx5 plants were significantly greater than corresponding values for wild-type plants. Moreover, with regard to the transcriptome, comparison of differential gene expression of transgenic versus nontransgenic lines at 0 h and 3 h of salt stress exposure revealed 500 and 194 differentially expressed genes (DEGs), respectively, that were mainly functionally linked to catalytic activity and binding process. Pull-down experiments showed that ThTrx bound 2-Cys peroxiredoxin BAS1-like protein that influences stress response-associated redox, hormone signal transduction, and transcription factor functions. Therefore, this work provides important insights into ThTrx5 mechanisms that promote salt tolerance in plants.

8.
Int J Med Sci ; 17(2): 263-273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32038110

RESUMO

Background: Human bone marrow mesenchymal stem cell-derived hepatocyte-like cells (hBMSC-HLCs) are a promising alternative for primary human hepatocytes (HHs) for treating liver disease. However, the molecular characteristics of HLCs remain unclear. Here, we aimed to clarify the transcriptome characteristics of hBMSC-HLCs for future clinical application. Materials and Methods: hBMSCs were isolated from the bone marrow of healthy volunteers and differentiated into hepatocytes. mRNA sequencing was used in the transcriptome profiling of hBMSC-HLCs, with hBMSCs and HHs as controls. Results: hBMSC-HLCs exhibited a polygonal morphology, glycogen accumulation and albumin expression. A total of 630 upregulated and 1082 downregulated genes were observed in hBMSC-HLCs and HHs compared with undifferentiated hBMSCs. The upregulated genes were mainly involved in hepatic metabolism and inflammatory and immune responses. The downregulated genes were mainly associated with stem cell characteristics (multipotent differentiation, cell cycle regulation, etc.). Confirmatory qRT-PCR of 9 upregulated and 9 downregulated genes with log2 fold changes > 5 showed similar results. In vivo transdifferentiation of hBMSCs in pigs with fulminant hepatic failure confirmed the similarly upregulated expression of 5 hepatogenic genes (TDO2, HP, SERPINA3, LBP and SAA1), showing a 150-fold change in liver tissues at 7 days after hBMSC transplantation. These 5 genes mainly contributed to liver metabolism and inflammation. Conclusion: hBMSC-HLCs possess a hepatic transcriptome profile and express hepatic-specific genes in vitro and in vivo, which might be useful for future clinical applications. The five upregulated genes identified herein could be potential biomarkers for the characterization of hBMSC-HLCs.

9.
Neural Netw ; 123: 305-316, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31896462

RESUMO

The efforts devoted to manually increasing the width and depth of convolutional neural network (CNN) usually require a large amount of time and expertise. It has stimulated a rising demand of neural architecture search (NAS) over these years. However, most popular NAS approaches solely optimize for low prediction error without penalizing high structure complexity. To this end, this paper proposes MOPSO/D-Net, a CNN architecture search method with multiobjective particle swarm optimization based on decomposition (MOPSO/D). The main goal is to reformulate NAS as a multiobjective evolutionary optimization problem, where the optimal architecture is learned by minimizing two conflicting objectives, namely the error rate of classification and number of parameters of the network. Along with the hybrid binary encoding and adaptive penalty-based boundary intersection, an improved MOPSO/D is further proposed to solve the formulated multiobjective NAS and provide diverse tradeoff solutions. Experimental studies verify the effectiveness of MOPSO/D-Net compared with current manual and automated CNN generation methods. The proposed algorithm achieves impressive classification performance with a small number of parameters on each of two benchmark datasets, particularly, 0.4% error rate with 0.16M params on MNIST and 5.88% error rate with 8.1M params on CIFAR-10, respectively.

10.
J Colloid Interface Sci ; 564: 418-427, 2020 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-31923829

RESUMO

Spinel-type structured materials have attracted considerable attention and been regarded as promising alternative catalysts for oxygen evolution reaction (OER). However, the regulation of catalytically active octahedral sites in spinel structure to realize high activity and good stability for OER electrocatalysis is still a great challenge. Herein, we propose a self-doping strategy to boost OER performance of spinel-type Ni3S4 enriched high valence Ni3+ as active sites. By sacrificing Ni-based metal-organic framework, the ultrathin Ni3S4 manosheets are topologically grown on conductive Ni foam substrate and realize the simultaneous Ni3+ self-doping and surface oxygen incorporation during in situ sulfidation conversion process. These compositional and structural characteristics endow it with enhanced adsorption binding strength, enabling the highly efficient OER. As a result, the Ni3S4/NF exhibits excellent activity and outstanding stability toward OER electrocatalysis in alkaline medium, which only demands an ultralow overpotential of 266 mV to deliver a current density of 10 mA cm-2 and manifests the stable OER process for at least 75 h. Moreover, when used as an effective overall water splitting electrolyzer, the Ni3S4/NF achieves a current density of 10 mA cm-2 at only 1.638 V with good long-term stability.

11.
Biochim Biophys Acta Mol Cell Res ; 1867(4): 118647, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31926942

RESUMO

Cisplatin-based chemotherapies have long been considered as a standard chemotherapy in ovarian cancer. However, cisplatin resistance restricts beneficial therapy for patients with ovarian cancer. The ubiquitin-like protein interferon-stimulated gene 15 (ISG15) encodes a 15-kDa protein, that is implicated in the post-translational modification of diverse proteins. In this work, we found that ISG15 was downregulated in cisplatin resistant tissues and cell lines of ovarian cancer. Functional studies demonstrated that overexpression of wild type (WT) ISG15, but not nonISGylatable (Mut) ISG15 increased cell responses to cisplatin in resistant ovarian cancer cells. Furthermore, we found that WT ISG15 decreased ABCC2 expression at the protein level. Importantly, overexpression of ABCC2 blocked sensitizing effect of ISG15 on cisplatin. In addition, we identified that hnRNPA2B1 was recruited to 5'UTR of ABCC2 mRNA and promoted its translation, which was blocked by ISG15. We further demonstrated that hnRNPA2B1 could be ISGylated, and ISGylation blocked its recruitment to ABCC2 mRNA, thereby suppressed translation of ABCC2. Altogether, our data support targeting ISG15 might be a potential therapeutic strategy for patients with cisplatin-resistant ovarian cancer.

12.
Am J Clin Nutr ; 2020 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-31927564

RESUMO

BACKGROUND: The association between circulating folate concentrations and risk of coronary artery disease (CAD) has been evaluated in Western populations with inconsistent results; however, the observational and causal associations in Chinese populations with relatively low folate concentrations remain unclear. OBJECTIVES: We aimed to examine the association of circulating folate concentrations with incident CAD in Chinese adults, and further evaluated the causal relation using Mendelian randomization (MR) analysis. METHODS: We measured baseline serum folate in 1605 incident CAD cases and 1605 age- and sex-matched controls nested within the Dongfeng-Tongji (DFTJ) cohort, which recruited 27,009 individuals with a mean age of 63.6 y in 2008-2010 and followed up until the end of 2013 (mean: 4.4 y). We quantified the observational association between folate and incident CAD using conditional logistic regression models. A 2-sample MR analysis was performed using summary statistics obtained for genetic variants identified from a genome-wide association study (GWAS) of circulating folate concentrations in participants of European ancestry (n = 37,341) and from the CardiogramplusC4D 1000 genomes-based GWAS meta-analysis (n = 184,305). We also conducted 1-sample MR among 1545 incident CAD cases and 1444 controls with genotyping data in the DFTJ cohort. RESULTS: In the DFTJ cohort, higher serum folate concentrations were associated with a lower risk of CAD: the OR (95% CI) across sex-specific quartiles of folate (from lowest to highest concentrations) was 1.00 (reference), 0.78 (0.63, 0.97), 0.77 (0.61, 0.97), and 0.75 (0.60, 0.95), respectively (P-trend = 0.01). In the MR analysis, the OR of CAD per SD increase in genetically predicted serum folate was 0.99 (0.82, 1.20) and 0.88 (0.59, 1.32) for European and Chinese populations, respectively. CONCLUSIONS: We found an inverse association between circulating folate concentrations and incident CAD among Chinese populations. However, we confirmed that there was no genetic evidence to support the causal relation in both European and Chinese populations.

13.
Int J Mol Med ; 45(2): 647-657, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31894307

RESUMO

The molecular mechanisms underlying the activation of primordial follicles are poorly understood. The serine/threonine protein kinase phosphoinositide­dependent kinase 1 (PDK1), a pivotal downstream effector of phosphatidyl inositol­3 kinase (PI3K) signaling, plays a vital role in cellular signaling. In order to identify the function of PDK1 in ovarian follicle development, this study used conditional Pdk1 deletion in mouse oocytes by crossing Pdk1loxP/loxP mice with transgenic mice carrying Gdf­9 promoter­mediated Cre recombinase and found that Pdk1flx/flxGdf9Cre mice were subfertile with increased serum follicle­stimulating hormone (FSH) and luteinizing hormone (LH) levels compared with Pdk1flx/flx mice. The deletion of Pdk1 in oocytes induced massive primordial follicle activation, leading to premature ovarian failure (POF). Further investigation revealed that enhanced Yes­associated protein (YAP) expression and an increased pro­inflammatory response also contributed to massive primordial follicle activation. PDK1 formed the complex with the core kinases of Hippo signaling and regulated the expression levels of YAP. On the whole, the findings of the present study demonstrate that PDK1 serves as an indispensable gatekeeper for maintaining the primordial follicle pool and provide a deeper understanding of POF treatment.

14.
Int Immunol ; 2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31930291

RESUMO

Chronic allograft rejection is the most common cause of long-term allograft failure. One reason is that current diagnostics and therapeutics for chronic allograft rejection are very limited. We here show that enhanced NFκB signaling in kidney grafts contributes to chronic active antibody-mediated rejection (CAAMR), which is a major pathology of chronic kidney allograft rejections. Moreover, we found that urinary orosomucoid 1 (ORM1) is a candidate marker molecule and therapeutic target for CAAMR. Indeed, urinary ORM1 concentration was significantly higher in kidney transplant recipients pathologically diagnosed with CAAMR than in kidney transplant recipients with normal histology, calcineurin inhibitor toxicity, or interstitial fibrosis and tubular atrophy. Additionally, we found that kidney biopsy samples with CAAMR expressed more ORM1 and had higher NFκB and STAT3 activation in tubular cells than samples from non-CAAMR samples. Consistently, ORM1 production was induced after cytokine-mediated NFκB and STAT3 activation in primary kidney tubular cells. The loss- and gain-of-function of ORM1 suppressed and promoted NFκB activation, respectively. Finally, ORM1 enhanced NFκB-mediated inflammation development in vivo. These results suggest that an enhanced NFκB-dependent pathway following NFκB and STAT3 activation in the grafts is involved in the development of chronic allograft rejection after kidney transplantation and that ORM1 is a non-invasive candidate biomarker and possible therapeutic target for chronic kidney allograft rejection.

15.
Ann Hum Genet ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31960406

RESUMO

OBJECTIVE: Nonalcoholic fatty liver disease (NAFLD) is one of the leading causes of chronic liver diseases. However, the pathogenesis of NAFLD is largely unknown. Here, we investigated the specific role of miR-499-5p in NAFLD. METHODS: Free fatty acid was used to induce HL-7702 cell line to establish a NAFLD cell model, and animal models of NAFLD were constructed by feeding C57BL/6 mice with a high-fat diet. Expression levels of miR-499-5p in the HL-7702 cells and C57BL/6 mice were determined by quantitative real-time polymerase chain reaction. In addition, functional experiments were carried out through transfecting miR-499-5p inhibitor into NAFLD cells, and injecting NAFLD mice with a lentiviral vector with the miR-499-5p inhibitor. Furthermore, the effects of miR-499-5p on lipidation and inflammation were investigated by oil red O staining, hematoxylin-eosin staining, and biochemical analysis. RESULTS: Compared with normal controls, the expression of miR-499-5p was significantly up-regulated in NAFLD cells and tissues in mouse. After NAFLD cells transfected by miR-499-5p inhibitor, the expression of miR-499-5p was inhibited, the lipid deposition and content of triglycerides (TGs) were reduced, and the lipidation was improved. Simultaneously, after NAFLD mice were injected with the miR-499-5p lentiviral vector, the degree of lipid droplet deposition and content of TGs were also reduced. In addition, it decreased the levels of total cholesterol and aspartate aminotransferase in serum, and improved hepatic lipid metabolism. CONCLUSIONS: Inhibition of miR-499-5p expression improved NAFLD in mice, which provided a new direction for the treatment of NAFLD.

16.
Biomolecules ; 10(2)2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31991759

RESUMO

Heart failure (HF) is a deadly disease that is difficult to accurately diagnose. Circular RNAs (circRNAs) are a novel class of noncoding RNAs that might play important roles in many cardiovascular diseases. However, their role in HF remains unclear. CircRNA microarrays were performed on plasma samples obtained from three patients with HF and three healthy controls. The profiling results were validated by quantitative reverse transcription polymerase chain reaction. The diagnostic value of circRNAs for HF was evaluated by receiver operating characteristic (ROC) curves. The expression profiles indicated that 477 circRNAs were upregulated and 219 were downregulated in the plasma of patients with HF compared with healthy controls. Among the dysregulated circRNAs, hsa_circ_0112085 (p = 0.0032), hsa_circ_0062960 (p = 0.0006), hsa_circ_0053919 (p = 0.0074) and hsa_circ_0014010 (p = 0.025) showed significantly higher expression in patients with HF compared with healthy controls. The area under the ROC curve for hsa_circ_0062960 for HF diagnosis was 0.838 (p < 0.0001). Correlation analysis showed that the expression of hsa_circ_0062960 was highly correlated with B-type natriuretic peptide (BNP) serum levels. Some differential circRNAs were found to be related to platelet activity by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. The landscape of circRNA expression profiles may play a role in HF pathogenesis and improve our understanding of platelet function in HF. Moreover, hsa_circ_0062960 has potential as a novel diagnostic biomarker for HF.

17.
Parasitol Res ; 119(1): 105-114, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31773309

RESUMO

The protistan pathogens Cryptosporidium and Enterocytozoon bieneusi can cause significant intestinal diseases in animals and humans. However, limited information is available regarding prevalence and molecular characterization of Cryptosporidium and E. bieneusi in ruminants in Northern China. In this study, the overall prevalence of Cryptosporidium and E. bieneusi was 19.3% (62/321) and 28.97% (93/321) in dairy calves and 1.10% (9/818) and 13.57% (111/818) in sika deer (Cervus nippon) in four provinces in Northern China, respectively. The prevalence of Cryptosporidium and E. bieneusi in different factor groups was various. Five Cryptosporidium species/genotypes were identified, of which C. parvum, C. ryanae, C. bovis, and C. andersoni were only found in dairy calves, and only Cryptosporidium deer genotype was found in sika deer. Moreover, J, I, and BEB4 ITS genotypes of E. bieneusi were found in dairy calves, and six known genotypes (JLD-III, JLD-IX, JLD-VII, EbpC, BEB6, and I) and ten novel genotypes (namely LND-I and JLD-XV to JLD-XXIII) were found in sika deer in this study. Cryptosporidium parvum and E. bieneusi genotype J were identified as the predominant species/genotypes in dairy calves, whereas the predominance of Cryptosporidium spp. and E. bieneusi in sika deer was Cryptosporidium deer genotype and BEB6, respectively. The present study reported the prevalence and genotypes of Cryptosporidium and E. bieneusi in dairy calves and sika deer in four provinces in northern China. The present findings also suggest that investigated dairy calves and sika deer may play an important role in the transmission of E. bieneusi and Cryptosporidium to humans and other animals, and also in an effort to better understand the epidemiology of these enteric pathogens in China.

18.
Cancer Invest ; 38(1): 1-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31797701

RESUMO

Purpose: The function of long noncoding RNAs (lncRNA) in breast cancer metastasis remains largely unknown. In this work, the role of HOXC-AS3 in breast cancer progression was investigated.Methods: By using Cancer Genome Atlas (TCGA) Database, we investigated the expression of HOXC-AS3 in breast cancer and explored the association between HOXC-AS3 expression and prognosis. Then, we studied the biological function of HOXC-AS3 in cell migration and invasion both in vitro and in vivo. Furthermore, the target miRNA of HOXC-AS3, and the target mRNA of miR-3922-5p were proved.Results: HOXC-AS3 is aberrantly overexpressed in breast cancers especially the HER2+ type. Moreover, high expression of HOXC-AS3 has a relationship with poor clinical outcomes of breast cancer. In addition, HOXC-AS3 regulates cell Invasion and migration both in vitro and in vivo. Our results demonstrated that miR-3922-5p was a direct target of HOXC-AS3, and PPP1R1A was a target of miR-3922-5p in breast cancer.Conclusions: The novel lncRNA HOXC-AS3 acts as a miR-3922-5p sponge to upregulate PPP1R1A protein expression, and thus results in promoting breast cancer metastasis. HOXC-AS3 could be a novel therapeutic target for breast cancer therapeutics.

19.
J Cell Mol Med ; 24(1): 562-572, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31657880

RESUMO

Solid tumour frequently undergoes metabolic stress during tumour development because of inadequate blood supply and the high nutrient expenditure. p53 is activated by glucose limitation and maintains cell survival via triggering metabolic checkpoint. However, the exact downstream contributors are not completely identified. BAG3 is a cochaperone with multiple cellular functions and is implicated in metabolic reprogramming of pancreatic cancer cells. The current study demonstrated that glucose limitation transcriptionally suppressed BAG3 expression in a p53-dependent manner. Importantly, hinderance of its down-regulation compromised cellular adaptation to metabolic stress triggered by glucose insufficiency, supporting that BAG3 might be one of p53 downstream contributors for cellular adaptation to metabolic stress. Our data showed that ectopic BAG3 expression suppressed p53 accumulation via direct interaction under metabolic stress. Thereby, the current study highlights the significance of p53-mediated BAG3 suppression in cellular adaptation to metabolic stress via facilitating p53 accumulation.

20.
Exp Eye Res ; 190: 107823, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31600485

RESUMO

Administration of RC28-E, a VEGF/bFGF dual decoy receptor (IgG1 Fc-fusion protein), have shown relative therapeutic value in ocular in vivo models, including laser-induced choroidal neovascularization (CNV) in monkeys and streptozotocin (STZ)-induced diabetic retinopathy (DR) in rats. In the present study, we have elucidated the pharmacokinetics profiles of RC28-E at the systemic, vitreous and aqueous humor after administration in a primate model (Macaca fascicularis). Moreover, here we tease out the ocular tissue distribution of RC28-E after intravitreal administration, and we also determine the systemic bioavailability after both intravitreal and intravenous administration. Our results show that RC28-E is rapidly and well-distributed into ocular tissues after intravitreal administration. Drug exposure in choroid and retina was approximately one-quarter and one-twelfth of that in vitreous humor, while its half-life in vitreous and aqueous humor were well-sustained (3.3 and 3.0 days). Remarkably, RC28-E could cross the blood-ocular barrier, and the systemic bioavailability of RC28-E was ~25%. No drug accumulation after multiple administration was noticed, but low titers of antibody produce against RC28-E were detected. Overall, RC28-E exhibited high clinical value due to adequate pharmacokinetic profiling, safety and efficacy.

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