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1.
Nutrients ; 13(6)2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34208504

RESUMO

The soybean allergen Gly m 4 is known to cause severe allergic reactions including anaphylaxis, unlike other Bet v 1 homologues, which induce mainly local allergic reactions. In the present study, we aimed to investigate whether the food Bet v 1 homologue Gly m 4 can be a sensitizer of the immune system. Susceptibility to gastrointestinal digestion was assessed in vitro. Transport through intestinal epithelium was estimated using the Caco-2 monolayer. Cytokine response of different immunocompetent cells was evaluated by using Caco-2/Immune cells co-culture model. Absolute levels of 48 cytokines were measured by multiplex xMAP technology. It was shown that Gly m 4 can cross the epithelial barrier with a moderate rate and then induce production of IL-4 by mature dendritic cells in vitro. Although Gly m 4 was shown to be susceptible to gastrointestinal enzymes, some of its proteolytic fragments can selectively cross the epithelial barrier and induce production of Th2-polarizing IL-5, IL-10, and IL-13, which may point at the presence of the T-cell epitope among the crossed fragments. Our current data indicate that Gly m 4 can potentially be a sensitizer of the immune system, and intercommunication between immunocompetent and epithelial cells may play a key role in the sensitization process.


Assuntos
Antígenos de Plantas/farmacologia , Hipersensibilidade Alimentar/terapia , Imunização/métodos , Antígenos de Plantas/imunologia , Células CACO-2/efeitos dos fármacos , Células CACO-2/imunologia , Quimiocinas/metabolismo , Técnicas de Cocultura , Citocinas/metabolismo , Escherichia coli/metabolismo , Hipersensibilidade Alimentar/imunologia , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Modelos Biológicos , Organismos Geneticamente Modificados , Células THP-1/efeitos dos fármacos , Células THP-1/imunologia
2.
Nat Commun ; 12(1): 4071, 2021 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-34210974

RESUMO

Molecular left-right (L-R) asymmetry is established at the node of the mouse embryo as a result of the sensing of a leftward fluid flow by immotile cilia of perinodal crown cells and the consequent degradation of Dand5 mRNA on the left side. We here examined how the fluid flow induces Dand5 mRNA decay. We found that the first 200 nucleotides in the 3' untranslated region (3'-UTR) of Dand5 mRNA are necessary and sufficient for the left-sided decay and to mediate the response of a 3'-UTR reporter transgene to Ca2+, the cation channel Pkd2, the RNA-binding protein Bicc1 and their regulation by the flow direction. We show that Bicc1 preferentially recognizes GACR and YGAC sequences, which can explain the specific binding to a conserved GACGUGAC motif located in the proximal Dand5 3'-UTR. The Cnot3 component of the Ccr4-Not deadenylase complex interacts with Bicc1 and is also required for Dand5 mRNA decay at the node. These results suggest that Ca2+ currents induced by leftward fluid flow stimulate Bicc1 and Ccr4-Not to mediate Dand5 mRNA degradation specifically on the left side of the node.


Assuntos
Embrião de Mamíferos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estabilidade de RNA/fisiologia , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptores CCR4/metabolismo , Regiões 3' não Traduzidas , Animais , Regulação da Expressão Gênica no Desenvolvimento , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Camundongos Knockout , Proteínas de Ligação a RNA/genética , Receptores CCR4/genética , Canais de Cátion TRPP/metabolismo , Fatores de Transcrição
3.
Int J Mol Sci ; 22(13)2021 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-34206648

RESUMO

The aim of this study was to investigate the C-terminal cleavage of (pyr)-apelin-13 in human endothelial cells with respect to the role and subcellular location of prolyl carboxypeptidase (PRCP). Human umbilical vein and aortic endothelial cells, pre-treated with prolyl carboxypeptidase-inhibitor compound 8o and/or angiotensin converting enzyme 2 (ACE2)-inhibitor DX600, were incubated with (pyr)-apelin-13 for different time periods. Cleavage products of (pyr)-apelin-13 in the supernatant were identified by mass spectrometry. The subcellular location of PRCP was examined via immunocytochemistry. In addition, PRCP activity was measured in supernatants and cell lysates of LPS-, TNFα-, and IL-1ß-stimulated cells. PRCP cleaved (pyr)-apelin-13 in human umbilical vein and aortic endothelial cells, while ACE2 only contributed to this cleavage in aortic endothelial cells. PRCP was found in endothelial cell lysosomes. Pro-inflammatory stimulation induced the secretion of PRCP in the extracellular environment of endothelial cells, while its intracellular level remained intact. In conclusion, PRCP, observed in endothelial lysosomes, is responsible for the C-terminal cleavage of (pyr)-apelin-13 in human umbilical vein endothelial cells, while in aortic endothelial cells ACE2 also contributes to this cleavage. These results pave the way to further elucidate the relevance of the C-terminal Phe of (pyr)-apelin-13.


Assuntos
Aorta/citologia , Carboxipeptidases/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Enzima de Conversão de Angiotensina 2/metabolismo , Linhagem Celular , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Mediadores da Inflamação/metabolismo , Peptídeos/sangue , Proteólise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
4.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070923

RESUMO

Increasing numbers of miRNAs have been observed as oncogenes or tumor suppressors in colorectal cancer (CRC). It was recently reported that hsa-miR-106b-5p (miR-106b) promoted CRC cell migration and invasion. However, there were also studies showing contradictory results. Therefore, in the present study, we further explore the role of miR-106b and its downstream networks in the carcinogenesis of CRC. We observed that the expression of miR-106b is significantly increased in Pan-Cancer and CRC tissues compared with normal tissues from The Cancer Genome Atlas (TCGA) database. Furthermore, we used Transwell, Cell Counting Kit-8, and colony formation assays to clarify that miR-106b promotes the migratory, invasive, and proliferative abilities of CRC cells. For the first time, we systematically screened the target mRNAs and lncRNAs of miR-106b using TCGA database and the bioinformatics algorithms. Dual-luciferase reporter assay confirmed that NR2F2-AS1 and PLEKHO2 are the direct targets of miR-106b. Furthermore, NR2F2-AS1 acts as a competing endogenous RNA (ceRNA) to regulate PLEKHO2 expression by sponging miR-106b. The results of Gene set enrichment analysis (GSEA) and Western blot indicated that they play important roles in CRC progression by regulating MAPK pathway. Thus, miR-106b/NR2F2-AS1/PLEKHO2/MAPK signaling axis may suggest the potential usage in CRC treatment.


Assuntos
Fator II de Transcrição COUP/genética , Carcinogênese/genética , Neoplasias Colorretais/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , MicroRNAs/genética , RNA Longo não Codificante/genética , Atlas como Assunto , Sequência de Bases , Sítios de Ligação , Fator II de Transcrição COUP/metabolismo , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Bases de Dados Genéticas , Regulação Neoplásica da Expressão Gênica , Genes Reporter , Células HCT116 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Luciferases/genética , Luciferases/metabolismo , Sistema de Sinalização das MAP Quinases , MicroRNAs/metabolismo , RNA Longo não Codificante/metabolismo
5.
Ecotoxicol Environ Saf ; 220: 112408, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34111662

RESUMO

BACKGROUND: Epidemiologic evidence suggests that PM2.5 exposure aggravates asthma, but the molecular mechanisms are not fully discovered. METHODS: Ovalbumin (OVA)-induced mice exposed to PM2.5 were constructed. Pathological staining and immunofluorescence were performed in in vivo study. Gene set enrichment analysis (GSEA) was performed to identify the pathway involved in asthma severity by using U-BIOPRED data (human bronchial biopsies) and RNA-seq data (Beas-2B cells treated with PM2.5). Lentiviruses transfection, Real-time qPCR, immunofluorescence staining and trans-epithelial electrical resistance (TEER) measurement were performed for mechanism exploration in vitro. RESULTS: PM2.5 exposure aggravated airway inflammation and mucus secretion in OVA-induced mice. Based on transcriptome analysis of mild-to-severe asthma from human bronchial biopsies, gene set enrichment analysis (GSEA) showed that up-regulated reactive oxygen species (ROS) pathway gene set and down-regulated apical junction gene set correlated with asthma severity. Consistent with the analysis of mild-to-severe asthma, after PM2.5 exposure, the ROS pathway in Beas-2B cells was up-regulated with the down-regulation of apical junction. The expression levels of genes involved in the specific gene sets were validated by using qPCR. The mRNA levels of junction genes, ZO-1, E-cadherin and Occludin, were significantly decreased in cells exposed to PM2.5. Moreover, it confirmed that inhibition of ROS recovered the expression levels of E-cadherin, Occludin and ZO-1, and ameliorated inflammation and mucus secretion in airway in OVA-induced mice exposed to PM2.5. Meanwhile, ROS level was elevated by PM2.5. By checking trans-epithelial electrical resistance (TEER) value, we also found that epithelial barrier was damaged after PM2.5 exposure. Importantly, Stanniocalcin 2 (STC2) was identified as a key gene in regulation of epithelial barrier. It showed that STC2 expression was up-regulated by PM2.5, which was recovered by NAC as well. Over-expression of STC2 could decrease the expression levels of ZO-1, Occludin and E-cadherin. Contrarily, suppression of STC2 could increase the expression levels of ZO-1, Occludin and E-cadherin reduced by PM2.5. CONCLUSIONS: By using transcriptome analysis, we revealed that STC2 played a key role in PM2.5 aggravated airway dysfunction through regulation of epithelial barrier in OVA-induced mice.


Assuntos
Asma/induzido quimicamente , Modelos Animais de Doenças , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Material Particulado/efeitos adversos , Mucosa Respiratória/patologia , Animais , Asma/genética , Asma/metabolismo , Asma/patologia , Perfilação da Expressão Gênica , Glicoproteínas/genética , Humanos , Inflamação , Peptídeos e Proteínas de Sinalização Intercelular/genética , Camundongos , Ovalbumina/efeitos adversos , Espécies Reativas de Oxigênio/metabolismo , Mucosa Respiratória/efeitos dos fármacos , Mucosa Respiratória/metabolismo , Transcriptoma/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos
6.
Cancer Sci ; 112(7): 2592-2606, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33938090

RESUMO

Immunotherapy has revolutionized cancer treatment, however, not all tumor types and patients are completely responsive to this approach. Establishing predictive pre-clinical models would allow for more accurate and practical immunotherapeutic drug development. Mouse models are extensively used as in vivo system for biomedical research. However, due to the significant differences between rodents and human, it is impossible to translate most of the findings from mouse models to human. Pharmacological development and advancing personalized medicine using patient-derived xenografts relies on producing mouse models in which murine cells and genes are substituted with their human equivalent. Humanized mice (HM) provide a suitable platform to evaluate xenograft growth in the context of a human immune system. In this review, we discussed recent advances in the generation and application of HM models. We also reviewed new insights into the basic mechanisms, pre-clinical evaluation of onco-immunotherapies, current limitations in the application of these models as well as available improvement strategies. Finally, we pointed out some issues for future studies.


Assuntos
Modelos Animais de Doenças , Imunoterapia , Neoplasias/terapia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos Monoclonais/uso terapêutico , Citocinas/metabolismo , Desenvolvimento de Medicamentos , Engenharia Genética , Rejeição de Enxerto/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Imunoterapia Adotiva/métodos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células Matadoras Naturais/imunologia , Camundongos , Camundongos SCID , Neoplasias/imunologia , Medicina de Precisão , Pesquisa Médica Translacional , Transplante Heterólogo
7.
Aging (Albany NY) ; 13(10): 13859-13875, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34029211

RESUMO

Atherosclerosis (AS) is a chronic progressive inflammatory disease and a leading cause of death worldwide. Being a novel adipokine, chemerin is reported to be positively correlated with the severity of AS, yet its underlying mechanisms in AS remains elusive. It is well-known that AS development is significantly attributed to abnormal proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, we investigated the role of the chemerin / chemokine-like receptor 1 (CMKLR1, chemerin receptor) signaling, and the potential therapeutic effect of curcumin in VSMCs proliferation and migration during AS by establishing a high fat diet (HFD) mouse model. We found that CMKLR1 was highly expressed in HFD-induced AS tissues and that its expression level was positively correlated with aortic proliferation. Knockdown of CMKLR1 significantly inhibited VSMCs proliferation and migration, as evidenced by the EdU-incorporation assay, wound healing assay, and the induction of proliferating cell nuclear antigen (PCNA) and matrix metalloproteinase-9 (MMP-9) expression. Furthermore, we discovered that Lipocalin-2 (LCN2) acts as a key factor involved in CMKLR1-mediated VSMCs proliferation and migration via the p38 / MAPK and Wnt / ß-catenin signaling pathways, and we demonstrated that curcumin inhibits VSMCs proliferation and migration by inhibiting chemerin / CMKLR1 / LCN2, thereby reducing AS progression. Our findings suggest that chemerin / CMKLR1 activation promotes the development of AS; hence, targeting the chemerin / CMKLR1 / LCN2 signaling pathway may be a reasonable treatment modality for AS.


Assuntos
Movimento Celular/efeitos dos fármacos , Quimiocinas/metabolismo , Curcumina/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipocalina-2/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Receptores de Quimiocinas/metabolismo , Transdução de Sinais , Animais , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Dieta Hiperlipídica , Técnicas de Silenciamento de Genes , Masculino , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Placa Aterosclerótica/patologia , Transdução de Sinais/efeitos dos fármacos
8.
Aging (Albany NY) ; 13(10): 13926-13940, 2021 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-34030134

RESUMO

Peroxiredoxin II (Prx II) is involved in proliferation, differentiation, and aging in various cell types. However, Prx II-mediated stem cell regulation is poorly understood. Here, dermal mesenchymal stem cells (DMSCs), cell-growth factor-rich conditioned medium from DMSCs (DMSC-CM), and DMSC-derived exosomes (DMSC-Exos) were used to explore the regulatory role of Prx II in DMSC wound healing. Following treatment, wound healing was significantly decelerated in Prx II-/- DMSCs than in Prx II+/+ DMSCs. In vitro stimulation with 10 µM H2O2 significantly increased apoptosis in Prx II-/- DMSCs compared with Prx II+/+ DMSCs. The mRNA expression levels of EGF, b-FGF, PDGF-B, and VEGF did not significantly differ between Prx II-/- and Prx II+/+ DMSCs. Fibroblasts proliferated comparably when treated with Prx II+/+ DMSC-CM or Prx II-/- DMSC-CM. Wound healing was significantly higher in the Prx II-/- DMSC-Exos-treated group than in the Prx II+/+ DMSCs-Exos-treated group. Moreover, microRNA (miR)-21-5p expression levels were lower and miR-221 levels were higher in Prx II-/- DMSCs than in Prx II+/+ DMSCs. Therefore, our results indicate that Prx II accelerated wound healing by protecting DMSCs from reactive oxygen species-induced apoptosis; however, Prx II did not regulate cell/growth factor secretion. Prx II potentially regulates exosome functions via miR-21-5p and miR-221.


Assuntos
Derme/citologia , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/citologia , Peroxirredoxinas/metabolismo , Cicatrização , Animais , Apoptose , Meios de Cultivo Condicionados/farmacologia , Exossomos/efeitos dos fármacos , Exossomos/metabolismo , Exossomos/ultraestrutura , Deleção de Genes , Peróxido de Hidrogênio/toxicidade , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos Knockout , MicroRNAs/genética , MicroRNAs/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Cicatrização/genética
9.
Nat Immunol ; 22(5): 571-585, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33903764

RESUMO

Fibroblastic reticular cells (FRCs) are specialized stromal cells that define tissue architecture and regulate lymphocyte compartmentalization, homeostasis, and innate and adaptive immunity in secondary lymphoid organs (SLOs). In the present study, we used single-cell RNA sequencing (scRNA-seq) of human and mouse lymph nodes (LNs) to identify a subset of T cell-zone FRCs defined by the expression of Gremlin1 (Grem1) in both species. Grem1-CreERT2 knock-in mice enabled localization, multi-omics characterization and genetic depletion of Grem1+ FRCs. Grem1+ FRCs primarily localize at T-B cell junctions of SLOs, neighboring pre-dendritic cells and conventional dendritic cells (cDCs). As such, their depletion resulted in preferential loss and decreased homeostatic proliferation and survival of resident cDCs and compromised T cell immunity. Trajectory analysis of human LN scRNA-seq data revealed expression similarities to murine FRCs, with GREM1+ cells marking the endpoint of both trajectories. These findings illuminate a new Grem1+ fibroblastic niche in LNs that functions to maintain the homeostasis of lymphoid tissue-resident cDCs.


Assuntos
Células Dendríticas Foliculares/imunologia , Fibroblastos/imunologia , Linfonodos/imunologia , Células Estromais/imunologia , Idoso , Animais , Apoptose/genética , Apoptose/imunologia , Proliferação de Células/genética , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Células Dendríticas Foliculares/metabolismo , Feminino , Fibroblastos/metabolismo , Regulação da Expressão Gênica/imunologia , Técnicas de Introdução de Genes , Humanos , Imunidade Celular/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Linfonodos/citologia , Masculino , Camundongos , Camundongos Transgênicos , RNA-Seq , Análise de Célula Única , Células Estromais/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo
10.
Life Sci ; 278: 119530, 2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-33887347

RESUMO

AIMS: Chemerin is abundant in patients with high body mass index and metabolic syndrome possibly due to its activation in adipogenesis and glucose intolerance. It has reported that sera chemerin is positively associated with fatty liver with little known underlying mechanisms. Our aim is to study the role of chemerin in hepatic lipid metabolism. MAIN METHODS: Oil Red O staining and TG quantitative assay were used to detect intracellular lipid accumulation. PCR, QPCR and western blot were applied to measure lipid metabolism-related genes, CMKLR1, GPR1 and inflammation marker genes. Luciferase reporter assay was employed to uncover the down-regulation of proximate promoter activities of CMKLR1 and GPR1 by SREBP1c. Antibody neutralization assay was used to address the effects of chemerin on hepatic lipid synthesis. KEY FINDINGS: Over-expression of chemerin led to passive lipid accumulation, in human hepatoma cell line HepG2. The disable form of chemerin (chemerin 21-158) and active chemerin (chemerin 21-157) performed strongly effects on lipid metabolism in HepG2 cells. Heterologous expression of CMKLR1 or G-protein coupled receptor1 (GPR1) played similar roles in hepatocyte lipid metabolism as chemerin. Chemerin exerted its effects on lipid metabolism via GPR1 in HepG2 cells. Furthermore, free fatty acids and high concentration insulin inhibited chemerin expression. Consistently, the key lipogenic transcription factor Sterol regulatory element binding protein 1c suppressed chemerin mRNA expression and proximate promoter activities of CMKLR1 and GPR1. SIGNIFICANCE: It implied the existence of negative feed-back regulation and further confirmed the involvement of chemerin in hepatic lipid metabolism.


Assuntos
Carcinoma Hepatocelular/metabolismo , Quimiocinas/metabolismo , Metabolismo dos Lipídeos , Receptores Acoplados a Proteínas G/metabolismo , Animais , Anticorpos/química , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Fígado Gorduroso/metabolismo , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Lipídeos/química , Neoplasias Hepáticas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Oxigênio/metabolismo
11.
Front Immunol ; 12: 532484, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897679

RESUMO

Human cytomegalovirus (HCMV) infection often leads to systemic disease in immunodeficient patients and congenitally infected children. Despite its clinical significance, the exact mechanisms contributing to HCMV pathogenesis and clinical outcomes have yet to be determined. One of such mechanisms involves HCMV-mediated NK cell immune response, which favors viral immune evasion by hindering NK cell-mediated cytolysis. This process appears to be dependent on the extent of HCMV genetic variation as high levels of variability in viral genes involved in immune escape have an impact on viral pathogenesis. However, the link between viral genome variations and their functional effects has so far remained elusive. Thus, here we sought to determine whether inter-host genetic variability of HCMV influences its ability to modulate NK cell responses to infection. For this purpose, five HCMV clinical isolates from a previously characterized cohort of pediatric patients with confirmed HCMV congenital infection were evaluated by next-generation sequencing (NGS) for genetic polymorphisms, phylogenetic relationships, and multiple-strain infection. We report variable levels of genetic characteristics among the selected clinical strains, with moderate variations in genome regions associated with modulation of NK cell functions. Remarkably, we show that different HCMV clinical strains differentially modulate the expression of several ligands for the NK cell-activating receptors NKG2D, DNAM-1/CD226, and NKp30. Specifically, the DNAM-1/CD226 ligand PVR/CD155 appears to be predominantly upregulated by fast-replicating ("aggressive") HCMV isolates. On the other hand, the NGK2D ligands ULBP2/5/6 are downregulated regardless of the strain used, while other NK cell ligands (i.e., MICA, MICB, ULBP3, Nectin-2/CD112, and B7-H6) are not significantly modulated. Furthermore, we show that IFN-γ; production by NK cells co-cultured with HCMV-infected fibroblasts is directly proportional to the aggressiveness of the HCMV clinical isolates employed. Interestingly, loss of NK cell-modulating genes directed against NK cell ligands appears to be a common feature among the "aggressive" HCMV strains, which also share several gene variants across their genomes. Overall, even though further studies based on a higher number of patients would offer a more definitive scenario, our findings provide novel mechanistic insights into the impact of HCMV genetic variability on NK cell-mediated immune responses.


Assuntos
Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologia , Células Cultivadas , Citomegalovirus/genética , Citomegalovirus/fisiologia , Infecções por Citomegalovirus/metabolismo , Infecções por Citomegalovirus/virologia , Citotoxicidade Imunológica/genética , Citotoxicidade Imunológica/imunologia , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Expressão Gênica , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Evasão da Resposta Imune/genética , Evasão da Resposta Imune/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Interferon gama/metabolismo , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/virologia , Ligantes , Masculino , Subfamília K de Receptores Semelhantes a Lectina de Células NK/genética , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa
12.
Science ; 372(6538): 171-175, 2021 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-33833120

RESUMO

Sexual reproduction in angiosperms relies on precise communications between the pollen and pistil. The molecular mechanisms underlying these communications remain elusive. We established that in Arabidopsis, a stigmatic gatekeeper, the ANJEA-FERONIA (ANJ-FER) receptor kinase complex, perceives the RAPID ALKALINIZATION FACTOR peptides RALF23 and RALF33 to induce reactive oxygen species (ROS) production in the stigma papillae, whereas pollination reduces stigmatic ROS, allowing pollen hydration. Upon pollination, the POLLEN COAT PROTEIN B-class peptides (PCP-Bs) compete with RALF23/33 for binding to the ANJ-FER complex, leading to a decline of stigmatic ROS that facilitates pollen hydration. Our results elucidate a molecular gating mechanism in which distinct peptide classes from pollen compete with stigma peptides for interaction with a stigmatic receptor kinase complex, allowing the pollen to hydrate and germinate.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Flores/metabolismo , Peptídeos/metabolismo , Pólen/fisiologia , Polinização , Proteínas Quinases/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Estado de Hidratação do Organismo , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Mol Sci ; 22(7)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33915805

RESUMO

Low birth weight and rapid postnatal weight gain are independent predictors of obesity and diabetes in adult life, yet the molecular events involved in this process remain unknown. In inbred and outbred mice, this study examines natural intrauterine growth restriction (IUGR) in relation to body weight, telomere length (TL), glucose tolerance, and growth factor gene (Igf1, Igf2, Insr, Igf1r, and Igf2r) mRNA expression levels in the brain, liver, and muscle at 2- and 10 days of age and then at 3- and 9 months of age. At birth, ~15% of the animals showed IUGR, but by 3 and 9 months, half of these animals had regained the same weight as controls without IUGR (recuperated group). At 10 days, there was no difference in TL between animals undergoing IUGR and controls. However, by 3 and 9 months of age, the recuperated animals had shorter TL than the control and IUGR-non recuperated animals and also showed glucose intolerance. Further, compared to controls, Igf1 and Igf2 growth factor mRNA expression was lower in Day 2-IUGR mice, while Igf2r and Insr mRNA expression was higher in D10-IUGR animals. Moreover, at 3 months of age, only in the recuperated group were brain and liver Igf1, Igf2, Insr, and Igf2r expression levels higher than in the control and IUGR-non-recuperated groups. These data indicate that catch-up growth but not IUGR per se affects TL and glucose tolerance, and suggest a role in this latter process of insulin/insulin-like growth signaling pathway gene expression during early development.


Assuntos
Peso Corporal , Retardo do Crescimento Fetal/metabolismo , Intolerância à Glucose/etiologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Homeostase do Telômero , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Feminino , Retardo do Crescimento Fetal/fisiopatologia , Regulação da Expressão Gênica no Desenvolvimento , Fígado/metabolismo , Masculino , Camundongos , Músculos/metabolismo
14.
Anticancer Res ; 41(4): 2117-2122, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813422

RESUMO

BACKGROUND/AIM: Stanniocalcin2 (STC2) is associated with proliferation, invasion, and metastasis in various cancers. We examined the clinical significance of STC2 mRNA expression in patients with colorectal cancer (CRC). PATIENTS AND METHODS: Relative expression levels of STC2 mRNA in CRC tissues and corresponding normal mucosa obtained from 202 patients were measured using quantitative real-time reverse transcriptase-polymerase chain reaction. RESULTS: Expression of STC2 mRNA was higher in the cancer tissue than in the adjacent normal mucosa. STC2 mRNA expression in cancer tissues was associated with tumour size, liver metastasis, venous invasion, and lymph node metastasis. High expression of STC2 mRNA was significantly associated with poorer postoperative survival (p=0.0003). Multivariate analysis showed that high expression of STC2 mRNA was an independent predictor of postoperative survival. CONCLUSION: High expression of STC2 mRNA in CRC tissue may be a useful prognostic marker in patients with CRC.


Assuntos
Adenocarcinoma/diagnóstico , Biomarcadores Tumorais/genética , Neoplasias Colorretais/diagnóstico , Glicoproteínas/genética , Peptídeos e Proteínas de Sinalização Intercelular/genética , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adenocarcinoma/cirurgia , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/cirurgia , Feminino , Regulação Neoplásica da Expressão Gênica , Glicoproteínas/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Prognóstico , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Análise de Sobrevida , Resultado do Tratamento
15.
Nature ; 592(7854): 428-432, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33790465

RESUMO

Chronic, sustained exposure to stressors can profoundly affect tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here we report that the stress hormone corticosterone-which is derived from the adrenal gland and is the rodent equivalent of cortisol in humans-regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. In the absence of systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, increased levels of corticosterone prolong HFSC quiescence and maintain hair follicles in an extended resting phase. Mechanistically, corticosterone acts on the dermal papillae to suppress the expression of Gas6, a gene that encodes the secreted factor growth arrest specific 6. Restoring Gas6 expression overcomes the stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity through its effect on the niche, and demonstrates that the removal of such inhibition drives HFSCs into frequent regeneration cycles, with no observable defects in the long-term.


Assuntos
Corticosterona/farmacologia , Folículo Piloso/citologia , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Glândulas Suprarrenais/cirurgia , Adrenalectomia , Animais , Divisão Celular/efeitos dos fármacos , Feminino , Folículo Piloso/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/metabolismo , Estresse Psicológico/patologia , Transcriptoma , Regulação para Cima
16.
Molecules ; 26(8)2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33917070

RESUMO

Hair loss by excessive stress from work and lifestyle changes has become a growing concern, particularly among young individuals. However, most drugs for alopecia impose a plethora of side effects. We have found the powerful impact of Malva verticillata seed extracts on alleviating hair loss. This study further isolated effective chemicals in M. verticillata seed extracts by liquid silica gel column chromatography. Under the screening for the growth rate (%) of human follicles dermal papilla cells (HFDPCs), we identified linoleic acid (LA) and oleic acid in n-hexane of M. verticillate (MH)2 fraction. LA treatment activated Wnt/ß-catenin signaling and induced HFDPCs growth by increasing the expression of cell cycle proteins such as cyclin D1 and cyclin-dependent kinase 2. LA treatment also increased several growth factors, such as vascular endothelial growth factor, insulin-like growth factor-1, hepatocyte growth factor, and keratinocyte growth factor, in a dose-dependent manner. Besides, LA significantly inhibited Dickkopf-related protein expression (DKK-1), a primary alopecia signaling by dihydrotestosterone. Our findings suggest that LA treatment may alleviate a testosterone-induced signaling molecule and induces HFDPCs growth by activating Wnt/ß-catenin signaling.


Assuntos
Folículo Piloso/citologia , Peptídeos e Proteínas de Sinalização Intercelular/agonistas , Ácido Linoleico/farmacologia , Malva/química , Extratos Vegetais/farmacologia , Sementes/química , Biomarcadores , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Fracionamento Químico , Expressão Gênica , Folículo Piloso/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácido Linoleico/química , Ácido Linoleico/isolamento & purificação , Modelos Biológicos , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Via de Sinalização Wnt/efeitos dos fármacos
17.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33649839

RESUMO

Hepatic fibrosis, a common pathological manifestation of chronic liver injury, is generally considered to be the end result of an increase in extracellular matrix produced by activated hepatic stellate cells (HSCs). The aim of the present study was to target the mechanisms underlying HSC activation in order to provide a powerful therapeutic strategy for the prevention and treatment of liver fibrosis. In the present study, a high­throughput screening assay was established, and the histone deacetylase inhibitor givinostat was identified as a potent inhibitor of HSC activation in vitro. Givinostat significantly inhibited HSC activation in vivo, ameliorated carbon tetrachloride­induced mouse liver fibrosis and lowered plasma aminotransferases. Transcriptomic analysis revealed the most significantly regulated genes in the givinostat treatment group in comparison with those in the solvent group, among which, dermokine (Dmkn), mesothelin (Msln) and uroplakin­3b (Upk3b) were identified as potential regulators of HSC activation. Givinostat significantly reduced the mRNA expression of Dmkn, Msln and Upk3b in both a mouse liver fibrosis model and in HSC­LX2 cells. Knockdown of any of the aforementioned genes inhibited the TGF­ß1­induced expression of α­smooth muscle actin and collagen type I, indicating that they are crucial for HSC activation. In summary, using a novel strategy targeting HSC activation, the present study identified a potential epigenetic drug for the treatment of hepatic fibrosis and revealed novel regulators of HSC activation.


Assuntos
Carbamatos/farmacologia , Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Fígado/efeitos dos fármacos , Animais , Tetracloreto de Carbono , Linhagem Celular , Feminino , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/metabolismo , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Estreladas do Fígado/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/genética , Camundongos , Camundongos Endogâmicos C57BL , Ratos , Uroplaquina III/genética , Uroplaquina III/metabolismo
18.
Int J Biol Macromol ; 181: 136-149, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-33766597

RESUMO

This study investigated the relationships between lignin molecular and supramolecular structures and their functional properties within cellulose-based solid matrix, used as a model biodegradable polymer carrier. Two types of derivatives corresponding to distinct structuration levels were prepared from a single technical lignin sample (PB1000): phenol-enriched oligomer fractions and colloidal nanoparticles (CLP). The raw lignin and its derivatives were formulated with cellulose nanocrystals or nanofibrils to prepare films by chemical oxidation or pressure-assisted filtration. The films were tested for their water and lignin retention capacities, radical scavenging capacity (RSC) and antimicrobial properties. A structural investigation was performed by infrared, electron paramagnetic resonance spectroscopy and microscopy. The composite morphology and performance were controlled by both the composition and structuration level of lignin. Phenol-enriched oligomers were the compounds most likely to interact with cellulose, leading to the smoothest film surface. Their RSC in film was 4- to 6-fold higher than that of the other samples. The organization in CLP led to the lowest RSC but showed capacity to trap and stabilize phenoxy radicals. All films were effective against S. aureus (gram negative) whatever the lignin structure. The results show the possibility to tune the performances of these composites by exploiting lignin multi-scale structure.


Assuntos
Lignina/química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Escherichia coli/efeitos dos fármacos , Sequestradores de Radicais Livres/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Testes de Sensibilidade Microbiana , Microscopia de Força Atômica , Nanopartículas/química , Nanopartículas/ultraestrutura , Fenóis/química , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Suspensões , Água/química
19.
Mol Immunol ; 133: 146-153, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667984

RESUMO

BACKGROUND: Hemodialysis (HD) patients often develop chronic inflammation, which is associated with an increased risk of cardiovascular complications and mortality. Axl and its ligand, growth arrest 6 (Gas6), have been reported to play key roles in regulating the immune response. However, the function of Axl in HD patients has not been clarified. METHODS: In the present study, we enrolled 130 HD patients and 117 normal controls (NCs) and evaluated the levels of inflammatory markers, soluble Axl (sAxl), membrane Axl (mAxl), and Gas6 in all participants. The potential downstream cascades of Gas6-Axl signaling in HD patients were identified by quantitative real time polymerase chain reaction and western blotting. RESULTS: The levels of inflammatory cytokines-tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ)-plasma sAxl, and Gas6, were significantly increased in HD patients compared to NCs. Additionally, sAxl was positively associated with the inflammatory factor, interleukin-6 (IL-6), in HD patients. Moreover, we found that mAxl in CD14+ mononuclear cells and CD19+ B cells was increased upon HD. Furthermore, we discovered that the metalloproteinase ADAM17, also called TACE, contributed to the cleavage of mAxl into sAxl, and not ADAM10, in the peripheral blood mononuclear cells (PBMCs) of HD patients. The upregulation of Gas6-mAxl signaling caused the activation of the STAT1-SOCS3 pathway in the PBMCs of HD patients. After two years follow-up, patients with lower sAxl levels had longer survival time than those with higher sAxl levels. CONCLUSION: Our results suggest that Axl may play a significant role in systemic inflammation in HD patients.


Assuntos
Inflamação/patologia , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/sangue , Receptores Proteína Tirosina Quinases/metabolismo , Diálise Renal/efeitos adversos , Proteína ADAM10/metabolismo , Proteína ADAM17/metabolismo , Adulto , Secretases da Proteína Precursora do Amiloide/metabolismo , Linfócitos B/metabolismo , Feminino , Humanos , Inflamação/genética , Inflamação/imunologia , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Interferon gama/sangue , Interleucina-6/sangue , Leucócitos Mononucleares/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas/genética , Reação em Cadeia da Polimerase em Tempo Real , Receptores Proteína Tirosina Quinases/genética , Fator de Transcrição STAT1/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Fator de Necrose Tumoral alfa/sangue
20.
Biochem Biophys Res Commun ; 554: 25-32, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33774276

RESUMO

Osteosarcoma, a highly aggressive malignant tumor of the bone, usually occurs in children and young adults. However, although the considerable achievement in the clinical treatment of osteosarcoma recent years, the overall survival of osteosarcoma patients has not been obviously improved. Cancer cells preferentially use glycolysis instead of oxidative phosphorylation to meet their increased energetic and biosynthetic demands, a phenomenon known as the Warburg effect. Glycolysis is a driving factor in multiple cancers and is emerging as a new cancer target treatment. In the present study, we established a model to screen for glycolysis-associated genes in osteosarcoma. This risk score of the model were correlated with clinical characteristics osteosarcoma patients. Besides, a functional assay identified that STC2 enhanced the glycolysis of osteosarcoma cells. Modulation of STC2 changes glucose consumption and lactate production as well as GLUT1 expression in osteosarcoma. Furthermore, we identified that change in the expression levels of STC2 affected the proliferation, invasion, and migration of osteosarcoma cells. Our findings showed STC2 as a new tumor-promoting factor of osteosarcoma cells through enhancing glycolysis.


Assuntos
Neoplasias Ósseas/metabolismo , Neoplasias Ósseas/patologia , Glucose/metabolismo , Glicoproteínas/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Ácido Láctico/metabolismo , Osteossarcoma/metabolismo , Osteossarcoma/patologia , Neoplasias Ósseas/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Biologia Computacional , Bases de Dados Genéticas , Glicólise , Glicoproteínas/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/genética , Osteossarcoma/genética , Prognóstico , Taxa de Sobrevida
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