Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.241
Filtrar
2.
Cell Death Dis ; 13(12): 1044, 2022 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-36522320

RESUMO

Accumulating evidence indicates that the extracellular matrix (ECM) is not only a consequence of fibrosis, but also contributes to the progression of fibrosis, by creating a profibrotic microenvironment. Tenascin-C (TNC) is an ECM glycoprotein that contains multiple functional domains. We showed that following kidney injury, TNC was markedly induced in fibrotic areas in the kidney from both mouse models and humans with kidney diseases. Genetically deletion of TNC in mice significantly attenuated unilateral ureteral obstruction-induced kidney fibrosis. Further studies showed that TNC promoted the proliferation of kidney interstitial cells via STAT3 activation. TNC-expressing cells in fibrotic kidney were activated fibroblast 2 (Act.Fib2) subpopulation, according to a previously generated single nucleus RNA-seq dataset profiling kidney of mouse UUO model at day 14. To identify and characterize TNC-expressing cells, we generated a TNC-promoter-driven CreER2-IRES-eGFP knock-in mouse line and found that the TNC reporter eGFP was markedly induced in cells around injured tubules that had lost epithelial markers, suggesting TNC was induced in response to epithelium injury. Most of the eGFP-positive cells were both NG2 and PDGFRß positive. These cells did not carry markers of progenitor cells or macrophages. In conclusion, this study provides strong evidence that matrix protein TNC contributes to kidney fibrosis. TNC pathway may serve as a potential therapeutic target for interstitial fibrosis and the progression of chronic kidney disease.


Assuntos
Nefropatias , Obstrução Ureteral , Humanos , Camundongos , Animais , Tenascina/genética , Tenascina/metabolismo , Proteína C/metabolismo , Fibrose , Nefropatias/metabolismo , Matriz Extracelular/metabolismo , Obstrução Ureteral/metabolismo , Rim/metabolismo , Modelos Animais de Doenças , Fator de Transcrição STAT3/metabolismo
3.
J Tissue Eng Regen Med ; 16(12): 1249-1260, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36346015

RESUMO

Human mesenchymal stem cells/multipotent stromal cells (MSCs) hold great promise in aiding wound healing through their ability to modulate all phases of repair and regeneration, most notably their secretion of pro-regenerative paracrine factors. However, MSC clinical utility is hindered by poor survival rates post-transplantation due to the harsh microenvironment in injured tissue. Previous work has shown that the matricellular protein Tenascin-C (TNC) provides survival signaling to MSCs via the epidermal growth factor receptor by restricting its activation at the plasma membrane, resulting in enhanced prosurvival signals. Herein, we investigate how TNC influences MSC survival and MSC-mediated promotion of the wound healing process. This study examined the survival and angiogenic potential of MSCs cultured on TNC-coated surfaces under ischemic duress in vitro. We also assessed the angiogenic and wound healing outcomes of MSC + TNC in vivo using a CXCR3-/- mouse model that exhibits a delayed healing phenotype within the tissue replacement phase of repair. We found that MSCs in the presence of TNC exhibit higher levels of angiogenic-promoting processes, collagen maturation, and an overall better wound healing outcome than MSCs administered alone. This was seen in vitro in terms of enhanced tube formation. In vivo, the MSCs in the presence of TNC stabilized with a coacervate delivery system resulted in more regenerative wounds with accelerated maturation of the dermis. These findings suggest the coupling of TNC to MSCs as a promising tool for future MSC-ECM combinatorial therapies for wound healing applications.


Assuntos
Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , Tenascina , Cicatrização , Animais , Humanos , Camundongos , Matriz Extracelular/metabolismo , Tenascina/metabolismo
4.
Biomolecules ; 12(11)2022 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-36421704

RESUMO

(1) Background: Injury repair is a complex physiological process in which multiple cells and molecules are involved. Tenascin-C (TNC), an extracellular matrix (ECM) glycoprotein, is essential for angiogenesis during wound healing. This study aims to provide a comprehensive review of the dynamic changes and functions of TNC throughout tissue regeneration and to present an up-to-date synthesis of the body of knowledge pointing to multiple mechanisms of TNC at different restoration stages. (2) Methods: A review of the PubMed database was performed to include all studies describing the pathological processes of damage restoration and the role, structure, expression, and function of TNC in post-injury treatment; (3) Results: In this review, we first introduced the construction and expression signature of TNC. Then, the role of TNC during the process of damage restoration was introduced. We highlight the temporal heterogeneity of TNC levels at different restoration stages. Furthermore, we are surprised to find that post-injury angiogenesis is dynamically consistent with changes in TNC. Finally, we discuss the strategies for TNC in post-injury treatment. (4) Conclusions: The dynamic expression of TNC has a significant impact on angiogenesis and healing wounds and counters many negative aspects of poorly healing wounds, such as excessive inflammation, ischemia, scarring, and wound infection.


Assuntos
Tenascina , Cicatrização , Humanos , Tenascina/genética , Tenascina/metabolismo , Matriz Extracelular/metabolismo , Inflamação/metabolismo
5.
J Pak Med Assoc ; 72(9): 1827-1830, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36280984

RESUMO

Oral fungal infections can be caused by certain species of fungi among which candida albicans is the most implicated. Oral candidiasis is correlated with multiple conditions, such as coronavirus disease-2019, oral leukoplakia and oral erythroplakia. Tenascin is a glycoprotein and is present at the site of tissue injury and chronic inflammation, and tends to be over-expressed in cases of malignancy. Matrix metalloproteinase-9 belongs to a family of zinc-dependent endopeptidases and is involved in the degradation of extracellular matrix, leading to tissue invasion and metastasis. The current narrative review was planned to shed light on the fungal co-infections of coronavirus disease-2019 and molecular mechanisms of matrix metalloproteinase-9 and tenascin involved in the pathogenesis of fungus-associated oral leukoplakia and oral erythroplakia.


Assuntos
COVID-19 , Lesões Pré-Cancerosas , Humanos , Candida , SARS-CoV-2 , Metaloproteinase 9 da Matriz , Tenascina , Leucoplasia Oral , Biomarcadores , Zinco
6.
Eur J Med Res ; 27(1): 208, 2022 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-36271425

RESUMO

BACKGROUND: The recovery from cardiac surgery involves resolving inflammation and remodeling with significant connective tissue turnover. Dynamics of smoldering inflammation and injury (white blood cells, platelets, CRP, IL-8, IL-6), vascular inflammation (IL-15, VEGF, RANTES), connective tissue remodeling (tenascin, MMP-9), cardiac injury and remodeling (YKL-40), and vascular remodeling (epiregulin, MCP-1, VEGF) were assessed up to 3 months after cardiac surgery. We hypothesize that at 3 months, studied markers will return to pre-surgical levels. METHODS: Patients (n = 139) scheduled for non-emergent heart surgery were included, except for patients with pre-existing immunological aberrancies. Blood was collected before surgery(tbaseline), 24 h later(t24h) after the first sample, 7 days(t7d), and 3 months(t3m) after tbaseline. Serum markers were measured via multiplex or ELISA. Electronic medical records (EMR) were used to extract demographical, pre-existing conditions and clinical data. Disposition (discharge home, discharge to facility, death, re-admission) was determined at 28 days and 3 months from admission. RESULTS: Not all inflammatory markers returned to baseline (CRP↑↑, leukocytosis, thrombocytosis, IL-8↓, IL-6↓). Tenascin and YKL-40 levels remained elevated even at t3m. YKL-40 serum levels were significantly elevated at t24h and t7d while normalized at t3m. VEGF returned to the baseline, yet MCP-1 remained elevated at 3 months. CCL28 increased at 3 months, while RANTES and IL-15 declined at the same time. Disposition at discharge was determined by serum MMP-9, while YKL-40 correlated with duration of surgery and APACHE II24h. CONCLUSIONS: The data demonstrated an ongoing extracellular matrix turnover at 3 months, while acute inflammation and vascular remodeling resolved only partially.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Metaloproteinase 9 da Matriz , Humanos , Tenascina , Interleucina-15 , Epirregulina , Proteína 1 Semelhante à Quitinase-3 , Interleucina-6 , Fator A de Crescimento do Endotélio Vascular , Remodelação Vascular , Interleucina-8 , Biomarcadores , Inflamação , Procedimentos Cirúrgicos Cardíacos/efeitos adversos
7.
Biochem Biophys Res Commun ; 632: 69-75, 2022 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-36206596

RESUMO

Autosomal recessive nonsyndromic auditory neuropathy is attributed to a genetic etiology. We identified a compound heterozygous missense variant, c.G736A (p.G246S) and c.C2954T (p.T985 M) in TNN of affected patients in a pedigree via candidate gene screening and exome sequencing. To determine the genetic etiology of deafness in the pedigree with a heterozygous missense variant in the gene TNN encoding tenascin-W associated with autosomal recessive nonsyndromic auditory neuropathy, the cochlear expression of tenascin-W was evaluated at mRNA and protein levels in mice, and Tnn knock out mice were generated and utilized to study the function of Tnn in the auditory system. Immunofluorescence stainings showed that tenascin-W was mainly expressed in the somatic cytoplasm of spiral ganglion neurons of mice. Homozygous Tnn knockout was lethal in mice, whereas Tnn heterozygous mice showed decreases in spiral ganglion neuron density and progressive hearing loss. We demonstrate that tenascin-W is expressed in the murine cochleae and is essential for the development of spiral ganglion neurons. An abnormal expression of tenascin-W can influence the development and function of SGNs and affect the function of the auditory system.


Assuntos
Perda Auditiva Central , Tenascina , Animais , Camundongos , Perda Auditiva Central/genética , Perda Auditiva Central/metabolismo , RNA Mensageiro/metabolismo , Gânglio Espiral da Cóclea/metabolismo , Tenascina/genética , Tenascina/metabolismo , Humanos
8.
Genes (Basel) ; 13(10)2022 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-36292682

RESUMO

BACKGROUND: Skiing is a popular outdoor sport posing different requirements on musculoskeletal and cardiorespiratory function to excel in competition. The extent to which genotypic features contribute to the development of performance with years of ski-specific training remains to be elucidated. We therefore tested whether prominent polymorphisms in genes for angiotensin converting enzyme (ACE-I/D, rs1799752), tenascin-C (TNC, rs2104772), actinin-3 (ACTN3, rs1815739) and PTK2 (rs7460 and rs7843014) are associated with the differentiation of cellular hallmarks of muscle metabolism and contraction in high level skiers. MATERIAL & METHODS: Forty-three skiers of a world-leading national ski team performed exhaustive cardiopulmonary exercise testing as well as isokinetic strength testing for single contractions, whereby 230 cardiopulmonary measurements were performed in the period from 2015-2018. A total of 168 and 62 data measurements were from the Alpine and Nordic skiing squads, respectively. Ninety-five and one hundred thirty-five measurements, respectively, were from male and female athletes. The average (±SD) age was 21.5 ± 3.0 years, height 174.0 ± 8.7 cm, and weight 71.0 ± 10.9 kg for the analysed skiers. Furthermore, all skiers were analysed concerning their genotype ACE-I/D, Tenascin C, ACTN3, PTK2. RESULTS: The genotype distribution deviated from Hardy-Weinberg equilibrium for the ACTN3 genotype, where rs1815739-TT genotypes (corresponding to the nonsense mutation) were overrepresented in world-class skiers, indicating a slow muscle fibre phenotype. Furthermore, the heterozygous rs2104772-AT genotypes of TNC also demonstrated the best scaled peak power output values during ramp exercise to exhaustion. The highest values under maximum performance for heart rate were associated with the rs1799752-II and rs1815739-CC genotypes. The lowest values for peak power of single contractions were achieved for rs1815739-CC, rs1799752-II and rs7843014-CT genotypes. The skiing discipline demonstrated a main influence on cardiorespiratory parameters but did not further interact with genotype-associated variability in performance. DISCUSSION: Classically, it is pointed out that muscles of, for example, alpine skiers do not possess a distinct fibre type composition, but that skiers tend to have a preponderance of slow-twitch fibres. Consequently, our findings of an overrepresentation of ACTN3-TT genotypes in a highly selective sample of elite world class skiers support the potential superiority of a slow fibre type distribution. CONCLUSIONS: We suggest that one competitive advantage that results from a slow, typically fatigue-resistant fibre type distribution might be that performance during intense training days is better preserved, whereby simply a higher technical training volume can be performed, yielding to a competitive advantage.


Assuntos
Esqui , Masculino , Feminino , Humanos , Esqui/fisiologia , Actinina/genética , Peptidil Dipeptidase A/genética , Tenascina/genética , Códon sem Sentido , Atletas , Fibras Musculares Esqueléticas/fisiologia
9.
Front Endocrinol (Lausanne) ; 13: 1031210, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36299463

RESUMO

Background: Laryngeal cancer (LC) is a prevalent head and neck malignancy; however, the essential pathophysiological mechanism underlying its tumorigenesis and progression remains elusive. Due to the perduring scarcity of effective targeted drugs for laryngeal cancer, insights into the disease's pathophysiological mechanisms would substantially impact the treatment landscape of laryngeal cancer. Methods: To ensure quality consistency, 10 tumor and 9 non-tumor samples underwent proteomic analysis on a single mass spectrometer using a label-free technique. Subsequently, gene expression variations between laryngeal squamous cell carcinoma and normal tissues were analyzed using The Cancer Genome Atlas (TCGA) database. Immunohistochemical expressions of insulin-like growth factor 2 receptor (IGF2R), fibronectin (FN), vimentin, and α-smooth muscle actin (SMA) in LC tissues and normal tissues were determined. Results: In the tumor group, significant variations were detected for 433 upregulated and 61 downregulated proteins. Moreover, the heatmap revealed that the expressions of RNA translation-related proteins and proteins involved in RNA metabolism, such as IGF2R, tenascin C (TNC), periostin (POSTN), proteasome 26S subunit ATPase 4 (PSMC4), serpin family A member 3 (SERPINA3), heat shock protein family B (small) member 6 (HSPB6), osteoglycin (OGN), chaperonin containing TCP1 subunit 6A (CCT6A), and chaperonin containing TCP1 subunit 6B (CCT6B), were prominently elevated in the tumor group. Nonsense-mediated RNA decay (NMD), RNA translation, and protein stability were significantly altered in LC tumors. IGF2R was remarkably upregulated in LC tumors. In the TCGA database, the IGF2R mRNA level was significantly upregulated in LSCC tissues. Additionally, IGF2R mRNA expression was lowest in clinical grade 1 samples, with no significant difference between grades 2 and 3. In LSCC patients, a significant positive correlation between IGF2R expression and the stromal score was detected using the ESTIMATE algorithm to estimate the immune score, stromal score, and tumor purity in the tumor microenvironment. Lastly, immunohistochemical analysis revealed that IGF2R is overexpressed in LC. Conclusion: These results demonstrate the vital role of IGF2R in LC carcinogenesis and progression and may facilitate the identification of new therapeutic targets for the prevention and treatment of LC.


Assuntos
Carcinoma de Células Escamosas , Neoplasias Laríngeas , Humanos , Actinas , Adenosina Trifosfatases , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Chaperoninas , Fibronectinas , Proteínas de Choque Térmico , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Complexo de Endopeptidases do Proteassoma , Proteômica , RNA Mensageiro/genética , Serpinas , Somatomedinas , Tenascina , Microambiente Tumoral , Vimentina
10.
Dis Markers ; 2022: 8735551, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36193505

RESUMO

Background: Although the prognosis of papillary thyroid cancer (PTC) is relatively good, some patients experience recurrence or distant metastasis after thyroidectomy and progress to radioactive iodine refractory stage. Therefore, accurate prediction of clinical outlook can aid to screen out the minority of patients with poorer prognosis and avoid excessive treatment in low-risk patients. Methods: The RNA-seq and clinical data of PTC patients was downloaded from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. Multivariate and Lasso Cox regression analyses were used to construct a prognostic nomogram to predict overall survival (OS). Thereafter, quantitative RT-PCR and Human Protein Atlas (HPA) database were employed to verify the expression of key genes. Results: A four-gene risk score comprising ABI3BP, DPT, MRO, and TENM1 was exhibited strong prognostic value. Moreover, an integrated nomogram was established based on the risk score, age, AJCC (American Joint Commission on Cancer) stage, tumor size, extrathyroidal extension, and history of neoadjuvant treatment, which exhibited significantly better predictive performance than TNM stage system (P < 0.05). GSEA (Gene Set Enrichment Analysis) and GSVA (Gene Set Variation Analysis) revealed that the different tumor-associated hallmarks, biological processes, and pathways were substantially enriched in the poor-prognosis group. In addition, a ceRNA network was constructed by including the four genes (ABI3BP, DPT, MRO, and TENM1), 54 lncRNAs, and 10 miRNAs. Finally, both the relative mRNA and protein expression of ABI3BP, DPT, MRO, and TENM1 were validated. Conclusion: The present study identified a four-gene risk signature and developed a novel nomogram, which could be regarded as a reliable prognostic model for PTC patients. The findings also revealed preliminary potential mechanisms that may influence the prognosis outcome. These results can be conducive to design personalized treatment and prognosis management in affected patients.


Assuntos
MicroRNAs , RNA Longo não Codificante , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proteínas de Transporte , Proteoglicanas de Sulfatos de Condroitina , Proteínas da Matriz Extracelular , Humanos , Radioisótopos do Iodo , MicroRNAs/genética , Proteínas de Neoplasias , Proteínas do Tecido Nervoso , Nomogramas , Prognóstico , RNA Longo não Codificante/genética , RNA Mensageiro/genética , Tenascina , Câncer Papilífero da Tireoide/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
11.
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
12.
Stem Cell Res Ther ; 13(1): 477, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-36114555

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) secrete paracrine factors and extracellular matrix proteins that contribute to their ability to support tissue healing and regeneration. Both the transcriptome and the secretome of MSCs can be altered by treating the cells with cytokines, but neither have been thoroughly investigated following treatment with the specific cytokine transforming growth factor (TGF)-ß2. METHODS: RNA-sequencing and western blotting were used to compare gene and protein expression between untreated and TGF-ß2-treated equine bone marrow-derived MSCs (BM-MSCs). A co-culture system was utilized to compare equine tenocyte migration during co-culture with untreated and TGF-ß2-treated BM-MSCs. RESULTS: TGF-ß2 treatment significantly upregulated gene expression of collagens, extracellular matrix molecules, and growth factors. Protein expression of collagen type I and tenascin-C was also confirmed to be upregulated in TGF-ß2-treated BM-MSCs compared to untreated BM-MSCs. Both untreated and TGF-ß2-treated BM-MSCs increased tenocyte migration in vitro. CONCLUSIONS: Treating equine BM-MSCs with TGF-ß2 significantly increases production of paracrine factors and extracellular matrix molecules important for tendon healing and promotes the migration of tenocytes in vitro.


Assuntos
Células-Tronco Mesenquimais , Fator de Crescimento Transformador beta2 , Animais , Medula Óssea/metabolismo , Colágeno Tipo I/metabolismo , Citocinas/metabolismo , Cavalos , Células-Tronco Mesenquimais/metabolismo , Comunicação Parácrina , RNA/metabolismo , Tenascina/genética , Tenascina/metabolismo , Tendões/metabolismo , Fator de Crescimento Transformador beta2/genética , Fatores de Crescimento Transformadores/metabolismo
13.
Biomed Res Int ; 2022: 8537959, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36119932

RESUMO

Tendon-derived stem cells (TDSCs) play a vital role in repair of rotator cuff tear injuries by secreting paracrine proteins that regulate resident cell functions. Secreted exosomes may play a role in tendon injury repair by mediating intercellular communication; however, the detailed mechanisms by which TDSC-derived exosomes affect tenocyte development remain unknown. Here, we examined the effects of exosomes isolated from conditioned medium of TDSCs on tenocyte differentiation, migration, and transition to a fibroblastic phenotype in vitro. Successful isolation of exosomes from TDSCs was confirmed by high expression levels of CD81, CD63, CD9, and TSG101. Treatment with TDSC-derived exosomes promoted the growth and migration of cultured rat tenocytes, and increased the levels of the fibrosis markers collagen I, collagen III, scleraxis, tenascin C, and α-smooth muscle actin. Furthermore, vascular endothelial growth factor A (VEGFA) expression was higher in TDSC-derived exosomes than in TDSCs, and genetic knockdown of VEGFA suppressed the stimulatory effect of TDSC-derived exosomes on tenocyte development. Overall, these results demonstrate that VEGFA-enriched exosomes isolated from TDSCs promote differentiation and migration of cultured tenocytes and their transition to a fibroblastic phenotype. These data provide a new potential clinical treatment strategy for tendon injury.


Assuntos
Exossomos , Traumatismos dos Tendões , Actinas/metabolismo , Animais , Colágeno/metabolismo , Meios de Cultivo Condicionados/farmacologia , Fenótipo , Ratos , Células-Tronco/metabolismo , Tenascina/metabolismo , Traumatismos dos Tendões/terapia , Tendões/metabolismo , Tenócitos , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
J Proteome Res ; 21(10): 2421-2434, 2022 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-36112477

RESUMO

We present a mass spectral library-based method for analyzing site-specific N-linked protein glycosylation. Its operation and utility are illustrated by applying it to both newly measured and available proteomics data of human milk glycoproteins. It generates two varieties of mass spectral libraries. One contains glycopeptide abundance distribution spectra (GADS). The other contains tandem mass spectra of the underlying glycopeptides. Both originate from identified glycopeptides in proteolytic digests of human milk and purified glycoproteins, which include tenascin, lactoferrin, and several antibodies. Analysis was also applied to digests of a NIST human milk standard reference material (SRM), leading to a GADS library of N-glycopeptides, enabling the direct comparison of glycopeptide distributions for individual proteins. Tandem spectra underlying each glycopeptide GADS peak are combined to create a second type of library that contains spectra of the underlying glycopeptide spectra. These were acquired by higher-energy (stepped) collision dissociation fragmentation followed by ion-trap fragmentation. Spectra are annotated using MS_Piano, recently reported annotation software. This data, with extensions of a widely used spectral library search and display software, provides accessible mass spectral libraries.


Assuntos
Proteínas do Leite , Leite Humano , Glicopeptídeos/análise , Glicoproteínas/metabolismo , Glicosilação , Humanos , Lactoferrina/metabolismo , Proteínas do Leite/metabolismo , Leite Humano/química , Tenascina/metabolismo
15.
J Cell Sci ; 135(18)2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36102918

RESUMO

The roles of the extracellular matrix molecule tenascin-C (TNC) in health and disease have been extensively reviewed since its discovery over 40 years ago. Here, we will describe recent insights into the roles of TNC in tumorigenesis, angiogenesis, immunity and metastasis. In addition to high levels of expression in tumors, and during chronic inflammation, and bacterial and viral infection, TNC is also expressed in lymphoid organs. This supports potential roles for TNC in immunity control. Advances using murine models with engineered TNC levels were instrumental in the discovery of important functions of TNC as a danger-associated molecular pattern (DAMP) molecule in tissue repair and revealed multiple TNC actions in tumor progression. TNC acts through distinct mechanisms on many different cell types with immune cells coming into focus as important targets of TNC in cancer. We will describe how this knowledge could be exploited for cancer disease management, in particular for immune (checkpoint) therapies.


Assuntos
Neoplasias , Tenascina , Animais , Carcinogênese/genética , Carcinogênese/metabolismo , Matriz Extracelular/metabolismo , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Tenascina/genética , Tenascina/metabolismo
16.
Cells ; 11(17)2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36078128

RESUMO

Prostaglandin E2 (PGE2) is an important metabolite of arachidonic acid which plays a crucial role in vascular physiology and pathophysiology via its four receptors (EP1-4). However, the role of vascular smooth muscle cell (VSMC) EP4 in neointimal hyperplasia is largely unknown. Here we showed that VSMC-specific deletion of EP4 (VSMC-EP4) ameliorated, while VSMC-specific overexpression of human EP4 promoted, neointimal hyperplasia in mice subjected to femoral artery wire injury or carotid artery ligation. In vitro studies revealed that pharmacological activation of EP4 promoted, whereas inhibition of EP4 suppressed, proliferation and migration of primary-cultured VSMCs. Mechanically, EP4 significantly increased the protein expression of tenascin C (TN-C), a pro-proliferative and pro-migratory extracellular matrix protein, at the translational level. Knockdown of TN-C markedly suppressed EP4 agonist-induced VSMC proliferation and migration. Further studies uncovered that EP4 upregulated TN-C protein expression via the PKA/mTORC1/Ribosomal protein S6 (rpS6) pathway. Together, our findings demonstrate that VSMC EP4 increases TN-C protein expression to promote neointimal hyperplasia via the PKA-mTORC1-rpS6 pathway. Therefore, VSMC EP4 may represent a potential therapeutic target for vascular restenosis.


Assuntos
Dinoprostona , Hiperplasia , Receptores de Prostaglandina E Subtipo EP4 , Tenascina , Lesões do Sistema Vascular , Animais , Proliferação de Células , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Dinoprostona/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Músculo Liso Vascular/metabolismo , Neointima/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Proteína S6 Ribossômica/metabolismo , Tenascina/metabolismo
17.
Thorac Cancer ; 13(20): 2904-2907, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36047568

RESUMO

Radiation-induced lung damage (RILD) is a critical problem in lung cancer radiotherapy, and it is difficult to predict its severity. Although no biomarkers for RILD have been established, tenascin C (TNC) is an extracellular matrix glycoprotein involved in the remodeling of damaged tissues and has been implicated in inflammation and fibrosis. We report the unique case of a 36-year-old man with adenocarcinoma of the lung, Union for International Cancer Control stage IIIB, who was treated with radiotherapy before lung surgery. The surgical specimen showed histopathological expression of TNC in the region where radiation pneumonitis was observed radiographically. Serum TNC levels were elevated after radiotherapy. In this case, TNC is suggested to be implicated in RILD and may be a potential candidate as a biomarker for the onset and severity of the condition.


Assuntos
Matriz Extracelular , Tenascina , Adulto , Biomarcadores/metabolismo , Matriz Extracelular/metabolismo , Glicoproteínas , Humanos , Inflamação , Pulmão , Masculino , Tenascina/metabolismo
18.
Mol Neurobiol ; 59(11): 6857-6873, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36048342

RESUMO

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with a malignant prognosis. GBM is characterized by high cellular heterogeneity and its progression relies on the interaction with the central nervous system, which ensures the immune-escape and tumor promotion. This interplay induces metabolic, (epi)-genetic and molecular rewiring in both domains. In the present study, we aim to characterize the time-related changes in the GBM landscape, using a syngeneic mouse model of primary GBM. GL261 glioma cells were injected in the right striatum of immuno-competent C57Bl/6 mice and animals were sacrificed after 7, 14, and 21 days (7D, 14D, 21D). The tumor development was assessed through 3D tomographic imaging and brains were processed for immunohistochemistry, immunofluorescence, and western blotting. A human transcriptomic database was inquired to support the translational value of the experimental data. Our results showed the dynamic of the tumor progression, being established as a bulk at 14D and surrounded by a dense scar of reactive astrocytes. The GBM growth was paralleled by the impairment in the microglial/macrophagic recruitment and antigen-presenting functions, while the invasive phase was characterized by changes in the extracellular matrix, as shown by the analysis of tenascin C and metalloproteinase-9. The present study emphasizes the role of the molecular changes in the microenvironment during the GBM progression, fostering the development of novel multi-targeted, time-dependent therapies in an experimental model similar to the human disease.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Glioma , Evasão Tumoral , Microambiente Tumoral , Animais , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Glioblastoma/imunologia , Glioblastoma/patologia , Glioma/imunologia , Glioma/patologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Tenascina/metabolismo
19.
ACS Biomater Sci Eng ; 8(9): 3819-3830, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-35994527

RESUMO

The endometrium undergoes profound changes in tissue architecture and composition, both during the menstrual cycle as well as in the context of pregnancy. Dynamic remodeling processes of the endometrial extracellular matrix (ECM) are a major element of endometrial homeostasis, including changes across the menstrual cycle. A critical element of this tissue microenvironment is the endometrial basement membrane, a specialized layer of proteins that separates the endometrial epithelium from the underlying endometrial ECM. Bioengineering models of the endometrial microenvironment that present an appropriate endometrial ECM and basement membrane may provide an improved environment to study endometrial epithelial cell (EEC) function. Here, we exploit a tiered approach using two-dimensional high-throughput microarrays and three-dimensional gelatin hydrogels to define patterns of EEC attachment and cytokeratin 18 (CK18) expression in response to combinations of endometrial basement membrane proteins. We identify combinations (collagen IV + tenascin C; collagen I + collagen III; hyaluronic acid + tenascin C; collagen V; collagen V + hyaluronic acid; collagen III; and collagen I) that facilitate increased EEC attachment, increased CK18 intensity, or both. We also identify significant EEC mediated remodeling of the methacrylamide-functionalized gelatin matrix environment via analysis of nascent protein deposition. Together, we report efforts to tailor the localization of basement membrane-associated proteins and proteoglycans in order to investigate tissue-engineered models of the endometrial microenvironment.


Assuntos
Gelatina , Hidrogéis , Colágeno/metabolismo , Endométrio/metabolismo , Células Epiteliais , Matriz Extracelular/metabolismo , Feminino , Gelatina/metabolismo , Humanos , Ácido Hialurônico/metabolismo , Hidrogéis/metabolismo , Queratina-18/metabolismo , Gravidez , Tenascina/metabolismo
20.
Cell Commun Signal ; 20(1): 119, 2022 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-35948987

RESUMO

BACKGROUND: Bone metastatic prostate cancer does not completely respond to androgen-targeted therapy and generally evolves into lethal castration resistant prostate cancer (CRPC). Expression of AR-V7- a constitutively active, ligand independent splice variant of AR is one of the critical resistant mechanisms regulating metastatic CRPC. TNC is an extracellular matrix glycoprotein, crucial for prostate cancer progression, and associated with prostate cancer bone metastases. In this study, we investigated the mechanisms that regulate AR-V7 expression in prostate cancer cells interacting with osteogenic microenvironment including TNC. METHODS: Prostate cancer/preosteoblast heterotypical organoids were evaluated via immunofluorescence imaging and gene expression analysis using RT-qPCR to assess cellular compartmentalization, TNC localization, and to investigate regulation of AR-V7 in prostate cancer cells by preosteoblasts and hormone or antiandrogen action. Prostate cancer cells cultured on TNC were assessed using RT-qPCR, Western blotting, cycloheximide chase assay, and immunofluorescence imaging to evaluate (1) regulation of AR-V7, and (2) signaling pathways activated by TNC. Identified signaling pathway induced by TNC was targeted using siRNA and a small molecular inhibitor to investigate the role of TNC-induced signaling activation in regulation of AR-V7. Both AR-V7- and TNC-induced signaling effectors were targeted using siRNA, and TNC expression assessed to evaluate potential feedback regulation. RESULTS: Utilizing heterotypical organoids, we show that TNC is an integral component of prostate cancer interaction with preosteoblasts. Interaction with preosteoblasts upregulated both TNC and AR-V7 expression in prostate cancer cells which was suppressed by testosterone but elevated by antiandrogen enzalutamide. Interestingly, the results demonstrate that TNC-induced Src activation regulated AR-V7 expression, post-translational stability, and nuclear localization in prostate cancer cells. Treatment with TNC neutralizing antibody, Src knockdown, and inhibition of Src kinase activity repressed AR-V7 transcript and protein. Reciprocally, both activated Src and AR-V7 were observed to upregulate autocrine TNC gene expression in prostate cancer cells. CONCLUSION: Overall, the findings reveal that prostate cancer cell interactions with the cellular and ECM components in the osteogenic microenvironment plays critical role in regulating AR-V7 associated with metastatic CRPC. Video Abstract.


Assuntos
Neoplasias de Próstata Resistentes à Castração , Receptores Androgênicos , Antagonistas de Androgênios , Linhagem Celular Tumoral , Matriz Extracelular/metabolismo , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/patologia , Isoformas de Proteínas/metabolismo , RNA Interferente Pequeno , Receptores Androgênicos/metabolismo , Tenascina , Microambiente Tumoral
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...