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1.
J Food Sci ; 86(3): 960-968, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33527408

RESUMO

In this study, oyster protein hydrolysates (OPH) were obtained from oyster meat by hydrolysis using animal complex proteases and then encapsulated in nanoliposomes. The physicochemical properties, stability, and digestive characteristics of OPH-loaded nanoliposomes were evaluated. The average size and zeta potential ranged from 95.64 to 102.39 nm and from -47.36 to -36.43 mV, respectively. Liposomes containing 4 mg/mL OPH had the highest encapsulation efficiency (74.53%). Fourier transform infrared spectroscopy analysis showed that effective ionic complexation and hydrogen bonding existed between phospholipid and peptides. The liposomes exhibited the highest stability when stored at 4 °C. Liposomal encapsulation may protect the antioxidant peptides in OPH during storage and simulated digestion. The nanoliposomes were not hydrolyzed and the structural integrity was maintained in gastric digestion, but exhibited lower stability in the intestinal phase. A prolonged release of OPH from nanoliposomes was also observed as compared with free OPH. Liposome containing protein hydrolysates may be used as a formula in functional foods. PRACTICAL APPLICATION: This study provides some useful information on the application of oyster protein hydrolysates or peptides in functional foods. The incorporation into liposomes may protect the hydrolysates against harsh conditions during storage and digestion, and also prolong the release time.

2.
Mol Biol Rep ; 48(2): 1151-1159, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33565022

RESUMO

Leukocytes reflect the physiological and pathological states of each individual, and transcriptomic data of leukocytes have been used to reflect health conditions. Since the overall impact of ex vivo conditions on the leukocyte transcriptome before RNA stabilization remains unclear, we evaluated the influence of temporary storage conditions on the leukocyte transcriptome through RNA sequencing. We collected peripheral blood with EDTA tubes, which were processed immediately or stored either at 4 °C or room temperature (RT, 18-22 °C) for 2 h, 6 h and 24 h. Total cellular RNA was extracted from 42 leukocyte samples after red blood cells lysis for subsequent RNA sequencing. We applied weighted gene co-expression network analysis to construct co-expression networks of mRNA and lncRNA among the samples, and then performed gene ontology (GO) term enrichment to explore possible biological processes affected by storage conditions. Storage conditions change the gene expression of peripheral leukocytes. Comparing with fresh leukocytes, storage for 24 h at 4 °C and RT affected 1515 (1.51%) and 10,823 (10.82%) genes, respectively. Pathway enrichment analysis identified nucleosome assembly enriched in up-regulated genes at both conditions. When blood was stored at RT for 24 h, genes involved in apoptotic signaling pathway, negative regulation of cell cycle and lymphocyte activation were upregulated, while the relative proportion of neutrophils was significantly decreased. Temporary storage conditions profoundly affect the gene expression profiles of leukocytes and might further change cell viability and state. Storage of blood samples at 4 °C within 6 h largely maintains their original transcriptome.

3.
Neoplasia ; 23(2): 222-233, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33387960

RESUMO

Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/ß-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with ß-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/ß-catenin pathway and could serve as a potential therapeutic target in LUAD.

4.
Artigo em Inglês | MEDLINE | ID: mdl-33296314

RESUMO

Learning over massive data stored in different locations is essential in many real-world applications. However, sharing data is full of challenges due to the increasing demands of privacy and security with the growing use of smart mobile devices and Internet of thing (IoT) devices. Federated learning provides a potential solution to privacy-preserving and secure machine learning, by means of jointly training a global model without uploading data distributed on multiple devices to a central server. However, most existing work on federated learning adopts machine learning models with full-precision weights, and almost all these models contain a large number of redundant parameters that do not need to be transmitted to the server, consuming an excessive amount of communication costs. To address this issue, we propose a federated trained ternary quantization (FTTQ) algorithm, which optimizes the quantized networks on the clients through a self-learning quantization factor. Theoretical proofs of the convergence of quantization factors, unbiasedness of FTTQ, as well as a reduced weight divergence are given. On the basis of FTTQ, we propose a ternary federated averaging protocol (T-FedAvg) to reduce the upstream and downstream communication of federated learning systems. Empirical experiments are conducted to train widely used deep learning models on publicly available data sets, and our results demonstrate that the proposed T-FedAvg is effective in reducing communication costs and can even achieve slightly better performance on non-IID data in contrast to the canonical federated learning algorithms.

5.
J Am Heart Assoc ; 9(19): e015759, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33003970

RESUMO

Background The purpose of this study was to determine whether the presence of antegrade blood flow was related to stroke subtype in patients with acute intracranial large artery occlusion. Methods and Results The prospectively collected data for consecutive patients who had occlusion of the unilateral M1 segment of the middle cerebral artery with or without internal carotid artery and received reperfusion therapy were retrospectively reviewed. Stroke causes were determined according to the Trial of ORG 10172 in Acute Stroke Treatment standard. We defined antegrade flow as early opacification at the distal interface of the clot with subsequent distal extension on 4-dimensional computed tomography angiography. A total of 387 large artery occlusion patients were analyzed (229 men and 158 women; mean age, 71±14 years), including 77 (19.9%) with large artery atherosclerosis (LAA), 206 (53.2%) with cardioembolism, and 104 (26.9%) with undetermined causes. Antegrade flow was found in 206 (53.2%) patients, and 181 (46.8%) presented with retrograde flow. The rate of antegrade flow was much higher in patients with LAA than in those with cardioembolism (85.7% versus 42.2%, P<0.001). Multivariable logistic regression revealed that presence of antegrade flow was significantly associated with cuse of LAA after adjusting for confounding factors, when setting cardioembolism as reference (odds ratio, 5.650; 95% confidence interval, 2.451-13.158; P<0.001). The sensitivity, specificity, and positive and negative predictive values of the antegrade flow for predicting LAA were 43.1%, 91.5%, 85.7%, and 57.8%, respectively. Conclusions Using 4-dimensional computed tomography angiography, antegrade flow can be identified in more than half of acute anterior large artery occlusion patients and occurs more frequently in those with LAA as the cause of stroke.

6.
Cell Rep ; 33(3): 108284, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-33086070

RESUMO

The Hippo signaling pathway maintains organ size and tissue homeostasis via orchestration of cell proliferation and apoptosis. How this pathway triggers cell apoptosis remains largely unexplored. Here, we identify NR4A1 as a target of the Hippo pathway that mediates the pro-apoptotic and anti-tumor effects of the Hippo pathway whereby YAP regulates the transcription, phosphorylation, and mitochondrial localization of NR4A1. NR4A1, in turn, functions as a feedback inhibitor of YAP to promote its degradation, thereby inhibiting the function of YAP during liver regeneration and tumorigenesis. Our studies elucidate a regulatory loop between NR4A1 and YAP to coordinate Hippo signaling activity during liver regeneration and tumorigenesis and highlight NR4A1 as a marker of Hippo signaling, as well as a therapeutic target for hepatocellular carcinoma.

7.
Am J Transl Res ; 12(7): 3133-3148, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32774690

RESUMO

This study aims to reveal the biological relevancy between melanosis coli (MC) with colon cancer by analyzing the proteomics differences of tissues of melanosis coli, colon cancer, and normal ones to probe into the causes and development mechanisms of MC from the perspective of biomolecules. Fourteen differential protein spots were found in the study after using two-dimensional gel electrophoresis (2-DE) and bio-mass spectrometry (MALDI-TOF/TOF-MS). Specifically, six and eight differential protein spots in the melanosis coli tissues were detected, respectively, compared with the normal tissues and colon cancer tissues. Eight kinds of proteins, including keratin 8 (KRT8), keratin 18 (KRT18), fibrinogen beta chain isoform 2 preproprotein (FGB), catalase (CAT), 26s protease regulatory subunit 10b (PSMC6), isoform 1 of tropomyosin alpha-4 chain (TPM4), carbonic anhydrase 1 (CA1), isoform of prelammin-A/C (LMNA), were retrieved through the mass spectral database, which could be deemed as associated proteins of MC and colon cancer. The different expressions in the disease tissues indicate that these proteins may be connected with the carcinogenesis of MC as well as the malignant proliferation, development, differentiation, and diffusion of cancer cells.

8.
J Pharm Pharmacol ; 72(12): 1771-1786, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32648321

RESUMO

OBJECTIVES: Bavachin is a bioactive natural flavonoid with oestrogen-like activity. Here, we aimed to investigate its metabolic and disposal fates involving in CYPs, UGTs and efflux transporters. METHODS: Phase I metabolism and glucuronidation were performed by human liver microsomes (HLM). Reaction phenotyping and activity correlation analysis were performed to identify the main CYP and UGT isozymes. Chemical inhibition and gene knock-down approaches were employed to explore the function of BCRP and MRPs. KEY FINDINGS: Five phase I metabolites (M1-M5) and three glucuronides (G1-G3) were identified. The CLint values for M4 and G1 by HLM were 127.99 and 1159.07 µl/min per mg, respectively. Reaction phenotyping results suggested CYP1A1 (208.85 µl/min per mg) and CYP2C9 (107.51 µl/min per mg), and UGT1A1 (697.19 µl/min per mg), UGT1A7 (535.78 µl/min per mg), UGT1A8 (247.72 µl/min per mg) and UGT1A9 (783.68 µl/min per mg) all participated in the metabolism of bavachin. In addition, activity correlation analysis also supported the results above. Furthermore, the metabolism exhibited marked species differences, and rabbits were the appropriate model animals. Moreover, MRP4 was identified as the main contributor based on chemical inhibition and gene silencing approaches. CONCLUSIONS: CYP1A1 and CYP2C9, UGT1A1, UGT1A7, UGT1A8 and UGT1A9, and MRP4 all played important roles in the metabolism and disposition of bavachin.

9.
Environ Int ; 139: 105672, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32248022

RESUMO

There are currently increasingly concerns over DNA damage related to free radicals due to their vital roles in human health, especially high-performance detection method. Herein, we report an ultra- sensitive monitoring of DNA damage associated with free radicals exposure using interdigitated electrode (IDE) array for the first time. The proposed IDE array was equipped with DNA-wrapped carbon nanotube-based bridges, which utilized the DNA damage mechanism due to the free radicals' attack and the efficient electrical detection nature of the interdigitated electrode. Experiments have been performed, and the results showed the device's capability for detecting DNA damage induced by multiple free radicals generated from different sources, including the Fenton reaction, UV radiation and cigarette smoke, showing the promising ability for DNA damage detection. In addition, the carbon nanotubes bridge-based interdigitated electrode sensor enabled different levels of sensing of DNA damage with great sensitivity and a wide detection range. It was illustrated that the ultrasensitive detection of free radicals generated from ultraviolet radiation (15 min - 125 min), cigarette smoke tar (1 µg/mL to 10 µg/mL) and Fenton reaction under different concentration of H2O2 (2.5 pM - 100 pM), have been detected successfully. Typically, the IDE array supports further performance improvement for the electrochemical detection in an ultrasensitive and high throughput route.


Assuntos
Técnicas Biossensoriais , Nanotubos de Carbono , Dano ao DNA , Eletrodos , Humanos , Peróxido de Hidrogênio , Nanotubos de Carbono/toxicidade , Raios Ultravioleta
10.
Opt Express ; 28(5): 6966-6980, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-32225933

RESUMO

In this paper, the rate equations describing the operation of intracavity-pumped Q-switched terahertz parametric oscillators based on stimulated polariton scattering are given for the first time. The rate equations are obtained under the plane-wave approximation, the oscillating fundamental and Stokes waves are supposed to be round uniform beam spots. Considering the fact that the terahertz wave nearly traverses the pump and Stokes beams and using the coupled wave equations, the terahertz wave intensity is expressed as the function of the fundamental and Stokes intensities. Thus, the rate equations describing the evolution processes of the fundamental and Stokes waves are obtained in the first step. The THz wave properties are then obtained. Several curves based on the rate equations are generated to illustrate the effects of the nonlinear coefficient, the THz wave absorption coefficient, and pulse repetition rate on the THz laser characteristics. Taking the intracavity-pumped Mg:LiNbO3 TPO as an example, the THz frequency tuning characteristic and the dependences of the fundamental, Stokes, and THz wave powers on the incident diode pump power are calculated. The theoretical results are in agreement with the experimental results on the whole.

11.
Xenobiotica ; 50(8): 997-1008, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32116078

RESUMO

Corylifol A (CA), a phenolic compound from Psoralea corylifolia, possessed several biological properties but poor bioavailability. Here we aimed to investigate the roles of cytochromes P450s (CYPs), UDP-glucuronosyltransferases (UGTs) and efflux transporters in metabolism and disposition of CA.Metabolism of CA was evaluated in HLM, expressed CYPs and UGTs. Chemical inhibitors and shRNA-mediated gene silencing of multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP) were performed to assess the roles of transporters in CA disposition.Three oxidated metabolites (M1-M3) and two glucuronides (M4-M5) were detected. The intrinsic clearances (CLint) values of M1 and M4 in HLM were 48.10 and 184.03 µL/min/mg, respectively. Additionally, CYP1A1, 2C8 and 2C19 were identified as main contributors with CLint values of 13.01-49.36 µL/min/mg, while UGT1A1, 1A7, 1A8 and 1A9 were with CLint values ranging from 85.01 to 284.07 µL/min/mg. Furthermore, activity correlation analysis proved CYP2C8, UGT1A1 and 1A9 were the main active hepatic isozymes. Besides, rats and monkeys were appropriate model animals. Moreover, dipyridamole and MK571 both could significantly inhibit M4 efflux. Gene silencing results also indicated MRP4 and BCRP were major contributors in HeLa1A1 cells.Taken together, CYPs, UGTs, MRP4 and BCRP were important determinants of CA pharmacokinetics.


Assuntos
Flavonas/metabolismo , Animais , Transporte Biológico , Sistema Enzimático do Citocromo P-450/metabolismo , Glucuronosiltransferase/metabolismo , Células HeLa , Humanos , Psoralea , Ratos
12.
Sensors (Basel) ; 20(3)2020 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-32046019

RESUMO

A highly selective and sensitive molecularly imprinted electrochemiluminescence (MIECL) sensor was developed based on the multiwall carbon nanotube (MWCNT)-enhanced molecularly imprinted quantum dots (MIP-QDs) for the rapid determination of cyfluthrin (CYF). The MIP-QDs fabricated by surface grafting technique exhibited excellent selective recognition to CYF, resulting in a specific decrease of ECL signal at the MWCNT/MIP-QD modified electrode. Under optimal conditions, the MIECL signal was proportional to the logarithm of the CYF concentration in the range of 0.2 µg/L to 1.0 × 103 µg/L with a determination coefficient of 0.9983. The detection limit of CYF was 0.05 µg/L, and good recoveries ranging from 86.0% to 98.6% were obtained in practical samples. The proposed MIECL sensor provides a novel, rapid, high sensitivity detection strategy for successfully analyzing CYF in fish and seawater samples.

13.
Opt Lett ; 45(4): 861-864, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-32058490

RESUMO

Stimulated polariton scattering (SPS) and stimulated Raman scattering (SRS) in ${{\rm RbTiOPO}_4}$RbTiOPO4 (RTP) crystal are combined in an intracavity-pumped Stokes parametric oscillator (SPO) to extend the tunable Stokes laser spectral range. The pumping laser wavelength is 1064 nm from a diode-end-pumped acousto-optically Q-switched Nd:YAG laser. By the SPS process in the SPO, the SPS-Stokes wave can be discontinuously tuned in the range of 1075.7-1076.0 nm, 1077.7-1080.4 nm, 1081.8-1082.2 nm, and 1084.8-1087.8 nm, respectively. By the following SRS process in the same RTP crystal, the laser wavelength is further shifted in the range of 1107.7-1108.1 nm, 1109.0-1112.7 nm, 1114.3-1115.1 nm, and 1117.8-1121.1 nm, respectively. A maximal average output power of 970 mW is achieved for the SRS-Stokes wave at the peak wavelength of 1118.8 nm. It is obtained when the diode power is 7.9 W, and the pulse repetition frequency (PRF) is 10 kHz.

14.
J Cell Biochem ; 121(11): 4458-4469, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32030815

RESUMO

Cell proliferation, apoptosis, and autophagy have been reported to be related to myocardial ischemia injury. MicroRNAs have attracted wide attention on regulating cell proliferation, apoptosis, and autophagy. miR-1 expression has been reported to be dysregulated in cardiac tissue or cells with hypoxia, while the exact roles as well as underlying mechanism remain poorly understood. In this study, we investigated the potential roles of miR-1 in cell proliferation, apoptosis, and autophagy in hypoxia-treated cardiac injury and explored the underlying mechanism using H9c2 cells. Results showed that hypoxic stimulation inhibited cell proliferation and the expression of miR-1 but promoted cell apoptosis in H9c2 cells. Moreover, overexpression of miR-1 promoted cell apoptosis and inhibited cell proliferation and autophagy in H9c2 cells treated with hypoxia, while its knockdown played an opposite effect. In addition, bioinformatics, luciferase reporter, and RNA immunoprecipitation analyses indicated that NOTCH3 was a direct target of miR-1 and its upregulation reversed the effects of miR-1 on cell proliferation, apoptosis, and autophagy in hypoxia-treated H9c2 cells. Taken together, our data suggested that miR-1 promoted hypoxia-induced injury by targeting NOTCH3, indicating novel therapeutic targets for treatment of myocardial ischemia injury.

15.
Elife ; 92020 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-31934851

RESUMO

Tissue homeostasis and regeneration in the Drosophila midgut is regulated by a diverse array of signaling pathways including the Hippo pathway. Hippo signaling restricts intestinal stem cell (ISC) proliferation by sequestering the transcription co-factor Yorkie (Yki) in the cytoplasm, a factor required for rapid ISC proliferation under injury-induced regeneration. Nonetheless, the mechanism of Hippo-mediated midgut homeostasis and whether canonical Hippo signaling is involved in ISC basal proliferation are less characterized. Here we identify Lola as a transcription factor acting downstream of Hippo signaling to restrict ISC proliferation in a Yki-independent manner. Not only that Lola interacts with and is stabilized by the Hippo signaling core kinase Warts (Wts), Lola rescues the enhanced ISC proliferation upon Wts depletion via suppressing Dref and SkpA expressions. Our findings reveal that Lola is a non-canonical Hippo signaling component in regulating midgut homeostasis, providing insights on the mechanism of tissue maintenance and intestinal function.

16.
Molecules ; 25(3)2020 Jan 23.
Artigo em Inglês | MEDLINE | ID: mdl-31979295

RESUMO

The behavior of ice under extreme conditions undergoes the change of intermolecular binding patterns and leads to the structural phase transitions, which are needed for modeling the convection and internal structure of the giant planets and moons of the solar system as well as H2O-rich exoplanets. Such extreme conditions limit the structural explorations in laboratory but open a door for the theoretical study. The ice phases IX and XIII are located in the high pressure and low temperature region of the phase diagram. However, to the best of our knowledge, the phase transition boundary between these two phases is still not clear. In this work, based on the second-order Møller-Plesset perturbation (MP2) theory, we theoretically investigate the ice phases IX and XIII and predict their structures, vibrational spectra and Gibbs free energies at various extreme conditions, and for the first time confirm that the phase transition from ice IX to XIII can occur around 0.30 GPa and 154 K. The proposed work, taking into account the many-body electrostatic effect and the dispersion interactions from the first principles, opens up the possibility of completing the ice phase diagram and provides an efficient method to explore new phases of molecular crystals.


Assuntos
Gelo , Transição de Fase , Água/química , Temperatura Baixa , Cristalização , Modelos Moleculares , Pressão , Teoria Quântica , Análise Espectral Raman , Eletricidade Estática , Termodinâmica , Temperatura de Transição
17.
J Hazard Mater ; 389: 121884, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-31879102

RESUMO

Molecularly imprinted quantum dots (MIP-QDs) were successfully synthesized via reversed-phase microemulsion and used as the specific recognition element and signal probe of a fluorescence sensor or test strip to achieve the highly sensitive detection of propanil. The physical-chemical characteristics and excellent selectivity of MIP-QDs were elucidated. Under optimized parameters, the MIP-QDs had good linearity at the propanil concentration range of 1.0 µg/L to 20.0 × 103 µg/L by fluorescence quenching. The developed MIP-QD-based fluorescence sensor showed good recoveries ranging from 87.2 % to 112.2 %, and the relative standard deviation was below 6.0 % for the fish and seawater samples. In addition, the limits of detection (LODs) for fish and seawater were 0.42 µg/kg and 0.38 µg/L, respectively. The fluorescence test strip developed on the basis of the MIP-QDs also displayed satisfactory recoveries of 90.1 %-111.1 %, and the LOD for propanil in the seawater sample was 0.6 µg/L. The proposed fluorescence sensor and test strip were successfully used in propanil determination in environment and aquatic products.

18.
J Cereb Blood Flow Metab ; 40(9): 1797-1805, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31619117

RESUMO

Our purpose is to assess the role of deep medullary veins in pathogenesis of lacunes in patients with cerebral small vessel disease (cSVD). We included patients with baseline and 2.5-year follow-up MRI in CIRCLE study. Susceptibility Weighted Imaging-Phase images were used to evaluate deep medullary veins based on a brain region-based visual score, and T2-Fluid-Attenuated-Inversion-Recovery images were used to evaluate lacunes. Cerebral blood flow and microstructural parameters in white matter hyperintensities and normal appearing white matter were also analyzed. A total of 203 cSVD patients were analyzed and 101 (49.8%) patients had baseline lacunes. Among them, 64 patients had follow-up MRI, including 16 (25.0%) with new lacunes. The patients' deep medullary veins median score was 9 (7-12). At baseline, high deep medullary veins score was independently associated with the presence of lacunes after adjusting for age, diabetes mellitus, white matter hyperintensities volume and cerebral blood flow or white matter microstructural parameters (all p < 0.001). Longitudinally, high deep medullary veins score was independently associated with new lacunes after adjusting for gender (p < 0.001). The association was also independent of white matter hyperintensities volumes, cerebral blood flow or white matter microstructural parameters (all p < 0.05). Our results suggest that deep medullary veins disruption might be involved in pathogenesis of lacunes.

19.
Hepatology ; 71(6): 1988-2004, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31538665

RESUMO

BACKGROUND AND AIMS: The conserved Hippo pathway regulates organ size, tissue homeostasis, and tumorigenesis. Interferon regulatory factor 2 binding protein 2 (IRF2BP2) was originally identified as a transcriptional corepressor. However, the association between IRF2BP2 and the Hippo pathway remains largely unknown. In addition, the biological function and regulation mechanism of IRF2BP2 in liver cancer are poorly understood. APPROACH AND RESULTS: In this study, we uncovered the clinical significance of IRF2BP2 in suppressing hepatocellular carcinogenesis. We showed that IRF2BP2, a direct target repressed by the Yes-associated protein (YAP)/TEA domain transcription factor 4 (TEAD4) transcriptional complex, inhibited YAP activity through a feedback loop. IRF2BP2 stabilized vestigial-like family member 4 (VGLL4) and further enhanced VGLL4's inhibitory function on YAP. Moreover, liver-specific IRF2BP2 overexpression suppressed tumor formation induced by Hippo pathway inactivation. CONCLUSIONS: These results revealed the important role of IRF2BP2 in repressing liver cancer progression and highlighted a feedback loop underlying the Hippo pathway in organ-size control and tumorigenesis.

20.
Cell Mol Immunol ; 17(11): 1136-1147, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31511643

RESUMO

Interleukin-17A (IL-17A)-producing helper T (Th17) cells are a subset of CD4+ T cells that play important pathological roles in autoimmune diseases. Although the intrinsic pathways of Th17 cell differentiation have been well described, how instructive signals derived from the innate immune system trigger the Th17 response and inflammation remains poorly understood. Here, we report that mice deficient in REGγ, a proteasome activator belonging to the 11S family, exhibit significantly deteriorated autoimmune neuroinflammation in an experimental autoimmune encephalomyelitis (EAE) model with augmented Th17 cell polarization in vivo. The results of the adoptive transfer of CD4+ T cells or dendritic cells (DCs) suggest that this phenotype is driven by DCs rather than T cells. Furthermore, REGγ deficiency promotes the expression of integrin αvß8 on DCs, which activates the maturation of TGF-ß1 to enhance Th17 cell development. Mechanistically, this process is mediated by the REGγ-proteasome-dependent degradation of IRF8, a transcription factor for αvß8. Collectively, our findings delineate a previously unknown mechanism by which REGγ-mediated protein degradation in DCs controls the differentiation of Th17 cells and the onset of an experimental autoimmune disease.

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