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1.
Cell Regen ; 11(1): 8, 2022 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-35254536

RESUMO

Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes, especially skeletal muscle cell differentiation. Most of the lncRNAs identified to date are localized in the nucleus and play regulatory roles in gene expression. The cytoplasmic lncRNAs are less well understood. We previously identified a long intergenic non-coding RNA (linc-RNA) activator of myogenesis (Linc-RAM) that directly binds MyoD in the nucleus to enhance muscle cell differentiation. Here, we report that a substantial fraction of Linc-RAM is localized in the cytoplasm of muscle cells. To explore the molecular functions of cytoplasmic Linc-RAM, we sought to identify Linc-RAM-binding proteins. We report here that Linc-RAM physically interacts with glycogen phosphorylase (PYGM) in the cytoplasm. Knockdown of PYGM significantly attenuates the function of Linc-RAM in promoting muscle cell differentiation. Loss-of-function and gain-of function assays demonstrated that PYGM enhances muscle cell differentiation in an enzymatic activity-dependent manner. Finally, we show that the interaction between Linc-RAM and PYGM positively regulates the enzymatic activity of PYGM in muscle cells. Collectively, our findings unveil a molecular mechanism through which cytoplasmic Linc-RAM contributes to muscle cell differentiation by regulating PYGM activity. Our findings establish that there is crosstalk between lncRNAs and cellular metabolism during myogenic cell differentiation.

2.
Travel Med Infect Dis ; 46: 102267, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35091118

RESUMO

Human rabies is a serious public health problem that can't be ignored. Rabies immune globulin (RIG) is an indispensable component of rabies post-exposure prophylaxis (PEP). However, current PEP relies on RIG purified from pooled human or equine plasma, which are either in chronic shortage or associated with safety concerns. Monoclonal antibodies have become widely accepted as safer and more cost-effective alternatives to RIG products in recent years. Here, we assessed the neutralization breadth of human monoclonal antibody ormutivimab and its protective efficacy in PEP models. Ormutivimab was able to neutralize a broad panel of Chinese prevalent street RABVs with neutralizing potency form 198-1487.6 IU/mL. Furthermore, ormutivimab offered comparable protection to that with HRIG both at standard doses (20 IU/kg) and higher doses (100 IU/kg and 200 IU/kg). The interference of ormutivimab on vaccine potency was also analyzed and found slightly reduced neutralizing antibody titers similar to HRIG. The broad-spectrum neutralization activities, highly protective potency, and rapid onset of action make ormutivimab an effective candidate for human rabies PEP.


Assuntos
Vacinas Antirrábicas , Vírus da Raiva , Raiva , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Antivirais , Cavalos , Humanos , Modelos Animais , Profilaxia Pós-Exposição , Raiva/prevenção & controle
3.
Tissue Cell ; 73: 101611, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34358918

RESUMO

Versican (VCAN) is verified to promote development among many cancers, whose function on gastric cancer (GC) is less studied. This work explored the effect of VCNA on GC. The differentially expressed VCAN between tumor and normal samples, among different cancer stages and the overall survival of GC patients with high and low VCAN levels were predicted through Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The association between VCAN and clinicopathological parameters was analyzed by clinical investigation. AGS and NCI-N87 cells were transfected with VCAN short hairpin RNA (shVCAN) and VCAN overexpression plasmid. The VCNA, Cyclin D1, Cyclin E, E-Cadherin, N-Cadherin and Vimentin expression was detected through quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blot. Cell viability was assessed through MTT assay. Cell migration was measured by wound healing assay and cell invasion was evaluated through Transwell assay. Cell cycle was determined by flow cytometry assay. VCAN was upregulated in GC and its high expression related to advanced TNM stage, Lymph node metastasis, Depth of invasion and Grade. VCAN knockdown inhibited multiplication, migration, invasion, Cyclin D1, Cyclin E, N-Cadherin and Vimentin expression while induced cycle arrest and E-Cadherin level of GC cells, whereas overexpressed VCAN showed opposite results. VCAN had a potential to be a biomarker for GC and overexpressed VCAN promoted GC cell multiplication, migration and invasion.


Assuntos
Movimento Celular , Neoplasias Gástricas/patologia , Versicanas/metabolismo , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Neoplasias Gástricas/genética , Regulação para Cima/genética , Versicanas/genética
4.
PLoS One ; 16(4): e0250229, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33909667

RESUMO

In this era of technology development, every business wants to equip its salesforce with a sustainable salesforce automation system to improve sales performance and customer relationship management (CRM) capabilities. This study investigates the impact of big data analytics (BDA) on CRM capabilities and the sales performance of pharmaceutical organizations. A research model was tested based on 416 valid responses collected from pharmaceutical companies through a structured questionnaire. Structural equation modeling (SEM) was employed using Smart-PLS3 to confirm the contribution of BDA to improving CRM capabilities and sales performance. The study finds that individual characteristics such as self-efficacy, playfulness, and social norms, along with organizational characteristics such as voluntariness, user involvement, user participation, and management support, are positive predictors of salesforce perception of BDA. This positive perception of BDA increased the person-technology fit in the salesforce, which ultimately increased the CRM capabilities and sales performance.


Assuntos
Comércio/organização & administração , Ciência de Dados , Indústria Farmacêutica , Personalidade , Recursos Humanos , Comportamento do Consumidor , Humanos , Normas Sociais
5.
Medicine (Baltimore) ; 100(3): e24140, 2021 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-33546028

RESUMO

ABSTRACT: The present study was designed to determine the self-psychological safety maintenance and its influencing factors of community staff on the front-line during Coronavirus Disease 2019 (COVID-19) pandemic.A total of 126 frontline staff in community were involved in the current cross-section study. Online questionnaires including the anxiety sensitivity index-3 (ASI-3), patient health questionnaire (PHQ-9), simple coping style questionnaire (SCSQ) and general self-efficacy scale (GSES) were utilized to analyze psychological state, coping style and self-efficacy of the surveyed staff.The ASI-3 standard score of 126 community frontline staff was 10.01 ±â€Š2.82, of which 21 community frontline staff scored > 16, and the detection rate of anxiety was 16.67%. The anxiety state of doctors and nursing staff was significantly lower than that of administrative staff, logistics staff and other staff, and the rate of anxiety of having colleagues with suspected symptoms was significantly higher than that without colleagues with suspected symptoms (P < .05). The PHQ-9 standard score was 2.03 ±â€Š0.16, of which 19 frontline staff in the community scored more than 5, and the detection rate of depression was 15.08%. Among them, the depression state of those with bachelor degree or above was significantly lower than that of those with junior college education, and the rate of depressive symptoms of community frontline staff with colleagues harboring suspected symptoms were significantly higher than those without colleagues with suspected symptoms (P < .05). The aggregated results showed that most of the community frontline staff in anxiety state group and depression group adopted negative coping style while most of the community frontline staff in the non-anxiety group and the non-depression group adopted positive coping style (P < .05). Additionally, lower score of self-efficacy of the community frontline staff was observed in the anxiety state group and the depression state group (P < .05).During the outbreak of COVID-19, several community frontline staff showed negative psychology of anxiety and depression, which could affect their coping style and self-efficacy. Early and effective psychological safety maintenance was required to alleviate the negative psychology of community frontline staff.


Assuntos
Adaptação Psicológica , COVID-19/epidemiologia , Agentes Comunitários de Saúde/psicologia , Autoeficácia , Adulto , Ansiedade/epidemiologia , COVID-19/psicologia , COVID-19/terapia , China , Estudos Transversais , Depressão/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Adulto Jovem
6.
Biomed Res Int ; 2021: 2676745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33490265

RESUMO

BACKGROUND: Hepatocellular carcinoma (HCC) lacks effective treatments and has a poor prognosis. Therefore it is needed to develop more effective drug targets. Kinesin family member 11 (KIF11) has been reported to affect the progression of several cancers, and its high expression associates with the prognosis of patients. However, the relevant mechanisms of KIF11 in HCC progression have not been studied. METHOD: Through the cancer genome atlas (TCGA) database and immunohistochemical (IHC) staining of patients' specimens, we determined that KIF11 was highly expressed in HCC tissues and associated with prognosis. We established a KIF11 stably depleted hepatoma cell line, through cell-cloning experiments and cell counting kit-8 (CCK-8) assays to detect the effects on proliferation in vitro. The role of KIF11 in promoting cell proliferation was verified in mice. RESULT: The expression of KIF11 was negatively correlated with the overall survival (OS) and disease-free survival (DFS) and positively correlated with tumor size of HCC patients. KIF11 depletion inhibits cell proliferation and tumor growth in vitro and in vivo. Conclusion. KIF11 can be used as a positive correlation marker for HCC prognosis and served as a potential therapeutic target.


Assuntos
Carcinoma Hepatocelular , Proliferação de Células/genética , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Feminino , Técnicas de Silenciamento de Genes , Humanos , /metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade
7.
Mol Med Rep ; 23(1)2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33179076

RESUMO

At present, treatment options for thyroid carcinoma remain limited. The present study aimed to investigate the role of ZFAS1 in various major hallmarks of cancer and the underlying mechanisms in thyroid carcinoma cells. The interactions between long non­coding RNAs (lncRNAs), microRNAs (miRs) and target genes were predicted by bioinformatics and confirmed by performing dual­luciferase assays. The mRNA and protein expressions were determined by reverse transcription­quantitative PCR and western blotting. Cell invasion, migration, and viability were evaluated via Transwell, wound­healing and Cell Counting Kit­8 assays, respectively. The results demonstrated that lncRNA ZFAS1 expression was upregulated in thyroid carcinoma tissues, TT and SW579 cells, and was associated with the proliferation of these two cell lines. Notably, downregulation ZFAS1 reduced migration and invasion, and reversed the promotive effects of miR­302a­3p inhibitor on the proliferation, migration and invasion of TT and SW579 cells. Moreover, cyclin D1 (CCND1) is targeted by miR­302a­3p, and was regulated by ZFAS1. In addition, the downregulation of ZFAS1 not only reversed the promotive effects of miR­302a­3p inhibitor on CCND1 expression and the epithelial­mesenchymal transition (EMT) of TT and SW579 cells, but also targeted and increased the expression of miR­302a­3p, and further reduced the expression of CCND1, resulting in suppression of the proliferation, migration, invasion and EMT of thyroid carcinoma cells.


Assuntos
Ciclina D1/genética , Regulação para Baixo , MicroRNAs/genética , RNA Longo não Codificante/genética , Neoplasias da Glândula Tireoide/genética , Adulto , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Ciclina D1/metabolismo , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias da Glândula Tireoide/metabolismo
8.
J Biosci Bioeng ; 129(2): 242-249, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31561850

RESUMO

Trichoderma harzianum EU2-77 was a mutant strain of the wild-type strain T. harzianum NP13a isolated in Singapore. A multi-mutagenesis one-screening (MMOS) method was developed to further improve strain EU2-77 and a new mutant EUA20 was obtained. It exhibited filter paper cellulase (FPase) activity up to 14.79 IU/mL within 6 days shake flask cultivation. Activities of FPase, endoglucanase, ß-glucosidase, and xylanase, and protein content by EUA20 were respectively increased to 5.73, 4.35, 7.34, 1.80 and 2.70 folds. Using pretreated oil palm empty fruit bunch (OPEFB) and corncob powder as the substrates, strain EUA20 presented approximate 6.52 and 8.80 IU/ml FPase activity. Reducing sugar yield of 615.8 and 636.8 mg/g biomass were respectively obtained for OPEFB and corncob powder using cellulolytic enzymes of strain EUA20. Our results demonstrated that mutant strain EUA20 had great potential in on-site cellulase production for effective biomass bioconversion.


Assuntos
Celulase/metabolismo , Açúcares/metabolismo , Trichoderma/metabolismo , Biomassa , Mutagênese , Óleo de Palmeira/metabolismo , Trichoderma/genética , beta-Glucosidase/metabolismo
9.
Biotechnol Appl Biochem ; 67(5): 714-722, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31498481

RESUMO

Oil palm empty fruit bunch (OPEFB) is a lignocellulosic biomass generated in palm oil mills. It is a sustainable resource for fuels and chemicals. In this study, OPEFB was converted to ethanol by an integrative OPEFB conversion process including dilute alkaline pretreatment, cellulolytic enzyme production, separate OPEFB hydrolysis, and cofermentation using a hybrid xylose-fermenting yeast. OPEFB was pretreated using 1% (w/v) NaOH solution followed by 1% (v/v) H2 O2 . Further, cellulolytic enzymes were produced by submerged fermentation using Trichoderma reesei Rut C30 and used for OPEFB hydrolysis. The filter paper cellulase activity of the crude cellulolytic enzymes was 15.1 IU/mL, which was higher than those obtained by reported Trichoderma strains under laboratory conditions. Glucose and xylose yields reached 66.9% and 74.2%, respectively, at 30 filter paper unit (FPU)/g-biomass enzyme dosage and 10% (w/v) biomass loading. The hybrid yeast strain ScF2 was previously constructed through recursive genome shuffling of Pichia stipitis and Saccharomyces cerevisiae and was used in OPEFB hydrolysate fermentation. About 16.9 g/L ethanol was produced with an ethanol yield of 0.34 g/g sugars, which was 67% of theoretical ethanol yield.


Assuntos
Etanol/metabolismo , Microbiologia Industrial , Óleo de Palmeira/metabolismo , Leveduras/metabolismo , Biocatálise , Biomassa , Celulase/metabolismo , Fermentação , Frutas/metabolismo , Proteínas Fúngicas/metabolismo , Hidrólise , Hypocreales/enzimologia , Hypocreales/metabolismo , Lignina/metabolismo , Pichia/enzimologia , Pichia/metabolismo , Saccharomyces cerevisiae/enzimologia , Saccharomyces cerevisiae/metabolismo , Xilose/metabolismo , Leveduras/enzimologia
10.
Onco Targets Ther ; 12: 7337-7345, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564916

RESUMO

Purpose: To investigate the role of zinc finger E­box­binding homeobox 2 antisense RNA 1 (ZEB2-AS1) in regulating laryngeal squamous cell carcinoma (LSCC) progression. Patients and methods: In this retrospective study, we included all patients who underwent a surgical operation at The First Hospital of Qiqihaer City for LSCC. Then, we compared the expression of ZEB2-AS1 in LSCC tissues and paired healthy tissues. Besides, we also performed a series of functional assays, CCK8 assays, colony formation assays, and transwell assays to examine the functions of LSCC cells after knockdown of ZEB2-AS1. Through bioinformatics analysis, we predicted that ZEB2-AS1 binds to miR-6840-3p and targets PLXNB1. Results: We indicated that the expression of ZEB2-AS1 was higher in LSCC tissues compared to the paired adjacent tissues, and ZEB2-AS1 was also highly expressed in LSCC cell lines. Furthermore, we discovered that ZEB2-AS1 promoted cell proliferation, migration and invasion and was associated with poor prognosis. To find the mechanism, we performed bioinformatics analysis. We identified that ZEB2-AS1 binds to miR-6840-3p and targets PLXNB1. Additionally, miR-6840-3p overexpression or knockdown of PLXNB1 decreased the abilities of cell migration and invasion. Conclusion: These findings demonstrated that overexpression of ZEB2-AS1 promotes LSCC progression. Overexpression of miR-6840-3p or downregulation of PLXNB1 can abrogate ZEB2-AS1-mediated LSCC malignant development.

11.
Neurosci Lett ; 708: 134346, 2019 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-31229624

RESUMO

AIMS: This study aimed to explore the synergistic effects of nitrogen-doped carbon nanocages (NCNCs) and human umbilical cord mesenchymal stem cells (HUC-MSCs) on ischemic stroke and investigate the potential underlying mechanisms. MAIN METHODS: The properties of NCNCs were analyzed by transmission electron microscopy, and the markers of HUC-MSCs were detected by flow cytometry. The cell toxicity of NCNCs was evaluated by MTT. Mice were induced cerebral infarction by transient middle cerebral artery occlusion (MCAO). NCNCs or HUC-MSCs or HUC-MSCs-NCNCs were intravenously injected thirty minutes after reperfusion. The infarct volume was examined by 2,3,5-triphenyltetrazolium chloride (TTC) staining, and behavior tests were evaluated by the modified Neurological Severity Score (mNSS) and rotarod test. The mRNA levels of TNF-α and IL-10 were detected by real-time PCR. The protein levels of TNF-α stimulated gene/protein 6 (TSG-6) and prostaglandin 2 (PGE2) were detected by ELISA. The microglia markers (CD86 and CD206) and the protein levels of TNF-α and IL-10 were examined by flow cytometry. The protein levels of Iba1 and CD16 were determined by immunostaining. KEY FINDINGS: NCNCs enhanced the therapeutic effects of HUC-MSCs on MCAO mice, including reducing infarct volume, improving behavior scores and inhibiting inflammation response. In addition, NCNCs and HUC-MSCs cooperatively inhibit the mRNA and protein levels of TNF-α, and increased the mRNA and protein levels of IL-10 and protein levels of PGE2 and TSG-6 in LPS-treated microglia. Furthermore, NCNCs exerted synergistic effects with HUC-MSCs on remodeling microglia polarization. SIGNIFICANCE: NCNCs enhance the therapeutic effects of HUC-MSCs on cerebral infarction in a mouse MCAO model, and inhibit the microglia reactivation and neuroinflammation, which indicates it as a potential treatment for ischemic stroke.


Assuntos
Isquemia Encefálica/prevenção & controle , Carbono , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Transplante de Células-Tronco Mesenquimais , Nanoestruturas , Acidente Vascular Cerebral/prevenção & controle , Animais , Isquemia Encefálica/etiologia , Isquemia Encefálica/metabolismo , Carbono/química , Polaridade Celular , Células Cultivadas , Humanos , Infarto da Artéria Cerebral Média/complicações , Inflamação/metabolismo , Inflamação/terapia , Masculino , Camundongos Endogâmicos C57BL , Microglia/fisiologia , Nanoestruturas/química , Nanoestruturas/toxicidade , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/metabolismo
12.
Nat Med ; 25(2): 312-322, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30643287

RESUMO

Primary tumors may create the premetastatic niche in secondary organs for subsequent metastasis. Humoral immunity contributes to the progression of certain cancers, but the roles of B cells and their derived antibodies in premetastatic niche formation are poorly defined. Using a mouse model of spontaneous lymph node metastasis of breast cancer, we show that primary tumors induced B cell accumulation in draining lymph nodes. These B cells selectively promoted lymph node metastasis by producing pathogenic IgG that targeted glycosylated membrane protein HSPA4, and activated the HSPA4-binding protein ITGB5 and the downstream Src/NF-κB pathway in tumor cells for CXCR4/SDF1α-axis-mediated metastasis. High serum anti-HSPA4 IgG was correlated with high tumor HSPA4 expression and poor prognosis of breast cancer subjects. Our findings identify a key role for tumor-educated B cells and their derived antibodies in lymph node premetastatic niche formation, providing potential targets for cancer intervention.


Assuntos
Linfócitos B/imunologia , Neoplasias da Mama/patologia , Proteínas de Choque Térmico HSP110/metabolismo , Imunoglobulina G/metabolismo , Metástase Linfática/patologia , Animais , Neoplasias da Mama/sangue , Linhagem Celular Tumoral , Quimiocina CXCL12/metabolismo , Glicosilação , Humanos , Imunoglobulina G/sangue , Linfonodos/patologia , Camundongos , NF-kappa B/metabolismo , Ligação Proteica , Receptores CXCR4 , Transdução de Sinais
13.
Circulation ; 136(9): 817-833, 2017 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-28637879

RESUMO

BACKGROUND: Platelets from patients with diabetes mellitus are hyperactive. Hyperactivated platelets may contribute to cardiovascular complications and inadequate responses to antiplatelet agents in the setting of diabetes mellitus. However, the underlying mechanism of hyperactivated platelets is not completely understood. METHODS: We measured P2Y12 expression on platelets from patients with type 2 diabetes mellitus and on platelets from rats with diabetes mellitus. We also assayed platelet P2Y12 activation by measuring cAMP and VASP phosphorylation. The antiplatelet and antithrombotic effects of AR-C78511 and cangrelor were compared in rats. Finally, we explored the role of the nuclear factor-κB pathway in regulating P2Y12 receptor expression in megakaryocytes. RESULTS: Platelet P2Y12 levels are 4-fold higher in patients with type 2 diabetes mellitus compared with healthy subjects. P2Y12 expression correlates with ADP-induced platelet aggregation (r=0.89, P<0.01). P2Y12 in platelets from patients with diabetes mellitus is constitutively activated. Although both AR-C78511, a potent P2Y12 inverse agonist, and cangrelor have similar antiplatelet efficacy on platelets from healthy subjects, AR-C78511 exhibits more powerful antiplatelet effects on diabetic platelets than cangrelor (aggregation ratio 36±3% versus 49±5%, respectively, P<0.05). Using a FeCl3-injury mesenteric arteriole thrombosis model in rats and an arteriovenous shunt thrombosis model in rats, we found that the inverse agonist AR-C78511 has greater antithrombotic effects on GK rats with diabetes mellitus than cangrelor (thrombus weight 4.9±0.3 mg versus 8.3±0.4 mg, respectively, P<0.01). We also found that a pathway involving high glucose-reactive oxygen species-nuclear factor-κB increases platelet P2Y12 receptor expression in diabetes mellitus. CONCLUSIONS: Platelet P2Y12 receptor expression is significantly increased and the receptor is constitutively activated in patients with type 2 diabetes mellitus, which contributes to platelet hyperactivity and limits antiplatelet drug efficacy in type 2 diabetes mellitus.


Assuntos
Plaquetas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Receptores Purinérgicos P2Y12/metabolismo , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Animais , Moléculas de Adesão Celular/genética , Moléculas de Adesão Celular/metabolismo , Linhagem Celular , Cloretos/toxicidade , AMP Cíclico/análise , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Agonismo Inverso de Drogas , Compostos Férricos/toxicidade , Fibrinolíticos/farmacologia , Fibrinolíticos/uso terapêutico , Humanos , Masculino , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo , NF-kappa B/metabolismo , Fosfoproteínas/genética , Fosfoproteínas/metabolismo , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação Plaquetária/farmacologia , Inibidores da Agregação Plaquetária/uso terapêutico , Ratos , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Trombose/induzido quimicamente , Trombose/tratamento farmacológico , Trombose/patologia
14.
Cell Death Dis ; 8(3): e2707, 2017 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-28358363

RESUMO

MicroRNAs (miRNAs) have recently been implicated in muscle stem cell function. miR-127 is known to be predominantly expressed in skeletal muscle, but its roles in myogenic differentiation and muscle regeneration are unknown. Here, we show that miR-127 is upregulated during C2C12 and satellite cell (SC) differentiation and, by establishing C2C12 cells stably expressing miR-127, demonstrate that overexpression of miR-127 in C2C12 cells enhances myogenic cell differentiation. To investigate the function of miR-127 during muscle development and regeneration in vivo, we generated miR-127 transgenic mice. These mice exhibited remarkably accelerated muscle regeneration compared with wild-type mice by promoting SC differentiation. Mechanistically, we demonstrated that the gene encoding sphingosine-1-phosphate receptor 3 (S1PR3), a G-protein-coupled receptor for sphingosine-1-phosphate, is a target of miR-127 required for its function in promoting myogenic cell differentiation. Importantly, overexpression of miR-127 in muscular dystrophy model mdx mice considerably ameliorated the disease phenotype. Thus, our findings suggest that miR-127 may serve as a potential therapeutic target for the treatment of skeletal muscle disease in humans.


Assuntos
Diferenciação Celular , MicroRNAs/metabolismo , Desenvolvimento Muscular , Células Satélites de Músculo Esquelético/metabolismo , Animais , Linhagem Celular , Camundongos , Camundongos Endogâmicos mdx , MicroRNAs/genética , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/terapia , Receptores de Lisoesfingolipídeo/biossíntese , Receptores de Lisoesfingolipídeo/genética , Receptores de Esfingosina-1-Fosfato
15.
Nat Commun ; 8: 14016, 2017 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-28091529

RESUMO

Long non-coding RNAs (lncRNAs) are important regulators of diverse biological processes. Here we report on functional identification and characterization of a novel long intergenic non-coding RNA with MyoD-regulated and skeletal muscle-restricted expression that promotes the activation of the myogenic program, and is therefore termed Linc-RAM (Linc-RNA Activator of Myogenesis). Linc-RAM is transcribed from an intergenic region of myogenic cells and its expression is upregulated during myogenesis. Notably, in vivo functional studies show that Linc-RAM knockout mice display impaired muscle regeneration due to the differentiation defect of satellite cells. Mechanistically, Linc-RAM regulates expression of myogenic genes by directly binding MyoD, which in turn promotes the assembly of the MyoD-Baf60c-Brg1 complex on the regulatory elements of target genes. Collectively, our findings reveal the functional role and molecular mechanism of a lineage-specific Linc-RAM as a regulatory lncRNA required for tissues-specific chromatin remodelling and gene expression.


Assuntos
Desenvolvimento Muscular , Proteína MyoD/metabolismo , Mioblastos/metabolismo , RNA Longo não Codificante/metabolismo , Animais , Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , DNA Helicases/genética , DNA Helicases/metabolismo , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/crescimento & desenvolvimento , Músculo Esquelético/metabolismo , Proteína MyoD/genética , Mioblastos/citologia , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Ligação Proteica , RNA Longo não Codificante/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
16.
EBioMedicine ; 5: 93-104, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27077116

RESUMO

Obesity has been linked to many health problems, such as diabetes. However, there is no drug that effectively treats obesity. Here, we reveal that miR-378 transgenic mice display reduced fat mass, enhanced lipolysis, and increased energy expenditure. Notably, administering AgomiR-378 prevents and ameliorates obesity in mice. We also found that the energy deficiency seen in miR-378 transgenic mice was due to impaired glucose metabolism. This impairment was caused by an activated pyruvate-PEP futile cycle via the miR-378-Akt1-FoxO1-PEPCK pathway in skeletal muscle and enhanced lipolysis in adipose tissues mediated by miR-378-SCD1. Our findings demonstrate that activating the pyruvate-PEP futile cycle in skeletal muscle is the primary cause of elevated lipolysis in adipose tissues of miR-378 transgenic mice, and it helps orchestrate the crosstalk between muscle and fat to control energy homeostasis in mice. Thus, miR-378 may serve as a promising agent for preventing and treating obesity in humans.


Assuntos
Metabolismo Energético/genética , MicroRNAs/genética , Obesidade/genética , Ciclização de Substratos/genética , Tecido Adiposo/metabolismo , Animais , Dieta Hiperlipídica , Glucose/metabolismo , Humanos , Lipólise/genética , Camundongos , Camundongos Transgênicos , MicroRNAs/administração & dosagem , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Obesidade/patologia , Obesidade/terapia , Oligorribonucleotídeos/administração & dosagem , Oligorribonucleotídeos/genética , Ácido Pirúvico/metabolismo , Termogênese
17.
Int J Clin Exp Pathol ; 8(6): 7059-71, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26261599

RESUMO

Within the past several years, inhibition of the PARP1 activity has been emerged as one of the most exciting and promising strategies for triple-negative breast cancer (TNBC) therapy. The purpose of this study is to assess PARP1 expression in TNBCs and to evaluate the association between polymorphisms in PARP1 promoter or 3' untranslated region (3'UTR) and PARP1 expression. It was found that PARP1 was overexpressed in nuclear (nPARP1), cytoplasm (cPARP1) and nuclear-cytoplasmic coexisting (coPARP1) of 187 TNBCs in comparison to that of 115 non-TNBCs (nPARP1, p<0.001; cPARP1, p<0.001; coPARP1, p<0.001). High expression of nPARP1 and cPARP1 in breast cancer was related to worse progression-free survival (nPARP1, p=0.007, cPARP1, p=0.003). Additionally, we identified seven published polymorphism sites in the promoter region and in 3'UTR of PARP1 by sequencing. rs7527192 and rs2077197 genotypes were found to be significantly associated with the cPARP1 expression in TNBC patients (rs7527192 AA+GA versus GG, p=0.014; rs2077197 AA+GA versus GG, p=0.041). These findings were confirmed in an independent validation set of 88 TNBCs (rs7527192 GG versus GA+AA, p=0.030; rs2077197 GG versus GA+AA, p=0.030). The PARP1 over-expression including nuclear, cytoplasm and nuclear-cytoplasmic coexisting is a feature of TNBCs and the assessment of its expression may help to predict the efficacy of chemotherapy with PARP1 inhibitor.


Assuntos
Regiões 3' não Traduzidas , Biomarcadores Tumorais/genética , Poli(ADP-Ribose) Polimerases/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais/análise , Núcleo Celular/enzimologia , Citoplasma/enzimologia , Intervalo Livre de Doença , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Heterozigoto , Homozigoto , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Fenótipo , Poli(ADP-Ribose) Polimerase-1 , Poli(ADP-Ribose) Polimerases/análise , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Reprodutibilidade dos Testes , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/terapia , Regulação para Cima
18.
Nat Commun ; 6: 7713, 2015 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-26151913

RESUMO

Skeletal muscle stem cells, called satellite cells, are a quiescent heterogeneous population. Their heterogeneity is influenced by Pax7, a well-defined transcriptional regulator of satellite cell functions that defines two subpopulations: Pax7(Hi) and Pax7(Lo). However, the mechanisms by which these subpopulations are established and maintained during myogenesis are not completely understood. Here we show that miR-431, which is predominantly expressed in the skeletal muscle, mediates satellite cell heterogeneity by fine-tuning Pax7 levels during muscle development and regeneration. In miR-431 transgenic mice, the Pax7(Lo) subpopulation is enriched, enhances myogenic differentiation and accelerates muscle regeneration. Notably, miR-431 attenuates the muscular dystrophic phenotype in mdx mice and may be a potential therapeutic target in muscular diseases. miR-431 transgenic mice are a unique genetic model for investigating the cellular features and biological functions of Pax7(Lo) satellite cells during muscle development and regeneration.


Assuntos
MicroRNAs/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiologia , Distrofia Muscular Animal/metabolismo , Fator de Transcrição PAX7/metabolismo , Animais , Diferenciação Celular , Regulação da Expressão Gênica/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , MicroRNAs/genética , Músculo Esquelético/lesões , Fator de Transcrição PAX7/genética , Condicionamento Físico Animal , Regeneração , Células Satélites de Músculo Esquelético/fisiologia
19.
J Cancer ; 6(7): 671-7, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26078798

RESUMO

There is an unmet clinical need to identify biomarkers for breast cancer neoadjuvant chemotherapy. Here, using miRNA TaqMan Low-Density Arrays (TLDA), we analyzed the miRNA expression profile in pre-treatment needle aspiration tumor samples from patients who received taxane-anthracycline-based neoadjuvant chemotherapy. Although, in an unsupervised hierarchical cluster analysis, the total miRNA expression profile could not generate a tree with clear distinction between pathologic complete response (pCR) and non-pCR classes, we found that elevated expression of miR-125b and miR-141 was associated with non-pCR. In vitro experiments indicated that inhibition of miR-125b and miR-141 expression reduced cellular survival in response to taxane-anthracycline treatment. Furthermore, co-transfection with miR-125b and miR-141 mimics increased resistance of MCF7 and BT549 cells to taxane-anthracycline induced cytotoxicity. Pathway analyses indicated that many of the target proteins of miR-125b are involved in apoptotic pathways and cell cycle control. Together, we provide evidence that elevated miR-125b and 141 expression predicts a poor clinical responsiveness of taxane-anthracycline-based neoadjuvant chemotherapy.

20.
Circulation ; 131(13): 1160-70, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25825396

RESUMO

BACKGROUND: Pattern recognition receptor nucleotide-binding oligomerization domain 2 (NOD2) is well investigated in immunity, but its expression and function in platelets has never been explored. METHOD AND RESULTS: Using reverse transcription polymerase chain reaction and Western blot, we show that both human and mouse platelets express NOD2, and its agonist muramyl dipeptide induced NOD2 activation as evidenced by receptor dimerization. NOD2 activation potentiates platelet aggregation and secretion induced by low concentrations of thrombin or collagen, and clot retraction, as well. These potentiating effects of muramyl dipeptide were not seen in platelets from NOD2-deficient mice. Plasma from septic patients also potentiates platelet aggregation induced by thrombin or collagen NOD2 dependently. Using intravital microscopy, we found that muramyl dipeptide administration accelerated in vivo thrombosis in a FeCl3-injured mesenteric arteriole thrombosis mouse model. Platelet depletion and transfusion experiments confirmed that NOD2 from platelets contributes to the in vivo thrombosis in mice. NOD2 activation also accelerates platelet-dependent hemostasis. We further found that platelets express receptor-interacting protein 2, and provided evidence suggesting that mitogen activated-protein kinase and nitric oxide/soluble guanylyl cyclase/cGMP/protein kinase G pathways downstream of receptor-interacting protein mediate the role of NOD2 in platelets. Finally, muramyl dipeptide stimulates proinflammatory cytokine interleukin-1ß maturation and accumulation in human and mouse platelets NOD2 dependently. CONCLUSIONS: NOD2 is expressed in platelets and functions in platelet activation and arterial thrombosis, possibly during infection. To our knowledge, this is the first study on NOD-like receptors in platelets that link thrombotic events to inflammation.


Assuntos
Plaquetas/metabolismo , Inflamação/sangue , Proteína Adaptadora de Sinalização NOD2/fisiologia , Ativação Plaquetária/fisiologia , Trombose/sangue , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Animais , Bacteriemia/sangue , Plaquetas/efeitos dos fármacos , Retração do Coágulo/fisiologia , GMP Cíclico/sangue , Dimerização , Hemostasia/fisiologia , Humanos , Interleucina-1beta/sangue , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Camundongos Endogâmicos NOD , Óxido Nítrico/sangue , Proteína Adaptadora de Sinalização NOD2/agonistas , Proteína Adaptadora de Sinalização NOD2/biossíntese , Proteína Adaptadora de Sinalização NOD2/sangue , Ativação Plaquetária/efeitos dos fármacos , Proteína Serina-Treonina Quinase 2 de Interação com Receptor/biossíntese , Proteína Serina-Treonina Quinases de Interação com Receptores/biossíntese , Transdução de Sinais/fisiologia
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