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1.
Gene ; 790: 145688, 2021 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-33961974

RESUMO

In contrast to mice or zebrafish, trout exhibits post-larval muscle growth through hypertrophy and formation of new myofibers (hyperplasia). The muscle fibers are formed by the fusion of mononucleated cells (myoblasts) regulated by several muscle-specific proteins such as Myomaker or Myomixer. In this work, we identified a unique gene encoding a Myomixer protein of 77 amino acids (aa) in the trout genome. Sequence analysis and phylogenetic tree showed moderate conservation of the overall protein sequence across teleost fish (61% of aa identity between trout and zebrafish Myomixer sequences). Nevertheless, the functionally essential motif, AxLyCxL is perfectly conserved in all studied sequences of vertebrates. Using in situ hybridization, we observed that myomixer was highly expressed in the embryonic myotome, particularly in the hyperplasic area. Moreover, myomixer remained readily expressed in white muscle of juvenile (1 and 20 g) although its expression decreased in mature fish. We also showed that myomixer is up-regulated during muscle regeneration and in vitro myoblasts differentiation. Together, these data indicate that myomixer expression is consistently associated with the formation of new myofibers during somitogenesis, post-larval growth and muscle regeneration in trout.


Assuntos
Hiperplasia/patologia , Larva/citologia , Desenvolvimento Muscular , Proteínas Musculares/metabolismo , Mioblastos/citologia , Oncorhynchus mykiss/embriologia , Regeneração , Sequência de Aminoácidos , Animais , Hiperplasia/metabolismo , Larva/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Proteínas Musculares/genética , Músculo Esquelético , Mioblastos/metabolismo , Oncorhynchus mykiss/metabolismo , Filogenia , Homologia de Sequência
2.
Mol Immunol ; 132: 30-40, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33540227

RESUMO

Psoriasis is a refractory inflammatory skin disease affecting 2 %-3 % of the world population, characterized by the infiltration and hyper-proliferation of inflammatory cells and aberrant differentiation of keratinocytes. Targeting the IL-23/ Th17 axis has been well recognized as a promising therapeutic strategy, as the IL-23/ Th17 signal plays a vital role in the pathology of psoriasis. Three pentacyclic triterpene compounds isolated from loquat leaves have been reported with significant inhibitory effects on RORγt transcription activity and Th17 cell differentiation, and excellent performance in preventing lupus nephritis pathogenesis. However, the potential effects of these pentacyclic triterpene compounds on psoriasis remain unknown. In this study, we demonstrated the potent therapeutic effects of these pentacyclic triterpene compounds on psoriasis. These three pentacyclic triterpene compounds significantly alleviated skin inflammation as well as aberrant keratinocyte proliferation in an imiquimod-induced mouse psoriasis model. These compounds also inhibited the infiltration of immune cells and the level of pro-inflammatory cytokine in the dermis, as well as the cells number and changed the cytokine profiling expression of Th17 cells. These compounds could reduce the amount of CD4+ and CD8+ T cells in local lymph node, but not in spleen, which is different from hydrocortisone, the positive control treatment. These results suggest better performance of these compounds than steroids on treating psoriasis with less side effects on the integrated immune system. In summary, our findings uncover the potent therapeutic effects of pentacyclic triterpene compounds on psoriasis, providing potential candidate compounds for drug development.


Assuntos
Eriobotrya/química , Hiperplasia/tratamento farmacológico , Inflamação/tratamento farmacológico , Triterpenos Pentacíclicos/uso terapêutico , Folhas de Planta/química , Psoríase/tratamento farmacológico , Células Th17/efeitos dos fármacos , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Epiderme/efeitos dos fármacos , Epiderme/patologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Imiquimode/toxicidade , Inflamação/patologia , Queratinócitos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Simulação de Acoplamento Molecular , Triterpenos Pentacíclicos/química , Triterpenos Pentacíclicos/metabolismo , Triterpenos Pentacíclicos/farmacologia , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Células Th17/imunologia , Células Th17/metabolismo
3.
Life Sci ; 260: 118412, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32926924

RESUMO

AIMS: Rat models of duodenogastric reflux have been used to study gastric stump cancer (GSC), but the underlying molecular mechanisms are poorly understood. Unlike rats, mice can be genetically modified, providing a superior model for studying the molecular mechanisms underlying GSC development, which is associated with duodenogastric reflux. This study aimed at developing a mouse model of duodenogastric reflux. MAIN METHOD: C57BL/6 mice were randomly assigned to the control (n = 6), sham operation (n = 9), or gastrojejunostomy group (n = 12). Mice were sacrificed at 1, 3, and 6 months after surgery. Stomach tissue was stained with hematoxylin and eosin. Lesions were classified as chronic inflammation, intestinal metaplasia, or atypical hyperplasia. KEY FINDINGS: Nine mice underwent gastrojejunostomy without mortality. The animals in the gastrojejunostomy group exhibited chronic inflammation at 1, 3, and 6 months after surgery, showing intestinal metaplasia (n = 2) and atypical hyperplasia (n = 1) at 3 months and intestinal metaplasia (n = 2) and atypical hyperplasia (n = 2) at 6 months. The mice in the control group did not exhibit chronic inflammation or intestinal metaplasia, whereas those in the sham operation group exhibited chronic inflammation at 1, 3, and 6 months after surgery, without intestinal metaplasia or atypical hyperplasia. Intestinal metaplasia or atypical hyperplasia were more common in the gastrojejunostomy group than in the sham operation group (p = 0.012). SIGNIFICANCE: A duodenogastric reflux mouse model can be created using gastrojejunostomy without gastrectomy.


Assuntos
Modelos Animais de Doenças , Refluxo Duodenogástrico/patologia , Mucosa Gástrica/patologia , Hiperplasia/patologia , Inflamação/patologia , Animais , Refluxo Duodenogástrico/cirurgia , Gastrectomia , Mucosa Gástrica/imunologia , Mucosa Gástrica/metabolismo , Hiperplasia/imunologia , Hiperplasia/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
PLoS One ; 15(6): e0225173, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32603328

RESUMO

Vascular hyperplasia after vascular trauma is one of the difficult problems in clinical treatment. Nowadays, there is no effective treatment for vascular hyperplasia. Previous studies have shown that integrinß1 andß3 activity play an important role in vascular hyperplasia. Kindlin-2 has been shown to modulate integrinß1 andß3 activity in cancer. Therefore, in this study, we hope to explore the relationship between Kindlin-2 and vascular hyperplasia. We overexpressed or knocked down Kindlin-2 by adenovirus. The results showed that Kindlin-2 overexpression could regulate integrinß1 andß3 activity through FAK-PIK3 signaling pathways ex vivo and in vivo, thereby affecting the proliferation and migration of VSMC, and then it causes the consequences of vascular hyperplasia. Therefore, Our results show that Kindlin-2 may be a potential target for the treatment of vascular hyperplasia.


Assuntos
Movimento Celular , Quinase 1 de Adesão Focal/metabolismo , Integrina beta1/metabolismo , Integrina beta3/metabolismo , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/citologia , Proteínas de Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Transdução de Sinais , Animais , Proliferação de Células , Técnicas de Silenciamento de Genes , Hiperplasia/metabolismo , Hiperplasia/patologia , Proteínas de Membrana/genética , Proteínas de Neoplasias/genética , Ratos
5.
Am J Pathol ; 190(9): 1843-1858, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32479820

RESUMO

The progression of Crohn disease to intestinal stricture formation is poorly controlled, and the pathogenesis is unclear, although increased smooth muscle mass is present. A previously described rat model of trinitrobenzenesulfonic acid-induced colitis is re-examined here. Although inflammation of the mid-descending colon typically resolved, a subset showed characteristic stricturing by day 16, with an inflammatory infiltrate in the neuromuscular layers including eosinophils, CD3-positive T cells, and CD68-positive macrophages. Closer study identified CD163-positive, CD206-positive, and arginase-positive cells, indicating a M2 macrophage phenotype. Stricturing involved ongoing proliferation of intestinal smooth muscle cells (ISMC) with expression of platelet-derived growth factor receptor beta and progressive loss of phenotypic markers, and stable expression of hypoxia inducible factor 1 subunit alpha. In parallel, collagen I and III showed a selective and progressive increase over time. A culture model of the stricture phenotype of ISMC showed stable hypoxia inducible factor 1 subunit alpha expression that promoted growth and improved both survival and growth in models of experimental ischemia. This phenotype was hyperproliferative to serum and platelet-derived growth factor BB, and unresponsive to transforming growth factor beta, a prominent cytokine of M2 macrophages, compared with control ISMC. We identified a hyperplastic phenotype of ISMC, uniquely adapted to an ischemic environment to drive smooth muscle layer expansion, which may reveal new targets for treating intestinal fibrosis.


Assuntos
Doença de Crohn/patologia , Intestinos/patologia , Macrófagos/metabolismo , Músculo Liso/patologia , Animais , Constrição Patológica/induzido quimicamente , Constrição Patológica/patologia , Hiperplasia/induzido quimicamente , Hiperplasia/metabolismo , Hiperplasia/patologia , Músculo Liso/metabolismo , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Ratos Sprague-Dawley , Ácido Trinitrobenzenossulfônico/toxicidade
6.
Nat Commun ; 11(1): 2711, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483135

RESUMO

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.


Assuntos
Transformação Celular Neoplásica/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Epiderme/metabolismo , Via de Sinalização Wnt/genética , Animais , Proliferação de Células/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Queratinócitos/metabolismo , Ceratose/genética , Ceratose/metabolismo , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Papiloma/genética , Papiloma/metabolismo , Papiloma/patologia
7.
Sci Rep ; 10(1): 7393, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32355175

RESUMO

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.


Assuntos
Refluxo Biliar , Mucosa Esofágica , Esofagite , Derivação Gástrica/efeitos adversos , Mucosa Gástrica , Modelos Biológicos , Obesidade Mórbida , Complicações Pós-Operatórias , Animais , Refluxo Biliar/etiologia , Refluxo Biliar/metabolismo , Refluxo Biliar/patologia , Refluxo Biliar/fisiopatologia , Doença Crônica , Mucosa Esofágica/metabolismo , Mucosa Esofágica/patologia , Mucosa Esofágica/fisiopatologia , Esofagite/etiologia , Esofagite/metabolismo , Esofagite/patologia , Esofagite/fisiopatologia , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Mucosa Gástrica/fisiopatologia , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Hiperplasia/fisiopatologia , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/cirurgia , Complicações Pós-Operatórias/metabolismo , Complicações Pós-Operatórias/patologia , Complicações Pós-Operatórias/fisiopatologia , Ratos , Ratos Wistar
8.
Virchows Arch ; 477(1): 121-130, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32388720

RESUMO

Overlapping histological features between benign and malignant lesions and a lack of firm diagnostic criteria for malignancy result in high rates of inter-observer variation in the diagnosis of melanocytic lesions. We aimed to investigate the differential expression of five miRNAs (21, 200c, 204, 205, and 211) in benign naevi (n = 42), dysplastic naevi (n = 41), melanoma in situ (n = 42), and melanoma (n = 42) and evaluate their potential as diagnostic biomarkers of melanocytic lesions. Real-time PCR showed differential miRNA expression profiles between benign naevi; dysplastic naevi and melanoma in situ; and invasive melanoma. We applied a random forest machine learning algorithm to classify cases based on their miRNA expression profiles, which resulted in a ROC curve analysis of 0.99 for malignant melanoma and greater than 0.9 for all other groups. This indicates an overall very high accuracy of our panel of miRNAs as a diagnostic biomarker of benign, dysplastic, and malignant melanocytic lesions. However, the impact of variable lesion percentage and spatial expression patterns of miRNAs on these real-time PCR results was also considered. In situ hybridisation confirmed the expression of miRNA 21 and 211 in melanocytes, while demonstrating expression of miRNA 205 only in keratinocytes, thus calling into question its value as a biomarker of melanocytic lesions. In conclusion, we have validated some miRNAs, including miRNA 21 and 211, as potential diagnostic biomarkers of benign, dysplastic, and malignant melanocytic lesions. However, we also highlight the crucial importance of considering tissue morphology and spatial expression patterns when using molecular techniques for the discovery and validation of new biomarkers.


Assuntos
Biomarcadores/análise , Síndrome do Nevo Displásico/patologia , Hiperplasia/patologia , Melanoma/genética , MicroRNAs/genética , Neoplasias Cutâneas/genética , Diagnóstico Diferencial , Síndrome do Nevo Displásico/diagnóstico , Síndrome do Nevo Displásico/metabolismo , Humanos , Hiperplasia/diagnóstico , Hiperplasia/metabolismo , Melanócitos/metabolismo , Melanócitos/patologia , Melanoma/patologia , Nevo Pigmentado/diagnóstico , Nevo Pigmentado/patologia , Neoplasias Cutâneas/patologia
9.
Horm Metab Res ; 52(3): 133-141, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32215884

RESUMO

Primary or adrenocorticotropin-independent adrenocortical tumors and hyperplasias represent a heterogeneous group of adrenocortical neoplasms that arise from various genetic defects, either in isolation or familial. The traditional classification as adenomas, hyperplasias, and carcinomas is non-specific. The recent identification of various germline and somatic genes in the development of primary adrenocortical hyperplasias has provided important new insights into the molecular pathogenesis of adrenal diseases. In this new era of personalized care and genetics, a gene-based classification that is more specific is required to assist in the understanding of their disease processes, hormonal functionality and signaling pathways. Additionally, a gene-based classification carries implications for treatment, genetic counseling and screening of asymptomatic family members. In this review, we discuss the genetics of benign adrenocorticotropin-independent adrenocortical hyperplasias, and propose a new gene-based classification system and diagnostic algorithm that may aid the clinician in prioritizing genetic testing, screening and counseling of affected, at risk individuals and their relatives.


Assuntos
Doenças do Córtex Suprarrenal/genética , Hiperplasia/genética , Doenças do Córtex Suprarrenal/diagnóstico , Doenças do Córtex Suprarrenal/tratamento farmacológico , Doenças do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/diagnóstico , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Hormônio Adrenocorticotrópico/metabolismo , Aconselhamento Genético , Humanos , Hiperplasia/diagnóstico , Hiperplasia/tratamento farmacológico , Hiperplasia/metabolismo
10.
Am J Clin Pathol ; 153(5): 695-704, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32076708

RESUMO

OBJECTIVES: Many studies have shown poor reproducibility among pathologists for diagnosing dysplasia in Barrett's esophagus (BE). Immunohistochemical stains (IHC) are not widely used due to overlapping expression patterns in reactive and dysplastic processes. We hypothesized that markers involved in cell-cycle (cyclin D1, Ki-67, P16), differentiation/cell-cell interaction (ß-catenin, SATB2 CD44, OCT4) and senescence (γH2AX) would produce different results in reactive and dysplastic processes. METHODS: A micrograph album of 40 H&E and matching IHCs depicting optimally oriented lesions were evaluated independently by 3 pathologists. Expression was scored separately in the surface, isthmus, and base regions of the glands. RESULTS: Statistical analysis showed that surface Ki-67 expression showed the largest difference in expression and smallest P value (P < .001) for identifying dysplasia. At a cutoff level of 5% or less, negative predictive value (NPV) was 100%. κ correlation between pathologists improved from substantial to almost perfect (0.70-0.95) using ancillary surface Ki-67. CONCLUSION: A case-control study with glass slides including all diagnostic categories using this parameter confirmed improved κ correlation among pathologists (0.29 vs 0.60), better correlation with outcomes (76% vs 69%), increased odd risks (15.3) for progression in positive cases, and an improvement in sensitivity (88% vs 64%) and NPV (88% vs 73%) compared to histology alone.


Assuntos
Esôfago de Barrett/diagnóstico , Antígeno Ki-67/metabolismo , Lesões Pré-Cancerosas/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/metabolismo , Esôfago de Barrett/patologia , Estudos de Casos e Controles , Progressão da Doença , Feminino , Humanos , Hiperplasia/diagnóstico , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Reprodutibilidade dos Testes
11.
Asian Pac J Cancer Prev ; 21(1): 157-161, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31983178

RESUMO

OBJECTIVE: To examine the immunohistochemical expression of Ki-67 and beta-catenin in pseudoepitheliomatous hyperplasia and squamous cell carcinoma (SCC) in oral mucosal biopsies. METHODS: In this comparative cross sectional study, 70 cases of each PEH and OSCC were taken from the patients of both genders and in all age groups. Study was conducted at Armed Forces Institute of Pathology (AFIP), Rawalpindi from Dec 2017 to March 2019. Statistical analysis was done with the help of SPSS Version 24.0. We used Chi-Squared test with p value of < 0.05 which was considered as statistically significant. RESULTS: In the current study, 80 (57.1%) male and 60 (42.8%) female patients with the mean age of 51.69 ± 16.121 (mean ± SD) years were included. It was found that 6-25% Ki-67 labeling index was observed in all (70) PEH cases, which involved only basal layer of the epithelium. Whereas, Ki-67 labeling index was highly expressed in tumor of high grade malignancy than tumor of low grade malignancy. On the other hand, expression of membranous beta-catenin was higher in PEH and cytoplasmic beta-catenin expression was higher in OSCC. CONCLUSION: It is concluded that Ki-67 and beta-catenin showed significant expression in PEH and OSCC in oral mucosal biopsies especially those with intense inflammation or unoriented tissue, helping the clinicians to arrive at a final diagnosis before planning any surgical intervention.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/metabolismo , Hiperplasia/metabolismo , Ceratoacantoma/metabolismo , Antígeno Ki-67/metabolismo , Neoplasias Bucais/metabolismo , beta Catenina/metabolismo , Carcinoma de Células Escamosas/patologia , Estudos Transversais , Feminino , Seguimentos , Humanos , Hiperplasia/patologia , Imuno-Histoquímica , Ceratoacantoma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Prognóstico
12.
Exp Cell Res ; 387(1): 111758, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31837294

RESUMO

Mucosal hyperplasia is common sequela of otitis media (OM), leading to the secretion of mucus and the recruitment of leukocytes. However, the pathogenic mechanisms underlying hyperplasia are not well defined. Here, we investigated the role of the AKT pathway in the development of middle mucosal hyperplasia using in vitro mucosal explants cultures and an in vivo rat model. The Akt inhibitor MK2206 treatment inhibited the growth of middle ear mucosal explants in a dose-dependent manner. In vivo, MK2206 also reduced mucosal hyperplasia. Unexpectedly, while PTEN is generally thought to act in opposition to AKT, the PTEN inhibitor BPV reduced mucosal explant growth in vitro. The results indicate that both AKT and PTEN are mediators of mucosal growth during OM, and could be potential therapeutic targets.


Assuntos
Otite Média/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Hiperplasia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/metabolismo , Otite Média/tratamento farmacológico , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
13.
Ann Diagn Pathol ; 44: 151421, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31751845

RESUMO

The formation, development and dissolution of germinal centers is a major part of immune system function. It is important to differentiate neoplastic processes from follicular hyperplasia and regressive follicular changes. Better understanding of germinal center development and dissolution also provides diagnostic clues to the underlying pathologic process. It is also important in identifying the immune basis of different pathologic entities as well as in immunotherapy decision making and follow up. In this study, we characterize the immunoarchitecture of lymphoid follicles with a focus on germinal center in one representative case, each of commonly encountered benign and malignant lymph node disorders, with morphologic and immunohistochemical alterations of germinal centers. The cases include reactive follicular hyperplasia (FH), florid follicular hyperplasia (FFH), follicular lymphoma (FL), angioimmunoblastic T-cell lymphoma (AITL), hyaline-vascular Castleman disease (HVCD), progressive transformation of germinal centers, nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), lymphocyte-rich classic Hodgkin lymphoma (LR-CHL), human immunodeficiency virus (HIV)-associated follicular dissolution and chronic lymphocytic leukemia (CLL) with proliferation centers (PC). A panel of antibodies were used namely CD3, CD20, CD10, BCL2, BCL6, CD21, CD23, CD35, FOXP1, GCET1, HGAL/GCET2, LMO2, MUM1, IgD, Ki67, PD1 and PD-L1. We found that these entities show distinct immunoarchitectural patterns of germinal center formation, development and regression, particularly, the distribution of mantle zone B-cells, follicular helper T cells (Tfh) and FDC meshworks, confirming the influence of antigenic stimulation and status of immune system in these changes. This also confirms the interrelationship of underlying immunologic mechanisms in these disease processes.


Assuntos
Biomarcadores/metabolismo , Centro Germinativo/patologia , Linfoma Folicular/patologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Centro Germinativo/imunologia , Centro Germinativo/metabolismo , Humanos , Hiperplasia/imunologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Linfoma Folicular/imunologia , Linfoma Folicular/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologia
14.
Am J Pathol ; 190(2): 453-468, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31734232

RESUMO

The aryl hydrocarbon receptor (AhR) is a transcription factor known as a dioxin receptor. Recently, Ahr-/- mice were revealed to develop cecal tumors with inflammation and Wnt/ß-catenin pathway activation. However, whether ß-catenin degradation is AhR dependent remains unclear. To determine whether other signaling pathways function in Ahr-/- cecal tumorigenesis, we investigated histologic characteristics of the tumors and cytokine/chemokine production in tumors and Ahr-/- peritoneal macrophages. AhR expression was also assessed in human colorectal carcinomas. Of the 28 Ahr-/- mice, 10 developed cecal lesions by 50 weeks of age, an incidence significantly lower than previously reported. Cecal lesions of Ahr-/- mice developed from serrated hyperplasia to adenoma/dysplasia-like neoplasia with enhanced proliferation. Macrophage and neutrophil infiltration into the lesions was also observed early in serrated hyperplasia, although adjacent mucosa was devoid of inflammation. Il1b, Il6, Ccl2, and Cxcl5 were up-regulated at lesion sites, whereas only IL-6 production increased in Ahr-/- peritoneal macrophages after lipopolysaccharide + ATP stimulation. Neither Myc (alias c-myc) up-regulation nor ß-catenin nuclear translocation was observed, unlike previously reported. Interestingly, enhanced phosphorylation of extracellular signal-regulated kinase, Src, and epidermal growth factor receptor and Amphiregulin up-regulation at Ahr-/- lesion sites were detected. In human serrated lesions, however, AhR expression in epithelial cells was up-regulated despite morphologic similarity to Ahr-/- cecal lesions. Our results suggest novel mechanisms underlying Ahr-/- cecal tumorigenesis, depending primarily on cecum-specific mitogen-activated protein kinase pathway activation and inflammation.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Carcinogênese/patologia , Neoplasias do Ceco/patologia , Neoplasias Colorretais/patologia , Inflamação/patologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Receptores de Hidrocarboneto Arílico/fisiologia , Adenocarcinoma/imunologia , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Carcinogênese/imunologia , Carcinogênese/metabolismo , Neoplasias do Ceco/imunologia , Neoplasias do Ceco/metabolismo , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Feminino , Hiperplasia/imunologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Inflamação/imunologia , Inflamação/metabolismo , Mediadores da Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Quinases Ativadas por Mitógeno/genética , Fosforilação , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo
15.
Am J Respir Cell Mol Biol ; 62(1): 87-94, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31310562

RESUMO

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage-colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55-90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.


Assuntos
Doenças Genéticas Inatas/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Doenças Pulmonares Intersticiais/metabolismo , Pulmão/metabolismo , Macrófagos Alveolares/metabolismo , Alvéolos Pulmonares/metabolismo , Animais , Enfisema/metabolismo , Células Epiteliais/metabolismo , Hiperplasia/metabolismo , Metaloproteinase 12 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Policitemia/metabolismo , Fator de Transcrição STAT5/metabolismo , Fumar/metabolismo
16.
Genes Cells ; 25(2): 76-85, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828897

RESUMO

Eukaryotic elongation factor 2 (eEF2) undergoes a unique post-translational modification called diphthamidation. Although eEF2 diphthamidation is highly conserved, its pathophysiological function is still largely unknown. To elucidate the function of diphthamidation in tumor, we examined the involvement of diphthamidation pathway enzyme Dph5 in tumor progression in Drosophila adult gut. Expression of oncogenic RasV12 in gut intestinal stem cells (ISCs) and enteroblasts (EBs) causes hypertrophy and disruption of gut epithelia, and shortened life span. Knockdown of Dph5 ameliorated these pathogenic phenotypes. Dph5 is required for gross translation activation and high dMyc protein level in RasV12 tumor-like hyperplasia. Transcriptome analysis revealed that Dph5 is involved in the regulation of ribosome biogenesis genes. These results suggest that diphthamidation is required for translation activation partly through the regulation of ribosome biogenesis in Ras-induced tumor-like hyperplasia model in Drosophila gut.


Assuntos
Neoplasias Gastrointestinais/metabolismo , Genes ras/genética , Histidina/genética , Histidina/metabolismo , Hiperplasia/metabolismo , Fator 2 de Elongação de Peptídeos/metabolismo , Animais , Drosophila/genética , Ingestão de Alimentos , Eucariotos , Regulação Neoplásica da Expressão Gênica , Técnicas de Silenciamento de Genes , Histidina/análogos & derivados , Masculino , Processamento de Proteína Pós-Traducional , Ribossomos/genética , Transcriptoma
17.
Int J Mol Sci ; 22(1)2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33396408

RESUMO

Epigenetic dysregulation is hypothesized to play a role in the observed association between inflammatory bowel disease (IBD) and colon tumor development. In the present work, DNA methylome, hydroxymethylome, and transcriptome analyses were conducted in proximal colon tissues harvested from the Helicobacter hepaticus (H. hepaticus)-infected murine model of IBD. Reduced representation bisulfite sequencing (RRBS) and oxidative RRBS (oxRRBS) analyses identified 1606 differentially methylated regions (DMR) and 3011 differentially hydroxymethylated regions (DhMR). These DMR/DhMR overlapped with genes that are associated with gastrointestinal disease, inflammatory disease, and cancer. RNA-seq revealed pronounced expression changes of a number of genes associated with inflammation and cancer. Several genes including Duox2, Tgm2, Cdhr5, and Hk2 exhibited changes in both DNA methylation/hydroxymethylation and gene expression levels. Overall, our results suggest that chronic inflammation triggers changes in methylation and hydroxymethylation patterns in the genome, altering the expression of key tumorigenesis genes and potentially contributing to the initiation of colorectal cancer.


Assuntos
Metilação de DNA , Proteínas de Ligação a DNA/fisiologia , Regulação da Expressão Gênica , Hiperplasia/patologia , Doenças Inflamatórias Intestinais/complicações , Interleucina-10/fisiologia , Transcriptoma , Animais , Modelos Animais de Doenças , Epigenômica , Feminino , Hiperplasia/etiologia , Hiperplasia/metabolismo , Masculino , Camundongos , Camundongos Knockout , Regiões Promotoras Genéticas
18.
Orphanet J Rare Dis ; 14(1): 293, 2019 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-31842965

RESUMO

BACKGROUND: Both mandibular condylar hyperplasia and condylar osteochondroma can lead to maxillofacial skeletal asymmetry and malocclusion, although they exhibit different biological behavior. This study attempted to compare the histological features of mandibular condylar hyperplasia and condylar osteochondroma using hematoxylin-and-eosin (H&E) staining, and immunohistochemistry staining of PCNA and EXT1 with quantitative analysis method. RESULTS: The H&E staining showed that condylar hyperplasia and condylar osteochondroma could be divided into four histological types and exhibited features of different endochondral ossification stages. There was evidence of a thicker cartilage cap in condylar osteochondroma as compared condylar hyperplasia (P = 0.018). The percentage of bone formation in condylar osteochondroma was larger than was found in condylar hyperplasia (P = 0.04). Immunohistochemical staining showed that PCNA was mainly located in the undifferentiated mesenchymal layer and the hypertrophic cartilage layer, and there were more PCNA positive cells in the condylar osteochondroma (P = 0.007). EXT1 was mainly expressed in the cartilage layer, and there was also a higher positive rate of EXT1 in condylar osteochondroma (P = 0.0366). The thicker cartilage cap, higher bone formation rate and higher PCNA positive rate indicated a higher rate of proliferative activity in condylar osteochondroma. The more significant positive rate of EXT1 in condylar osteochondroma implied differential biological characteristic as compared to condylar hyperplasia. CONCLUSIONS: These features might be useful in histopathologically distinguishing condylar hyperplasia and osteochondroma.


Assuntos
Hiperplasia/patologia , Côndilo Mandibular/patologia , Osteocondroma/patologia , Feminino , Humanos , Hiperplasia/metabolismo , Imuno-Histoquímica , Côndilo Mandibular/metabolismo , N-Acetilglucosaminiltransferases/metabolismo , Osteocondroma/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo
19.
Proc Natl Acad Sci U S A ; 116(51): 25697-25706, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31776260

RESUMO

Goblet cell metaplasia and mucus hypersecretion are observed in many pulmonary diseases, including asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. However, the regulation of goblet cell differentiation remains unclear. Here, we identify a regulator of this process in an N-ethyl-N-nitrosourea (ENU) screen for modulators of postnatal lung development; Ryk mutant mice exhibit lung inflammation, goblet cell hyperplasia, and mucus hypersecretion. RYK functions as a WNT coreceptor, and, in the developing lung, we observed high RYK expression in airway epithelial cells and moderate expression in mesenchymal cells as well as in alveolar epithelial cells. From transcriptomic analyses and follow-up studies, we found decreased WNT/ß-catenin signaling activity in the mutant lung epithelium. Epithelial-specific Ryk deletion causes goblet cell hyperplasia and mucus hypersecretion but not inflammation, while club cell-specific Ryk deletion in adult stages leads to goblet cell hyperplasia and mucus hypersecretion during regeneration. We also found that the airway epithelium of COPD patients often displays goblet cell metaplastic foci, as well as reduced RYK expression. Altogether, our findings reveal that RYK plays important roles in maintaining the balance between airway epithelial cell populations during development and repair, and that defects in RYK expression or function may contribute to the pathogenesis of human lung diseases.


Assuntos
Diferenciação Celular/fisiologia , Células Caliciformes , Pulmão , Receptores Proteína Tirosina Quinases/metabolismo , Via de Sinalização Wnt/fisiologia , Células A549 , Animais , Células Caliciformes/citologia , Células Caliciformes/metabolismo , Células Caliciformes/fisiologia , Humanos , Hiperplasia/metabolismo , Hiperplasia/patologia , Pulmão/citologia , Pulmão/crescimento & desenvolvimento , Pulmão/metabolismo , Camundongos , Muco/metabolismo , Pneumonia/metabolismo , Pneumonia/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , beta Catenina/metabolismo
20.
Life Sci ; 239: 117048, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730867

RESUMO

Benign prostatic hyperplasia (BPH) is an aging-related and progressive disease linked to an up-regulation of α1-adrenoceptors. The participation of EGF receptors (EGFR) in the GPCRs' signalosome has been described but so far data about the contribution of these receptors to prostatic stromal hyperplasia are scanty. We isolated and cultured vimentin-positive prostate stromal cells obtained from BPH patients. According to intracellular Ca2+ measurements, cell proliferation and Western blotting assays, these cultured hyperplastic stromal cells express functional α1-adrenoceptors and EGFR, and proliferate in response to the α1-adrenoceptor agonist phenylephrine. Interestingly, in these cells the inhibition of EGFR signaling with GM6001, CRM197, AG1478 or PD98059 was associated with full blockage of α1-adrenoceptor-mediated cell proliferation, while cell treatment with each inhibitor alone did not alter basal cell growth. Moreover, the co-incubation of AG1478 (EGFR inhibitor) with α1A/α1D-adrenoceptor antagonists showed no additive inhibitory effect. These findings highlight a putative role of EGFR signaling to α1-adrenoceptor-mediated human prostate hyperplasia, suggesting that the inhibition of this transactivation cascade could be useful to reduce BPH progression.


Assuntos
Receptores ErbB/metabolismo , Hiperplasia Prostática/metabolismo , Receptores Adrenérgicos alfa 1/fisiologia , Antagonistas de Receptores Adrenérgicos alfa 1/metabolismo , Antagonistas de Receptores Adrenérgicos alfa 1/farmacologia , Antagonistas Adrenérgicos alfa/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Humanos , Hiperplasia/metabolismo , Masculino , Piperazinas/farmacologia , Cultura Primária de Células , Próstata/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Receptores Adrenérgicos alfa 1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais
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