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1.
Pathol Oncol Res ; 28: 1610608, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36091936

RESUMO

Osteopontin (OPN) is a multifunctional glycoprotein that physiologically interacts with different types of integrins. It is considered to be a possible prognostic biomarker in certain tumor types; however, various splicing isoforms exist, which have not been investigated in melanoma. We aimed to define the relative expression pattern of five OPN isoforms and clarify the prognostic significance of the splice variants in melanoma. We also aimed to investigate the expression pattern of eight integrins in the same tumors. Gene expression analyses revealed that the relative expression of OPNa, OPNb, and OPNc is significantly higher in metastatic tumors compared to primary lesions (p < 0.01), whereas the expression of OPN4 and OPN5 was low in both. The more aggressive nodular melanomas had higher expression levels compared to the superficial spreading subtype (p ≤ 0.05). The relative expression of the eight tested integrins was low, with only the expression of ITGB3 being detectable in nodular melanoma (Medianlog2 = 1.274). A positive correlation was found between Breslow thickness and the expression of OPNc variant, whereby thicker tumors (>4 mm) had significantly higher expression (p ≤ 0.05). The Breslow thickness was negatively correlated with the expression of OPN4, and similarly with ITGA2. OPNc also exhibited significant positive correlation with the presence of metastasis. Our data show that high expression of OPNa, OPNb, and especially OPNc and low expression of OPN4 and ITGA2 are associated with an advanced stage of tumor progression and poor prognosis in melanoma.


Assuntos
Melanoma , Osteopontina , Expressão Gênica , Humanos , Integrinas/genética , Melanoma/genética , Osteopontina/genética , Osteopontina/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Neoplasias Cutâneas
2.
J Extracell Vesicles ; 11(9): e12265, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36107309

RESUMO

CD47 regulates the trafficking of specific coding and noncoding RNAs into extracellular vesicles (EVs), and the RNA contents of CD47+ EVs differ from that of CD63+ EVs released by the same cells. Single particle interferometric reflectance imaging sensing combined with immunofluorescent imaging was used to analyse the colocalization of tetraspanins, integrins, and CD47 on EVs produced by wild type and CD47-deficient Jurkat T lymphoblast and PC3 prostate carcinoma cell lines. On Jurkat cell-derived EVs, ß1 and α4 integrin subunits colocalized predominantly with CD47 and CD81 but not with CD63 and CD9, conserving the known lateral interactions between these proteins in the plasma membrane. Although PC3 cell-derived EVs lacked detectable α4 integrin, specific association of CD81 with ß1 and CD47 was preserved. Loss of CD47 expression in Jurkat cells significantly reduced ß1 and α4 levels on EVs produced by these cells while elevating CD9+ , CD63+ , and CD81+ EVs. In contrast, loss of CD47 in PC3 cells decreased the abundance of CD63+ and CD81+ EVs. These data establish that CD47+ EVs are mostly distinct from EVs bearing the tetraspanins CD63 and CD9, but CD47 also indirectly regulates the abundance of EVs bearing these non-interacting tetraspanins via mechanisms that remain to be determined.


Assuntos
Carcinoma , Vesículas Extracelulares , Neoplasias da Próstata , Antígeno CD47/metabolismo , Carcinoma/metabolismo , Vesículas Extracelulares/metabolismo , Humanos , Integrina alfa4/metabolismo , Integrinas/metabolismo , Masculino , Próstata , Neoplasias da Próstata/metabolismo , RNA/metabolismo , Tetraspaninas/metabolismo
3.
PLoS One ; 17(9): e0274667, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36108060

RESUMO

BACKGROUND: Increasing brain exposure of biotherapeutics is key to success in central nervous system disease drug discovery. Accessing the brain parenchyma is especially difficult for large polar molecules such as biotherapeutics and antibodies because of the blood-brain barrier. We investigated a new immunization strategy to identify novel receptors mediating transcytosis across the blood-brain barrier. METHOD: We immunized mice with primary non-human primate brain microvascular endothelial cells to obtain antibodies. These antibodies were screened for their capacity to bind and to be internalized by primary non-human primate brain microvascular endothelial cells and Human Cerebral Microvascular Endothelial Cell clone D3. They were further evaluated for their transcytosis capabilities in three in vitro blood-brain barrier models. In parallel, their targets were identified by two different methods and their pattern of binding to human tissue was investigated using immunohistochemistry. RESULTS: 12 antibodies with unique sequence and internalization capacities were selected amongst more than six hundred. Aside from one antibody targeting Activated Leukocyte Cell Adhesion Molecule and one targeting Striatin3, most of the other antibodies recognized ß1 integrin and its heterodimers. The antibody with the best transcytosis capabilities in all blood-brain barrier in vitro models and with the best binding capacity was an anti-αnß1 integrin. In comparison, commercial anti-integrin antibodies performed poorly in transcytosis assays, emphasizing the originality of the antibodies derived here. Immunohistochemistry studies showed specific vascular staining on human and non-human primate tissues. CONCLUSIONS: This transcytotic behavior has not previously been reported for anti-integrin antibodies. Further studies should be undertaken to validate this new mechanism in vivo and to evaluate its potential in brain delivery.


Assuntos
Células Endoteliais , Integrinas , Molécula de Adesão de Leucócito Ativado , Animais , Anticorpos/metabolismo , Encéfalo/metabolismo , Células Endoteliais/metabolismo , Integrina beta1/metabolismo , Integrinas/metabolismo , Camundongos
4.
Cell ; 185(19): 3463-3466, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36113425

RESUMO

Integrin receptors are established drug targets, but many of the drugs that have been developed act as partial agonists, inducing the receptor into a high-affinity, ligand-binding state. Lin et al. discovered a general mechanism to circumvent this problem-stabilizing a key water molecule that prevents receptor activation. Their findings are likely to impact future therapeutic development.


Assuntos
Integrinas , Água , Integrinas/química , Ligantes
5.
ACS Appl Mater Interfaces ; 14(36): 40559-40568, 2022 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-36047858

RESUMO

Piezo1 is a recently discovered Ca2+ permeable ion channel that has emerged as an integral sensor of hemodynamic forces within the cardiovascular system, contributing to vascular development and blood pressure regulation. However, how the composition of the extracellular matrix (ECM) affects the mechanosensitivity of Piezo1 in response to hemodynamic forces remains poorly understood. Using a combination of microfluidics and calcium imaging techniques, we probe the shear stress sensitivity of single HEK293T cells engineered to stably express Piezo1 in the presence of different ECM proteins. Our experiments show that Piezo1 sensitivity to shear stress is not dependent on the presence of ECM proteins. However, different ECM proteins regulate the sensitivity of Piezo1 depending on the shear stress level. Under high shear stress, fibronectin sensitizes Piezo1 response to shear, while under low shear stress, Piezo1 mechanosensitivity is improved in the presence of collagen types I and IV and laminin. Moreover, we report that α5ß1 and αvß3 integrins are involved in Piezo1 sensitivity at high shear, while αvß3 and αvß5 integrins are involved in regulating the Piezo1 response at low shear stress. These results demonstrate that the ECM/integrin interactions influence Piezo1 mechanosensitivity and could represent a mechanism whereby extracellular forces are transmitted to Piezo1 channels, providing new insights into the mechanism by which Piezo1 senses shear stress.


Assuntos
Canais Iônicos , Mecanotransdução Celular , Matriz Extracelular/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Células HEK293 , Humanos , Integrinas/metabolismo , Mecanotransdução Celular/fisiologia
6.
Mol Med Rep ; 26(5)2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36069233

RESUMO

Extracellular matrix tenascin­X (TNX) is the largest member of the tenascin family. Our previous study demonstrated that TNX was involved in hepatic dysfunction, including fibrosis, in mice that were administered a high­fat and high­cholesterol diet with high levels of phosphorus and calcium. The present study investigated whether overexpression of both the fibrinogen domain of TNX (TNX­FG) and integrin α11, one of the TNX cell surface receptors, induces in vitro fibrosis in LX­2 human hepatic stellate cells. Overexpression of both a 15­amino acid peptide (hTNX­FGFFFF) derived from the TNX­FG domain and integrin α11 induced the expression of type I collagen α1 chain (COL1A1). Treatment with verteporfin [YAP (Yes­associated protein) inhibitor] attenuated the elevated COL1A1 expression elicited by overexpression of both hTNX­FGFFFF and integrin α11. In addition, small interfering RNA­mediated knockdown of YAP1 resulted in a decrease in COL1A1 expression induced by overexpression of both hTNX­FGFFFF and integrin α11. These results indicated that overexpression of both hTNX­FGFFFF and integrin α11 induced COL1A1 expression via the YAP signaling pathway.


Assuntos
Integrinas , Tenascina , Aminoácidos , Animais , Matriz Extracelular/metabolismo , Fibrinogênio , Fibrose , Humanos , Cadeias alfa de Integrinas/metabolismo , Integrinas/metabolismo , Camundongos , Peptídeos , Tenascina/genética
7.
J Cell Biol ; 221(10)2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36074065

RESUMO

The formation of healthy tissue involves continuous remodeling of the extracellular matrix (ECM). Whilst it is known that this requires integrin-associated cell-ECM adhesion sites (CMAs) and actomyosin-mediated forces, the underlying mechanisms remain unclear. Here, we examine how tensin3 contributes to the formation of fibrillar adhesions (FBs) and fibronectin fibrillogenesis. Using BioID mass spectrometry and a mitochondrial targeting assay, we establish that tensin3 associates with the mechanosensors such as talin and vinculin. We show that the talin R11 rod domain binds directly to a helical motif within the central intrinsically disordered region (IDR) of tensin3, whilst vinculin binds indirectly to tensin3 via talin. Using CRISPR knock-out cells in combination with defined tensin3 mutations, we show (i) that tensin3 is critical for the formation of α5ß1-integrin FBs and for fibronectin fibrillogenesis, and (ii) the talin/tensin3 interaction drives this process, with vinculin acting to potentiate it.


Assuntos
Fibronectinas , Adesões Focais , Talina , Tensinas , Adesão Celular , Matriz Extracelular/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Adesões Focais/genética , Adesões Focais/metabolismo , Integrinas/metabolismo , Talina/genética , Talina/metabolismo , Tensinas/genética , Tensinas/metabolismo , Vinculina/genética , Vinculina/metabolismo
8.
Int J Mol Sci ; 23(17)2022 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-36077426

RESUMO

Exerkines are soluble factors secreted by exercised muscles, mimicking the effects of exercise in various organs, including the muscle itself. Lumican is reportedly secreted from muscles; however, its roles in skeletal muscle remain unknown. Herein, we found that lumican mRNA expression in the extensor digitorum longus was significantly higher in exercised mice than in unloading mice, and lumican stimulated myogenesis in vitro. Additionally, lumican knockdown significantly decreased muscle mass and cross-sectional area (CSA) of the muscle fiber in the gastrocnemius muscle of exercised mice. Lumican upregulated phosphorylation of p38 mitogen-activated protein kinase (MAPK) and a p38 inhibitor near completely blocked lumican-stimulated myogenesis. Inhibitors for integrin α2ß1 and integrin ανß3 also prevented lumican-stimulated myogenesis. Systemic lumican treatment, administered via the tail vein for 4 weeks, significantly increased relative muscle masses by 36.1% in ovariectomized mice. In addition, intramuscular lumican injection into unloaded muscles for 2 weeks significantly increased muscle mass by 8.5%. Both intravenous and intramuscular lumican treatment significantly increased muscle CSA. Our in vitro and in vivo experiments indicate that lumican is a muscle-secreted exerkine that affords protection against muscle loss by activating p38 MAPK via integrin receptors.


Assuntos
Músculo Esquelético , Doenças Musculares , Animais , Integrinas/metabolismo , Lumicana/metabolismo , Camundongos , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Fosforilação , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
9.
Cell Rep ; 40(12): 111390, 2022 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-36130502

RESUMO

Preservation of a small population of cancer stem cells (CSCs) within a heterogeneous carcinoma serves as a paradigm to understand how select cells in a tissue maintain their undifferentiated status. In both embryogenesis and cancer, Snail has been correlated with stemness, but the molecular underpinning of this phenomenon remains largely ill-defined. In models of cutaneous squamous cell carcinoma (cSCC), we discovered a non-epithelial-mesenchymal transition function for the transcription factor Snail in maintaining the stemness of epidermal keratinocytes. Snail-expressing cells secrete the matricellular protein Mindin, which functions in an autocrine fashion to activate a Src-STAT3 pathway to reinforce their stem/progenitor phenotype. This pathway is activated by the engagement of Mindin with the leukocyte-specific integrin, CD11b (ITGAM), which is also unexpectedly expressed by epidermal keratinocytes. Interestingly, disruption of this signaling module in human cSCC attenuates tumorigenesis, suggesting that targeting Mindin would be a promising therapeutic approach to hinder cancer recurrence.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Cutâneas , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Células Epiteliais/metabolismo , Proteínas da Matriz Extracelular , Humanos , Integrinas/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias Cutâneas/patologia , Fatores de Transcrição da Família Snail/metabolismo
10.
Medicine (Baltimore) ; 101(37): e30625, 2022 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-36123924

RESUMO

The present study aimed to explore the signaling pathways involved in development of early steroid-induced osteonecrosis of the femoral head (SONFH) and identify diagnostic biomarkers regulating peripheral blood in SONFH patients. We downloaded transcriptome data and identified differentially expressed genes (DEGs) using the R software. We used ClusterProfiler to perform enrichment analysis of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, and analyzed protein-protein interactions using the STRING database. Network X was used to visualize the networks in Python. A total of 584 DEGs were identified, of which 294 and 290 were upregulated and downregulated, respectively. Enrichment analysis showed that the DEGs were mainly involved in red blood cell differentiation, cell protein catabolism, gas transportation, activation of myeloid leukocytes, phagocytosis, and inflammatory response. Pathway analysis revealed that these DEGs were involved in regulation of mitophagy-animal, human T-cell leukemia virus-1 infection, Forkhead box O, phagocytosis, osteoclast differentiation, and cytokine-cytokine receptor interaction. Quantitative real-time polymerase chain reaction results were consistent with findings from protein-protein interaction network analysis. Several genes, including peroxiredoxin 2, haptoglobin, matrix metallopeptidase 8, formyl peptide receptor 2, and integrin subunit alpha X, promote SONFH occurrence by regulating the redox, inflammatory response, and osteoblast and osteoclast structure and function pathways. They may be important targets for designing approaches for early diagnosis and treatment of SONFH.


Assuntos
Osteonecrose , Transcriptoma , Biomarcadores , Citocinas , Cabeça do Fêmur , Haptoglobinas , Humanos , Integrinas , Metaloproteases , Peroxirredoxinas , Receptores de Citocinas , Receptores de Formil Peptídeo , Esteroides
11.
J Nanobiotechnology ; 20(1): 418, 2022 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-36123687

RESUMO

The cell/microenvironment interface is the starting point of integrin-mediated mechanotransduction, but many details of mechanotransductive signal integration remain elusive due to the complexity of the involved (extra)cellular structures, such as the glycocalyx. We used nano-bio-interfaces reproducing the complex nanotopographical features of the extracellular matrix to analyse the glycocalyx impact on PC12 cell mechanosensing at the nanoscale (e.g., by force spectroscopy with functionalised probes). Our data demonstrates that the glycocalyx configuration affects spatio-temporal nanotopography-sensitive mechanotransductive events at the cell/microenvironment interface. Opposing effects of major glycocalyx removal were observed, when comparing flat and specific nanotopographical conditions. The excessive retrograde actin flow speed and force loading are strongly reduced on certain nanotopographies upon strong reduction of the native glycocalyx, while on the flat substrate we observe the opposite trend. Our results highlight the importance of the glycocalyx configuration in a molecular clutch force loading-dependent cellular mechanism for mechanosensing of microenvironmental nanotopographical features.


Assuntos
Glicocálix , Mecanotransdução Celular , Actinas , Glicocálix/fisiologia , Integrinas , Percepção
12.
Mol Biol Cell ; 33(11): ar103, 2022 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-36001375

RESUMO

Cell-extracellular matrix (ECM) interactions represent fundamental exchanges during tumor progression, yet how particular signal-transduction factors prompt the conversion of tumor cells into migratory populations capable of systemic spread during metastasis remains elusive. We demonstrate that the noncanonical Wnt receptor, Ror2, regulates tumor cell-driven matrix remodeling and invasion in breast cancer. Ror2 loss-of-function (LOF) triggers the disruption of E-cadherin within tumor cells, accompanied by an increase in tumor cell invasion and collagen realignment in three-dimensional cultures. RNA sequencing of Ror2-deficient organoids further uncovered alterations in actin cytoskeleton, cell adhesion, and collagen cross-linking gene expression programs. Spatially, we pinpoint the up-regulation and redistribution of α5 and ß3 integrins together with the production of fibronectin in areas of invasion downstream of Ror2 loss. Wnt/ß-catenin-dependent and Wnt/Ror2 alternative Wnt signaling appear to regulate distinct functions for tumor cells regarding their ability to modify cell-ECM exchanges during invasion. Furthermore, blocking either integrin or focal adhesion kinase (FAK), a downstream mediator of integrin-mediated signal transduction, abrogates the enhanced migration observed upon Ror2 loss. These results reveal a critical function for the alternative Wnt receptor, Ror2, as a determinant of tumor cell-driven ECM exchanges during cancer invasion and metastasis.


Assuntos
Neoplasias da Mama , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Adesão Celular , Linhagem Celular Tumoral , Junções Célula-Matriz , Feminino , Humanos , Integrinas , Via de Sinalização Wnt
13.
Acta Virol ; 66(3): 216-227, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36029087

RESUMO

Acute infectious mononucleosis (AIM) is associated with Epstein-Barr virus (EBV) infection. We explored molecular mechanisms regarding the expression of CD8+T cells in convalescence stage (CONV). Differentially expressed genes (DEGs) were identified by analyzing GEO expression profiles. Subsequently, Gene Set Enrichment Analysis (GSEA), Protein-Protein Interactions (PPI) network, and gene-micro RNAs networks were used to identify hub genes and associated pathways. GSEA provided evidence that the top 3 gene sets in GSEA were all related to integrins. We identified ten hub genes in the PPI network and DGIdb was applied to predict potential targets that might reverse the expression of hub genes. Our study enhances a mechanistic understanding of the CD8+T cells expansion in acute EBV infection and provides potential treatment targets for further research. Keywords: acute infectious mononucleosis; bioinformatics; CD8+T cells; differentially expressed genes; EBV.


Assuntos
Infecções por Vírus Epstein-Barr , Mononucleose Infecciosa , Linfócitos T CD8-Positivos , Infecções por Vírus Epstein-Barr/genética , Herpesvirus Humano 4/genética , Humanos , Mononucleose Infecciosa/genética , Integrinas/genética , Transcriptoma
14.
J Hematol Oncol ; 15(1): 123, 2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36045419

RESUMO

The vast majority of our knowledge regarding cancer radiobiology and the activation of radioresistance mechanisms emerged from studies using external beam radiation therapy (EBRT). Yet, less is known about the cancer response to internal targeted radionuclide therapy (TRT). Our comparative phosphoproteomics analyzed cellular responses to TRT with lutetium-177-labeled minigastrin analogue [177Lu]Lu-PP-F11N (ß-emitter) and EBRT (É£-rays) in CCKBR-positive cancer cells. Activation of DNA damage response by p53 was induced by both types of radiotherapy, whereas TRT robustly increased activation of signaling pathways including epidermal growth factor receptor (EGFR), mitogen-activated protein kinases (MAPKs) or integrin receptor. Inhibition of EGFR or integrin signaling sensitized cancer cells to radiolabeled minigastrin. In vivo, EGFR inhibitor erlotinib increased therapeutic response to [177Lu]Lu-PP-F11N and median survival of A431/CCKBR-tumor bearing nude mice. In summary, our study explores a complex scenario of cancer responses to different types of irradiation and pinpoints the radiosensitizing strategy, based on the targeting survival pathways, which are activated by TRT.


Assuntos
Neoplasias , Radioisótopos , Animais , Linhagem Celular Tumoral , Receptores ErbB , Integrinas , Camundongos , Camundongos Nus , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Radioisótopos/uso terapêutico
15.
Dalton Trans ; 51(34): 12796-12803, 2022 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-35972045

RESUMO

Expression of the cellular transmembrane receptor αvß6 integrin is mostly restricted to malignant epithelial cells in a wide variety of carcinomas, including pancreatic and others derived from epithelial tissues. Thus, this protein is considered an attractive target for tumour imaging and therapy. Two different 68Ga hexadentate tris (3,4-hydroxypyridinone) (THP) chelators were produced in this study and coupled to the αvß6 integrin-selective peptide cyclo(FRGDLAFp(NMe)K) via NHS chemistry. Radiolabelling experiments confirmed a high radiochemical yield of the two PET probes. In addition, cellular binding studies showed high binding affinities in the nanomolar range. The two integrin αvß6-peptide-THP synthesized and radiolabeled in this study will facilitate in vivo monitoring of transmembrane receptor αvß6 integrin by using the advantage of THP chemistry for rapid, efficient and stable gallium chelation.


Assuntos
Radioisótopos de Gálio , Tomografia por Emissão de Pósitrons , Antígenos de Neoplasias/metabolismo , Quelantes , Integrina alfaVbeta3/metabolismo , Integrinas , Peptídeos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual
16.
Int Immunopharmacol ; 111: 109179, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36029666

RESUMO

Macrophage polarization is modulated by many different stimuli. However, the effect of fibrotic extracellular matrix (ECM) on macrophage polarization remains unclear. In this study, a mouse model of radiation induced pulmonary fibrosis (RIPF) was established. Alveolar macrophages (AMs) were seeded on separated decellularized ECM respectively derived from early RIPF lung tissue (dECM-RIPF) and normal lung tissue (dECM-Nor), on which the polarization of AMs was examined. By way of bio-AFM analysis, a significant difference in surface roughness, but no difference in stiffness, was found between dECM-RIPF and dECM-Nor. Compared with dECM-Nor, dECM-RIPF induced a higher M1 activation and increased the levels of TNF-α, IL-6 and IL-1ß, while it showed no significant effect M2 density. Nevertheless, such effects induced by dECM-RIPF could be abrogated by the integrin pan-inhibitor. Furthermore, dECM-RIPF caused integrin-dependent activation of NFκB, and NFκB inhibitor was capable of inhibiting dECM-RIPF-induced AMs proliferation and M1 activation. Animal experiments showed that NFκB inhibitor alleviated RIPF mainly through inhibiting M1 activation and down-regulating the levels of inflammatory cytokines. Our results showed that differential biophysical signaling from the fibrotic ECM of early RIPF promoted AMs polarization towards a M1 phenotype via integrin-NFκB. Inhibition of M1 activation may be an attractive approach for treating RIPF.


Assuntos
Macrófagos Alveolares , Fibrose Pulmonar , Animais , Matriz Extracelular , Integrinas , Pulmão , Camundongos , Fibrose Pulmonar/patologia
17.
Biomaterials ; 288: 121732, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-36031457

RESUMO

Regenerating defective bone in patients with diabetes mellitus remains a significant challenge due to high blood glucose level and oxidative stress. Here we aim to tackle this issue by means of a drug- and cell-free scaffolding approach. We found the nanoceria decorated on various types of scaffolds (fibrous or 3D-printed one; named nCe-scaffold) could render a therapeutic surface that can recapitulate the microenvironment: modulating oxidative stress while offering a nanotopological cue to regenerating cells. Mesenchymal stem cells (MSCs) recognized the nanoscale (tens of nm) topology of nCe-scaffolds, presenting highly upregulated curvature-sensing membrane protein, integrin set, and adhesion-related molecules. Osteogenic differentiation and mineralization were further significantly enhanced by the nCe-scaffolds. Of note, the stimulated osteogenic potential was identified to be through integrin-mediated TGF-ß co-signaling activation. Such MSC-regulatory effects were proven in vivo by the accelerated bone formation in rat calvarium defect model. The nCe-scaffolds further exhibited profound enzymatic and catalytic potential, leading to effectively scavenging reactive oxygen species in vivo. When implanted in diabetic calvarium defect, nCe-scaffolds significantly enhanced early bone regeneration. We consider the currently-exploited nCe-scaffolds can be a promising drug- and cell-free therapeutic means to treat defective tissues like bone in diabetic conditions.


Assuntos
Regeneração Óssea , Diabetes Mellitus , Células-Tronco Mesenquimais , Tecidos Suporte , Animais , Regeneração Óssea/efeitos dos fármacos , Diferenciação Celular , Cério/farmacologia , Cério/uso terapêutico , Diabetes Mellitus/metabolismo , Integrinas/metabolismo , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Osteogênese , Estresse Oxidativo , Ratos , Fator de Crescimento Transformador beta/metabolismo
18.
J Interferon Cytokine Res ; 42(8): 421-429, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35914102

RESUMO

Tuberculosis (TB) caused by the pathogenic bacterium Mycobacterium tuberculosis (Mtb) is one of the most lethal infectious diseases in the world. Presently, Bacillus Calmette-Guerin, the vaccine approved for use against TB, does not offer complete protection against the disease, which necessitates the development of new therapeutics to treat this infection. Overexpression of transforming growth factor beta (TGF-ß) is associated with pulmonary profibrotic changes. The inactive TGF-ß secreted is activated through its cleavage and release by αv integrins. Integrin-mediated regulation of TGF-ß is considered as a master switch in the profibrotic process and a potential therapeutic target. Thus, in this study, we sought to determine if treatment with a broad range antagonist of integrins, CWHM-12, has the potency to inhibit pulmonary fibrosis and enhance Mtb control in a highly susceptible mouse model of Mtb infection, namely the C3Heb/FeJ (FeJ). CWHM-12 treatment at the early stages of Mtb infection was efficacious in reducing disease severity and inflammation associated with decreased iNOS, MIP-2, and IL-10 production without degradation of collagen. This suggests a potential for CWHM-12 targeting of TGF-ß to be explored as an adjunct therapeutic for early Mtb infection.


Assuntos
Mycobacterium tuberculosis , Tuberculose , Animais , Integrinas , Camundongos , Fator de Crescimento Transformador beta/metabolismo , Fatores de Crescimento Transformadores , Tuberculose/tratamento farmacológico , Tuberculose/prevenção & controle
19.
Nano Lett ; 22(17): 6866-6876, 2022 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-35926215

RESUMO

Immune checkpoint blockade (ICB) therapy has revolutionized clinical oncology. However, the efficacy of ICB therapy is limited by the ineffective infiltration of T effector (Teff) cells to tumors and the immunosuppressive tumor microenvironment (TME). Here, we report a programmable tumor cells/Teff cells bispecific nano-immunoengager (NIE) that can circumvent these limitations to improve ICB therapy. The peptidic nanoparticles (NIE-NPs) bind tumor cell surface α3ß1 integrin and undergo in situ transformation into nanofibrillar network nanofibers (NIE-NFs). The prolonged retained nanofibrillar network at the TME captures Teff cells via the activatable α4ß1 integrin ligand and allows sustained release of resiquimod for immunomodulation. This bispecific NIE eliminates syngeneic 4T1 breast cancer and Lewis lung cancer models in mice, when given together with anti-PD-1 antibody. The in vivo structural transformation-based supramolecular bispecific NIE represents an innovative class of programmable receptor-mediated targeted immunotherapeutics to greatly enhance ICB therapy against cancers.


Assuntos
Neoplasias , Microambiente Tumoral , Animais , Imunomodulação , Integrinas , Camundongos , Neoplasias/tratamento farmacológico , Linfócitos T
20.
J Reprod Immunol ; 153: 103666, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35970081

RESUMO

Recurrent spontaneous abortion (RSA) is a disturbing pregnancy disorder experienced by ~2.5% of women attempting to conceive. The pathogenesis of RSA is still unclear. Previous findings revealed that transcription factor YIN-YANG 1(YY1) was related to the pathogenesis of RSA by influence trophoblastic cell invasion ability. Present study aimed to investigate more specific molecular mechanism of YY1 playing in trophoblastic cells. In our research, RNA-seq and Chip-seq were used to find significant changed genes between si-YY1(Knock down of YY1) HTR-8/SVneo cells(n = 3) and HTR-8/SVneo cells(n = 3). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis results suggested that Integrins related pathway maybe necessary to biological functions of trophoblastic cells. Chip-seq dataset analysis results predict YY1 can regulate ITGA3/7 expression by binding to the promoter region of ITGA3/7. Furthermore, results from chip experiment, RT-PCR, Dual-luciferase reporter gene assay showed that YY1 was able to bind to the promoter region of ITGA3 and regulate ITGA3 mRNA and protein expression. However, ITGA7 could not be significant influenced by YY1. Besides, gene silencing experiment, Western blot and Immunofluorescence assay confirmed that both YY1 and ITGA3 can accelerate phosphorylation focal adhesion kinase and affect cytoskeleton formation in HTR-8/SVneo cells. In conclusion, YY1/ITGA3 play a critical role in trophoblast invasion ability by regulating cytoskeleton formation.


Assuntos
Aborto Habitual , MicroRNAs , Aborto Habitual/patologia , Movimento Celular/genética , Proliferação de Células , Feminino , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Humanos , Integrina alfa3/metabolismo , Integrinas/metabolismo , MicroRNAs/genética , Gravidez , RNA Mensageiro/metabolismo , Fatores de Transcrição , Trofoblastos/metabolismo , Fator de Transcrição YY1/genética , Fator de Transcrição YY1/metabolismo
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