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1.
Front Psychol ; 13: 830377, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35465580

RESUMO

Dynamic capabilities are crucial to the survival and development of enterprises in the BOP (Base/Bottom of the Pyramid, hereinafter BOP) market. The research focuses on the double-edged sword impact of relational embeddedness on dynamic capabilities via ambidextrous learning, that is moderate embeddedness facilitates dynamic capabilities while overembeddedness inhibits them. Furthermore, this study investigates whether human capital moderates the relationships between relational embeddedness and ambidextrous learning. Selecting 264 samples for empirical research, firstly, the results show that the relational embeddedness in the BOP cooperation network has an inverted U-shaped influence on ambidextrous learning and dynamic capabilities. Secondly, exploratory learning and exploitative learning play a mediating role in relational embeddedness and dynamic capabilities. Thirdly, prior experience plays a positive moderating role in relational embeddedness and exploitative learning. The conclusions facilitate understanding the antecedents of dynamic capabilities and the black box of "embeddedness paradox," and provide empirical evidence for adjusting the human capital of enterprises, enhancing the exploratory learning capability and exploitative learning capability, and coping with the overembeddedness effects.

2.
J Virol ; 96(2): e0159721, 2022 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-34757838

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) is a major economically significant pathogen and has evolved several strategies to evade host antiviral response and provide favorable conditions for survival. In the present study, we demonstrated that a host microRNA, miR-376b-3p, was upregulated by PRRSV infection through the viral components, nsp4 and nsp11, and that miR-376b-3p can directly target tripartite motif-containing 22 (TRIM22) to impair its anti-PRRSV activity, thus facilitating the replication of PRRSV. Meanwhile, we found that TRIM22 induced degradation of the nucleocapsid protein (N) of PRRSV by interacting with N protein to inhibit PRRSV replication, and further study indicated that TRIM22 could enhance the activation of the lysosomal pathway by interacting with LC3 to induce lysosomal degradation of N protein. In conclusion, PRRSV increased miR-376b-3p expression and hijacked the host miR-376b-3p to promote PRRSV replication by impairing the antiviral effect of TRIM22. Therefore, our finding outlines a novel strategy of immune evasion exerted by PRRSV, which is helpful for better understanding the pathogenesis of PRRSV. IMPORTANCE Porcine reproductive and respiratory syndrome virus (PRRSV) causes enormous economic losses each year in the swine industry worldwide. MicroRNAs (miRNAs) play important roles during viral infections via modulating the expression of viral or host genes at the posttranscriptional level. TRIM22 has recently been identified as a key restriction factor that inhibited the replication of a number of human viruses, such as HIV, encephalomyocarditis virus (ECMV), hepatitis C virus (HCV), HBV, influenza A virus (IAV), and respiratory syncytial virus (RSV). In this study, we showed that host miR-376b-3p could be upregulated by PRRSV and functioned to impair the anti-PRRSV role of TRIM22 to facilitate PRRSV replication. Meanwhile, we found that TRIM22 inhibited the replication of PRRSV by interacting with viral N protein and accelerating its degradation through the lysosomal pathway. Collectively, the findings reveal a novel mechanism that PRRSV used to exploit the host miR-376b-3p to evade antiviral responses and provide new insight into the study of virus-host interactions.


Assuntos
MicroRNAs/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Proteínas com Motivo Tripartido/genética , Replicação Viral , Animais , Linhagem Celular , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno , Humanos , Lisossomos/metabolismo , MicroRNAs/antagonistas & inibidores , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas do Nucleocapsídeo/metabolismo , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Proteínas com Motivo Tripartido/metabolismo
3.
Viruses ; 13(12)2021 12 13.
Artigo em Inglês | MEDLINE | ID: mdl-34960763

RESUMO

Selective autophagy mediates the degradation of cytoplasmic cargos, such as damaged organelles, invading pathogens, and protein aggregates. However, whether it targets double-stranded RNA (dsRNA) of intracellular pathogens is still largely unknown. Here, we show that selective autophagy regulates the degradation of the infectious bursal disease virus (IBDV) dsRNA genome. The amount of dsRNA decreased greatly in cells that overexpressed the autophagy-required protein VPS34 or autophagy cargo receptor SQSTM1, while it increased significantly in SQSTM1 or VPS34 knockout cells or by treating wild-type cells with the autophagy inhibitor chloroquine or wortmannin. Confocal microscopy and structured illumination microscopy showed SQSTM1 colocalized with dsRNA during IBDV infection. A pull-down assay further confirmed the direct binding of SQSTM1 to dsRNA through amino acid sites R139 and K141. Overexpression of SQSTM1 inhibited the replication of IBDV, while knockout of SQSTM1 promoted IBDV replication. Therefore, our findings reveal the role of SQSTM1 in clearing viral dsRNA through selective autophagy, highlighting the antiviral role of autophagy in the removal of the viral genome.


Assuntos
Autofagia/fisiologia , Infecções por Birnaviridae/prevenção & controle , Vírus da Doença Infecciosa da Bursa/fisiologia , RNA de Cadeia Dupla/metabolismo , RNA Viral/metabolismo , Proteína Sequestossoma-1/fisiologia , Células HEK293 , Humanos , Vírus da Doença Infecciosa da Bursa/genética , Replicação Viral
4.
Front Endocrinol (Lausanne) ; 12: 778758, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34956090

RESUMO

Background: Neuroendocrine carcinoma (NEC) is a rare and highly malignant variation of prostate adenocarcinoma. We aimed to investigate the prognostic value of NEC in prostate cancer. Methods: A total of 530440 patients of prostate cancer, including neuroendocrine prostate cancer (NEPC) and adenocarcinoma from 2004 to 2018 were obtained from the national Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (PSM), multivariable Cox proportional hazard model, Kaplan-Meier method and subgroup analysis were performed in our study. Results: NEPC patients were inclined to be older at diagnosis (Median age, 69(61-77) vs. 65(59-72), P< 0.001) and had higher rates of muscle invasive disease (30.9% vs. 9.2%, P < 0.001), lymph node metastasis (32.2% vs. 2.2%, P < 0.001), and distal metastasis (45.7% vs. 3.6%, P < 0.001) compared with prostate adenocarcinoma patients. However, the proportion of NEPC patients with PSA levels higher than 4.0 ng/mL was significantly less than adenocarcinoma patients (47.3% vs. 72.9%, P<0.001). NEPC patients had a lower rate of receiving surgery treatment (28.8% vs. 43.9%, P<0.001), but they had an obviously higher rate of receiving chemotherapy (57.9% vs. 1.0%, P<0.001). A Cox regression analysis demonstrated that the NEPC patients faced a remarkably worse OS (HR = 2.78, 95% CI = 2.34-3.31, P < 0.001) and CSS (HR = 3.07, 95% CI = 2.55-3.71, P < 0.001) compared with adenocarcinoma patients after PSM. Subgroup analyses further suggested that NEPC patients obtained significantly poorer prognosis across nearly all subgroups. Conclusion: The prognosis of NEPC was worse than that of adenocarcinoma among patients with prostate cancer. The histological subtype of NEC is an independent prognostic factor for patients with prostate cancer.


Assuntos
Carcinoma Neuroendócrino/diagnóstico , Neoplasias da Próstata/diagnóstico , Adenocarcinoma/diagnóstico , Adenocarcinoma/epidemiologia , Adenocarcinoma/patologia , Idoso , Carcinoma Neuroendócrino/epidemiologia , Carcinoma Neuroendócrino/patologia , Bases de Dados Factuais/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Pontuação de Propensão , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Fatores de Risco , Programa de SEER
5.
Front Oncol ; 11: 775250, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804980

RESUMO

Hepatocellular carcinoma (HCC) is a highly lethal type of malignancies that possesses great loss of life safety to human beings worldwide. However, few effective means of curing HCC exist and its specific molecular basis is still far from being fully elucidated. Activation of nuclear factor kappa B (NF-κB), which is often observed in HCC, is considered to play a significant part in hepatocarcinogenesis and development. The emergence of regulatory non-coding RNAs (ncRNAs), particularly microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is a defining advance in cancer biology, and related research in this branch has yielded many diagnostic and therapeutic opportunities. Recent studies have suggested that regulatory ncRNAs act as inhibitors or activators in the initiation and progression of HCC by targeting components of NF-κB signaling or regulating NF-κB activity. In this review, we attach importance to the role and function of regulatory ncRNAs in NF-κB signaling of HCC and NF-κB-associated chemoresistance in HCC, then propose future research directions and challenges of regulatory ncRNAs mediated-regulation of NF-κB pathway in HCC.

6.
Cell Death Dis ; 12(9): 827, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34480020

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive brain tumor, with a 5-year survival ratio <5%. Invasive growth is a major determinant of the poor prognosis in GBM. In this study, we demonstrate that high expression of PPFIA binding protein 1 (PPFIBP1) correlates with remarkable invasion and poor prognosis of GBM patients. Using scratch and transwell assay, we find that the invasion and migration of GBM cells are promoted by overexpression of PPFIBP1, while inhibited by knockdown of PPFIBP1. Then, we illustrate that overexpression of PPFIBP1 facilitates glioma cell infiltration and reduces survival in xenograft models. Next, RNA-Seq and GO enrichment analysis reveal that PPFIBP1 regulates differentially expressed gene clusters involved in the Wnt and adhesion-related signaling pathways. Furthermore, we demonstrate that PPFIBP1 activates focal adhesion kinase (FAK), Src, c-Jun N-terminal kinase (JNK), and c-Jun, thereby enhancing Matrix metalloproteinase (MMP)-2 expression probably through interacting with SRCIN1 (p140Cap). Finally, inhibition of phosphorylation of Src and FAK significantly reversed the augmentation of invasion and migration caused by PPFIBP1 overexpression in GBM cells. In conclusion, these findings uncover a novel mechanism of glioma invasion and identify PPFIBP1 as a potential therapeutic target of glioma.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Movimento Celular , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Glioma/patologia , Sistema de Sinalização das MAP Quinases , Quinases da Família src/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Animais , Linhagem Celular Tumoral , Adesões Focais/metabolismo , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Glioma/diagnóstico por imagem , Glioma/genética , Células HEK293 , Humanos , Imageamento por Ressonância Magnética , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Fosforilação , Prognóstico , Ligação Proteica , Proteínas Proto-Oncogênicas c-jun/metabolismo , Análise de Sobrevida , Regulação para Cima/genética , Cicatrização
8.
PeerJ ; 9: e11420, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34123587

RESUMO

BACKGROUND: Osteoporosis (OP) is a systemic disease with bone loss and microstructural deterioration. Numerous noncoding RNAs (ncRNAs) have been proved to participate in various diseases, especially circular RNAs (circRNAs). However, the expression profile and mechanisms underlying circRNAs in male osteoporosis have not yet been explored. METHODS: The whole transcriptome expression profile and differences in mRNAs, circRNAs, and microRNAs (miRNAs) were investigated in peripheral blood samples of patients with osteoporosis and healthy controls consisting of males ≥ 60-years-old. RESULTS: A total of 398 circRNAs, 51 miRNAs, and 642 mRNAs were significantly and differentially expressed in osteoporosis compared to healthy controls. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that the host genes of significantly differentially expressed circRNAs were mainly enriched in the regulation of cell cycle process: biological process (BP), organelle part cellular components (CC), protein binding molecular function (MF), Toll-like receptor signaling pathway, tumor necrosis factor (TNF) signaling pathway, and thyroid hormone signaling pathway. circRNA-miRNA-mRNA regulatory network was constructed using the differentially expressed RNAs. Moreover, key circRNAs (hsa_circ_0042409) in osteoporosis were discovered and validated by qPCR. CONCLUSIONS: The key cicrRNAs plays a major role in the pathogenesis of osteoporosis and could be used as potential biomarkers or targets in the diagnosis and treatment of osteoporosis.

9.
Talanta ; 231: 122360, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-33965026

RESUMO

Amyloid-ß oligomer is an important biomarker and a potential therapeutic target of Alzheimer's disease in its early stage. Here, we combined superhydrophobic carbon fiber paper (CFP) with AuPt alloy nanoparticles to prepare a CFP/AuPt nanocomposite with larger specific surface area and hydrophobic surface. On this basis, we constructed an electrochemical aptasensor based on CFP/AuPt for the ultrasensitive detection of amyloid-ß oligomers. The surface-coated AuPt nanoparticles greatly enhanced the electroactive area, and the hydrophobic surface increased the resisting nonspecific adsorption performance of sensor. A combination of these two features significantly improved the sensitivity and specificity of the sensor. This electrochemical aptasensor based on CFP/AuPt displayed a low detection limit of 0.16 pg/mL. This work shows a promising future in clinical diagnosis of Alzheimer's disease and provides a possible solution to electrochemical biosensors that are susceptible to interference in biological fluids.


Assuntos
Aptâmeros de Nucleotídeos , Técnicas Biossensoriais , Nanopartículas Metálicas , Ligas , Peptídeos beta-Amiloides , Técnicas Eletroquímicas , Ouro , Limite de Detecção
10.
Med Sci Monit ; 27: e929170, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33875631

RESUMO

BACKGROUND Postmenopausal osteoporosis, a common disease among elderly women, is linked to estrogen deficiency, mechanical loading, and genotype. Circular RNAs (circRNAs) are formed through reverse splicing of the splice donor at the 3' end and the splice accepter at the 5' end in pre-mRNA and have been shown to be involved in the development of multiple diseases. Based on their high sequence conservation and stability, circRNAs may be useful biomarkers in different diseases. However, the roles of circRNAs in postmenopausal osteoporosis remain incompletely understood. MATERIAL AND METHODS Fifty-three postmenopausal women were assigned to either the postmenopausal osteoporosis group (n=28) or the control group (n=25). Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the differential expression of circRNAs between the 2 groups. Receiver-operating characteristic (ROC) curve analysis was conducted to evaluate the clinical diagnostic value of circRNA. Prediction of the binding sites between circRNA and miRNAs was conducted using miRanda and RNAhybrid. The function of the circRNA in osteoclastogenesis was determined by circRNA overexpression followed by tartrate-resistant acid phosphatase staining and RT-qPCR analysis. RESULTS Among 4 circRNAs previously identified by RNA-sequencing analysis as differentially expressed in patients with postmenopausal osteoporosis, only hsa_circ_0021739 showed a significant difference in expression between the groups and was downregulated in patients with postmenopausal osteoporosis. The hsa_circ_0021739 expression level was determined to be correlated with the lumbar vertebra, femur, and forearm T-scores. Overexpression of hsa_circ_0021739 decreased the level of hsa-miR-502-5p and inhibited the differentiation of osteoclasts. CONCLUSIONS The circRNA hsa_circ_0021739 is a potential blood biomarker for postmenopausal osteoporosis. In addition, hsa-miR-502-5p is a likely target of hsa_circ_0021739, which acts to regulate the differentiation of osteoclasts.


Assuntos
Leucócitos Mononucleares/imunologia , MicroRNAs/genética , Osteoclastos/fisiologia , Osteoporose Pós-Menopausa/genética , RNA Circular/genética , Idoso , Biomarcadores , Diferenciação Celular , Células Cultivadas , Regulação para Baixo , Feminino , Humanos , Osteoporose Pós-Menopausa/imunologia , Curva ROC , Transcriptoma
11.
Growth Change ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33821025

RESUMO

Over the last two decades, scholars have pointed to the significance of the impact of extreme events on consumption, a prominent part of national economies. How does the COVID-19 epidemic influence consumption? Using high-frequency payment system panel data, we explicitly consider the individual consumption changes and the substitution effect between online and offline markets of multiple categories by constructing autoregressive integrated moving average (ARIMA) models and conducting regression analyses. The p value and regression coefficients of the substitution elasticity are used to estimate the changes and the substitution effects from the offline to the online channels. The results show that consumption saw a remarkable decline after the surge of COVID-19 in 2020 compared to 2019. Overall, online markets were more resilient than the offline markets and the substitution effects after the epidemic's outbreak between the online and offline markets were significant for one-third of the consumption categories. However, the online market could not replace the offline market for some categories due to the product characteristics. The vulnerable industries in the face of the epidemic's intervention are determined as being traditional catering, transportation, tourism, and education, and the shortage of healthcare services in extreme events is also pointed out. The results provide suggestions for policies on targeted enterprises and public service.

12.
J Ethnopharmacol ; 270: 113776, 2021 Apr 24.
Artigo em Inglês | MEDLINE | ID: mdl-33421597

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: After cerebral ischemia/reperfusion injury, pro-inflammatory M1 and anti-inflammatory M2 phenotypes of microglia are involved in neuroinflammation, in which activation of NLRP3 inflammasome and subsequent pyroptosis play essential roles. Salvianolic Acids for Injection (SAFI) is Chinese medicine injection which composed of multiple phenolic acids extracted from Radix Salviae Miltiorrhizae, and has been reported to generate neuroprotective effects after cerebral ischemic insult in clinical and animal studies. AIM OF THE STUDY: The present study was designed to investigate whether SAFI exerts neuroprotective effects by switching microglial phenotype and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia. MATERIALS AND METHODS: The middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/reoxygenation (OGD/R) model in co-cultured primary neurons and primary microglia were utilized. The neuroprotective effect of SAFI was evaluated through measuring neurological deficit scores, neuropathological changes, inflammatory factors, cell phenotype markers, and related proteins of NLRP3 inflammasome/pyroptosis axis. RESULTS: The results showed that SAFI treatment was able to: (1) produce a significant increase in neurological deficit scores and decrease in infarct volumes, and alleviate histological injury and neuronal apoptosis in cerebral cortex in MCAO/R model; (2) increase neuronal viability and reduce neuronal apoptosis in the OGD model; (3) reshape microglial polarization patterns from M1-like phenotype to M2-like phenotype; (4) inhibit the activation of the NLRP3 inflammasome and the expression of proteins related to NLRP3 inflammasome/pyroptosis axis in vivo and in vitro. CONCLUSION: These findings indicate that SAFI exert neuroprotective effect, probably via reducing neuronal apoptosis, switching microglial phenotype from M1 towards M2, and inhibiting NLRP3 inflammasome/pyroptosis axis in microglia.


Assuntos
Alcenos/farmacologia , Anti-Inflamatórios não Esteroides/administração & dosagem , Inflamassomos/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fármacos Neuroprotetores/administração & dosagem , Polifenóis/farmacologia , Piroptose/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Sistema ASC de Transporte de Aminoácidos/genética , Sistema ASC de Transporte de Aminoácidos/metabolismo , Animais , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Caspase 1/genética , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Injeções Intraperitoneais , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas dos Microfilamentos/metabolismo , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteínas de Ligação a Fosfato/antagonistas & inibidores , Proteínas de Ligação a Fosfato/genética , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo
13.
Cell Commun Signal ; 19(1): 9, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33478523

RESUMO

BACKGROUND: To investigate the effect of lactic acid (LA) on the progression of bone metastasis from colorectal cancer (CRC) and its regulatory effects on primary CD115 (+) osteoclast (OC) precursors. METHODS: The BrdU assay, Annexin-V/PI assay, TRAP staining and immunofluorescence were performed to explore the effect of LA on the proliferation, apoptosis and differentiation of OC precursors in vitro and in vivo. Flow cytometry was performed to sort primary osteoclast precursors and CD4(+) T cells and to analyze the change in the expression of target proteins in osteoclast precursors. A recruitment assay was used to test how LA and Cadhein-11 regulate the recruitment of OC precursors. RT-PCR and Western blotting were performed to analyze the changes in the mRNA and protein expression of genes related to the PI3K-AKT pathway and profibrotic genes. Safranin O-fast green staining, H&E staining and TRAP staining were performed to analyze the severity of bone resorption and accumulation of osteoclasts. RESULTS: LA promoted the expression of CXCL10 and Cadherin-11 in CD115(+) precursors through the PI3K-AKT pathway. We found that CXCL10 and Cadherin-11 were regulated by the activation of CREB and mTOR, respectively. LA-induced overexpression of CXCL10 in CD115(+) precursors indirectly promoted the differentiation of osteoclast precursors through the recruitment of CD4(+) T cells, and the crosstalk between these two cells promoted bone resorption in bone metastasis from CRC. On the other hand, Cadherin-11 mediated the adhesion between osteoclast precursors and upregulated the production of specific collagens, especially Collagen 5, which facilitated fibrotic changes in the tumor microenvironment. Blockade of the PI3K-AKT pathway efficiently prevented the progression of bone metastasis caused by lactate. CONCLUSION: LA promoted metastatic niche formation in the tumor microenvironment through the PI3K-AKT pathway. Our study provides new insight into the role of LA in the progression of bone metastasis from CRC. Video Abstract.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Colorretais/metabolismo , Ácido Láctico/metabolismo , Animais , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Linfócitos T CD4-Positivos , Caderinas/genética , Caderinas/metabolismo , Adesão Celular , Diferenciação Celular , Movimento Celular , Células Cultivadas , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Técnicas de Cocultura , Colágeno/genética , Colágeno/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Osteoclastos , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Microambiente Tumoral
14.
Autophagy ; 17(9): 2166-2183, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-32876514

RESUMO

PDPK1 (3-phosphoinositide dependent protein kinase 1) is a phosphorylation-regulated kinase that plays a central role in activating multiple signaling pathways and cellular processes. Here, this study shows that PDPK1 turns on macroautophagy/autophagy as a SUMOylation-regulated kinase. In vivo data demonstrate that the SUMO modification of PDPK1 is a physiological feature in the brain and that it can be induced by viral infections. The SUMOylated PDPK1 regulates its own phosphorylation and subsequent activation of the AKT1 (AKT serine/threonine kinase 1)-MTOR (mechanistic target of rapamycin kinase) pathway. However, SUMOylation of PDPK1 is inhibited by binding to PIK3C3 (phosphatidylinositol 3-kinase catalytic subunit type 3). The nonSUMOylated PDPK1 then tethers LC3 to the endoplasmic reticulum to initiate autophagy, and it acts as a key component in forming the autophagic vacuole. Collectively, this study reveals the intricate molecular regulation of PDPK1 by post-translational modification in controlling autophagosome biogenesis, and it highlights the role of PDPK1 as a sensor of cellular stress and regulator of autophagosome biogenesis.Abbreviations: AKT1: AKT serine/threonine kinase 1; ATG14: autophagy related 14; Co-IP: co-immunoprecipitation; ER: endoplasmic reticulum; hpi: hours post-infection; mAb: monoclonal antibody; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; MTOR: mechanistic target of rapamycin kinase; pAb: polyclonal antibody; PDPK1: 3-phosphoinositide dependent protein kinase 1; PI3K: phosphoinositide 3-kinase; PIK3C3: phosphatidylinositol 3-kinase catalytic, subunit type 3; RPS6KB1: ribosomal protein S6 kinase B1; SGK: serum/glucocorticoid regulated kinase; SQSTM1: sequestosome 1; SUMO: small ubiquitin like modifier; UBE2I/UBC9: ubiquitin conjugating enzyme E2 I; UVRAG: UV radiation resistance associated.


Assuntos
Autofagossomos , Autofagia , Autofagossomos/metabolismo , Classe III de Fosfatidilinositol 3-Quinases/metabolismo , Macroautofagia , Transdução de Sinais
15.
BMJ Glob Health ; 5(11)2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33184065

RESUMO

INTRODUCTION: The COVID-19 pandemic caused a healthcare crisis in China and continues to wreak havoc across the world. This paper evaluated COVID-19's impact on national and regional healthcare service utilisation and expenditure in China. METHODS: Using a big data approach, we collected data from 300 million bank card transactions to measure individual healthcare expenditure and utilisation in mainland China. Since the outbreak coincided with the 2020 Chinese Spring Festival holiday, a difference-in-difference (DID) method was employed to compare changes in healthcare utilisation before, during and after the Spring Festival in 2020 and 2019. We also tracked healthcare utilisation before, during and after the outbreak. RESULTS: Healthcare utilisation declined overall, especially during the post-festival period in 2020. Total healthcare expenditure and utilisation declined by 37.8% and 40.8%, respectively, while per capita expenditure increased by 3.3%. In a subgroup analysis, we found that the outbreak had a greater impact on healthcare utilisation in cities at higher risk of COVID-19, with stricter lockdown measures and those located in the western region. The DID results suggest that, compared with low-risk cities, the pandemic induced a 14.8%, 26.4% and 27.5% reduction in total healthcare expenditure in medium-risk and high-risk cities, and in cities located in Hubei province during the post-festival period in 2020 relative to 2019, an 8.6%, 15.9% and 24.4% reduction in utilisation services; and a 7.3% and 18.4% reduction in per capita expenditure in medium-risk and high-risk cities, respectively. By the last week of April 2020, as the outbreak came under control, healthcare utilisation gradually recovered, but only to 79.9%-89.3% of its pre-outbreak levels. CONCLUSION: The COVID-19 pandemic had a significantly negative effect on healthcare utilisation in China, evident by a dramatic decline in healthcare expenditure. While the utilisation level has gradually increased post-outbreak, it has yet to return to normal levels.


Assuntos
Infecções por Coronavirus/epidemiologia , Gastos em Saúde/estatística & dados numéricos , Acesso aos Serviços de Saúde , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Pneumonia Viral/epidemiologia , Betacoronavirus , COVID-19 , China/epidemiologia , Humanos , Pandemias , SARS-CoV-2
16.
Front Microbiol ; 11: 566348, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117314

RESUMO

Autophagy can be utilized by the influenza A virus (IAV) to facilitate its replication. However, whether autophagy is induced at the stage of IAV entry is still unclear. Here, we report that IAV induces autophagy by hemagglutinin (HA) binding to heat shock protein 90AA1 (HSP90AA1) distributed on the cell surface. Virus overlay protein binding assay and pull-down assay indicated that IAV HA bound directly to cell surface HSP90AA1. Knockdown of HSP90AA1 weakened H1N1 infection. Incubation of IAV viral particles with recombinant HSP90AA1 or prior blockade of A549 cells with an anti-HSP90AA1 antibody could inhibit attachment of IAV. Moreover, we found that recombinant HA1 protein binding to cell surface HSP90AA1 was sufficient to induce autophagy through the AKT-MTOR pathway. Our study reveals that the HSP90AA1 on cell surface participates in IAV entry by directing binding to the HA1 subunit of IAV and subsequently induces autophagy.

17.
J Virol ; 94(24)2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967959

RESUMO

Selective autophagy regulates the degradation of cytoplasmic cargos, such as damaged organelles, invading pathogens, and aggregated proteins. Furthermore, autophagy is capable of degrading avibirnavirus, but the mechanism responsible for this process is unclear. Here, we show that autophagy cargo receptor p62 regulates the degradation of the avibirnavirus capsid protein VP2. Binding of p62 to VP2 enhances autophagic induction and promotes autophagic degradation of viral protein VP2. Further study showed that the interaction of p62 with viral protein VP2 is dependent on ubiquitination at the K411 site of VP2 and the ubiquitin-associated domain of p62. Mutation analysis showed that the K411R mutation of viral protein VP2 prohibits its p62-mediated degradation. Consistent with this finding, p62 lacking the ubiquitin-associated domain or the LC3-interacting region no longer promoted the degradation of VP2. Virus production revealed that the knockout of p62 but not the overexpression of p62 promotes the replication of avibirnavirus. Collectively, our findings suggest that p62 mediates selective autophagic degradation of avibirnavirus protein VP2 in a ubiquitin-dependent manner and is an inhibitor of avibirnavirus replication.IMPORTANCE Avibirnavirus causes severe immunosuppression and mortality in young chickens. VP2, the capsid protein of avibirnavirus, is responsible for virus assembly, maturation, and replication. Previous study showed that avibirnavirus particles could be engulfed into the autophagosome and degradation of virus particles took apart. Selective autophagy is a highly specific and regulated degradation pathway for the clearance of damaged or unwanted cytosolic components and superfluous organelles as well as invading microbes. However, whether and how selective autophagy removes avibirnavirus capsids is largely unknown. Here, we have shown that selective autophagy specifically clears ubiquitinated avibirnavirus protein VP2 by p62 recognition and that p62 is an inhibitor of avibirnavirus replication, highlighting the role of p62 as a potential drug target for mediating the removal of ubiquitinated virus components from cells.


Assuntos
Autofagia/efeitos dos fármacos , Avibirnavirus/efeitos dos fármacos , Proteínas do Capsídeo/metabolismo , Proteínas de Ligação a RNA/farmacologia , Proteínas Virais/metabolismo , Replicação Viral/efeitos dos fármacos , Animais , Infecções por Birnaviridae/virologia , Galinhas , Citosol/metabolismo , Técnicas de Inativação de Genes , Células HEK293 , Humanos , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ubiquitina/metabolismo
18.
Exp Neurol ; 332: 113399, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32652099

RESUMO

After cerebral ischemia/reperfusion injury, pro-inflammatory M1-like and anti-inflammatory M2-like phenotypes of microglia are involved in neuroinflammation, in which NLRP3 inflammasome plays an essential role. Kv1.3 channel has been recognized as neuro-immunomodulatory target, but it is not clear as to its role in the neuroinflammation after cerebral ischemic injury. The current study aimed to investigate the issue. Middle cerebral artery occlusion/reperfusion (MCAO/R) model in rats and oxygen-glucose deprivation/ reoxygenation (OGD/R) in primary microglia were utilized to mimic disease state of ischemic stroke. Treatment with PAP-1, a Kv1.3 channel blocker, produced a significant improvement in neurological deficit scores and a decrease in infarct volume in MCAO/R model. An increased number of M2-like phenotypic microglia and a reduced number of M1-like phenotypic microglia were observed by immunofluorescent staining in the in vivo model, which was further validated by flow cytometry in vitro. Western blot showed that PAP-1 treatment profoundly reduced cleavage of caspase-1 and IL-1ß in vivo and in vitro. Furthermore, PAP-1 administration reduced the number of NLRP3+/Iba1+ cells and NLRP3 protein levels in vivo, while reduced mRNA and protein expression levels of NLRP3 in vitro. Reduced mRNA expression levels of IL-1ß in vitro and protein level of IL-1ß in vivo were also observed. Taken together, our findings suggested that Kv1.3 channel blockade effectively alleviated cerebral ischemic injury, possibly by reshaping microglial phenotypic response from M1 towards M2, compromising the activation of NLRP3 inflammasome in microglia, and inhibiting release of IL-1ß.


Assuntos
Inflamassomos/efeitos dos fármacos , Canal de Potássio Kv1.3/antagonistas & inibidores , Microglia/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/agonistas , Bloqueadores dos Canais de Potássio/uso terapêutico , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Caspase 1/metabolismo , Infarto da Artéria Cerebral Média/tratamento farmacológico , Infarto da Artéria Cerebral Média/patologia , Interleucina-1beta/metabolismo , AVC Isquêmico/fisiopatologia , Masculino , Doenças do Sistema Nervoso/tratamento farmacológico , Doenças do Sistema Nervoso/etiologia , Fenótipo , Ratos , Ratos Sprague-Dawley
19.
J Obstet Gynaecol Res ; 46(8): 1298-1309, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32558037

RESUMO

AIM: Pre-eclampsia (PE) is the usual complication during pregnancy. Long noncoding RNAs are essential regulatory factors in many diseases. Nevertheless, the role of LINC00511 in the development of PE has not been fully elucidated. METHODS: The expression of LINC00511, homeobox protein A7 (HOXA7) and miR-31-5p was determined by quantitative real-time polymerase chain reaction. The levels of HOXA7 protein and autophagy-related proteins were measured by western blot analysis. Besides, cell proliferation was evaluated using cell counting kit 8 and colony formation assays. The apoptosis and invasion of cells were detected via flow cytometry and transwell assay, respectively. Further, the interaction between miR-31-5p and LINC00511 or HOXA7 was confirmed by dual-luciferase reporter assay. RESULTS: The LINC00511 and HOXA7 expression levels were decreased in placental tissues of PE patients, and the expression levels of both were positively correlated. LINC00511 knockdown suppressed proliferation, invasion and autophagy, while enhanced apoptosis in trophoblast cells. Meanwhile, the elevated HOXA7 expression promoted proliferation, invasion, autophagy, and inhibited the apoptosis of trophoblast cells. Besides, overexpression of HOXA7 also could reverse the effect of LINC00511 knockdown on the biological function of trophoblast cells. Further experiments confirmed that miR-31-5p could be sponged by LINC00511 and could target HOXA7. Also, miR-31-5p mimic could invert the promoting effect of LINC00511 overexpression on the biological function of trophoblast cells. CONCLUSION: LINC00511 expression was crucial for maintaining the normal function of trophoblast cells, and the decreased its expression might promote the progress of PE, which might provide some theoretical strategies for reducing the development of PE.


Assuntos
MicroRNAs , Pré-Eclâmpsia , RNA Longo não Codificante , Apoptose , Autofagia , Movimento Celular , Proliferação de Células , Feminino , Proteínas de Homeodomínio , Humanos , MicroRNAs/genética , Placenta , Pré-Eclâmpsia/genética , Gravidez , RNA Longo não Codificante/genética , Trofoblastos
20.
Front Cell Dev Biol ; 8: 184, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32296700

RESUMO

The altered expression of long non-coding RNAs (lncRNAs) has been implicated in the development and human diseases. However, functional roles and regulatory mechanisms of lncRNA as competing endogenous RNAs (ceRNAs) in osteoporosis and their potential clinical implication for osteoporosis risk are largely unexplored. In this study, we performed integrated analysis for paired expression profiles and regulatory relationships of dysregulated lncRNAs, mRNAs, and miRNAs based on "ceRNA hypothesis," and constructed an osteoporosis-related dysregulated miRNA-mediated lncRNA-mRNA ceRNA network (DysCeNet) composed of 105 nodes (including eight miRNAs, 24 mRNAs, and 73 lncRNAs) and 515 edges. Functional analysis suggested that the DysCeNet was involved in known osteoporosis or bone metabolism-related biological processes and pathways. Then, we performed random forest-based feature selection for 73 lncRNAs with ceRNA activity and identified 25 of 73 lncRNAs as potential diagnostic biomarkers. A random forest-based classifier composed of 25 lncRNA biomarkers (RF-25lncRNA) was developed for predicting osteoporosis risk. Performance evaluation with the leave-one-out cross-validation (LOOCV) procedure showed that the RF-25lncRNA achieved a good performance in distinguishing high- and low-bone mineral density (BMD) subjects in different osteoporosis datasets. Our study for the first time revealed a global view of lncRNA-associated ceRNA regulation in osteoporosis and provided novel lncRNAs with ceRNA activity as candidate epigenetic diagnostic biomarkers for early detection of osteoporosis risk.

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