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1.
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
2.
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
3.
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
4.
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
5.
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
6.
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
7.
J Comp Pathol ; 172: 80-87, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31690420

RESUMO

Oral cavity tumours and tumour-like lesions are common in dogs and cats, and their diagnosis and classification requires histopathological examination. The aim of this study was to analyse retrospectively oral cavity lesions in dogs and cats in order to evaluate the distribution of inflammatory, hyperplastic and neoplastic lesions manifested as tumours. A total of 486 oral cavity tumours and tumour-like lesions (340 canine; 146 feline), diagnosed routinely from 2015 to 2017, were included. The lesions were classified as inflammatory, hyperplastic or neoplastic (benign and malignant). Histopathological diagnosis was based on haematoxylin and eosin staining and, when necessary, May-Grünwald-Giemsa (for mast cell tumours) or Masson's Fontana (for melanomas) stains or immunohistochemistry (for CD3, CD79α and S100 markers). For dogs, 29.11% (99/340) of the lesions were benign tumours, 24.12% (82/340) were hyperplastic lesions and 14.7% (50/340) were inflammatory lesions. For cats, 4.79% (7/146) were benign tumours, 15.07% (22/146) were hyperplastic lesions and 57.53% (84/146) were inflammatory lesions. Furthermore, 23.24% (79/340) of canine cases were diagnosed with gingival hyperplasia and 19.12% (65/340) were diagnosed with peripheral odontogenic fibroma, while 43.84% (64/146) of feline cases were diagnosed with chronic lymphoplasmacytic stomatitis. Malignant tumours in dogs and cats constituted 32.06% (109/340) and 21.91% (32/146) of the lesions, respectively, with high-grade melanoma in dogs and squamous cell carcinoma in cats being the most common.


Assuntos
Biomarcadores/metabolismo , Doenças do Gato/diagnóstico , Doenças do Cão/diagnóstico , Neoplasias Bucais/veterinária , Boca/patologia , Animais , Doenças do Gato/patologia , Gatos , Doenças do Cão/patologia , Cães , Hiperplasia/metabolismo , Hiperplasia/patologia , Imuno-Histoquímica , Inflamação/metabolismo , Inflamação/patologia , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/patologia , Estudos Retrospectivos
8.
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
9.
Int J Mol Sci ; 20(21)2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31671790

RESUMO

For patients with end-stage renal disease requiring hemodialysis, their vascular access is both their lifeline and their Achilles heel. Despite being recommended as primary vascular access, the arteriovenous fistula (AVF) shows sub-optimal results, with about 50% of patients needing a revision during the year following creation. After the AVF is created, the venous wall must adapt to new environment. While hemodynamic changes are responsible for the adaptation of the extracellular matrix and activation of the endothelium, surgical dissection and mobilization of the vein disrupt the vasa vasorum, causing wall ischemia and oxidative stress. As a consequence, migration and proliferation of vascular cells participate in venous wall thickening by a mechanism of neointimal hyperplasia (NH). When aggressive, NH causes stenosis and AVF dysfunction. In this review we show how hypoxia, metabolism, and flow parameters are intricate mechanisms responsible for the development of NH and stenosis during AVF maturation.


Assuntos
Fístula Arteriovenosa/metabolismo , Hiperplasia/metabolismo , Hipóxia/metabolismo , Neointima/metabolismo , Proliferação de Células , Constrição Patológica , Hemodinâmica , Humanos , Isquemia , Nefropatias , Diálise Renal , Insuficiência Renal Crônica , Doenças Vasculares , Veias/patologia
10.
Life Sci ; 239: 116886, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678286

RESUMO

Enterochromaffin (EC) cell is the main cell type that responsible for 5-hydroxytryptamine (5-HT) synthesis, storage and release of the gut. Intestinal 5-HT play a key role in visceral sensation, intestinal motility and permeability, EC cell hyperplasia and increased 5-HT bioavailability in the gut have been found to be involved in the symptoms generation of irritable bowel syndrome and inflammatory bowel disease. EC cells originate from intestinal stem cells, the interaction between proliferation and differentiation signals on intestinal stem cells enable EC cell number to be regulated in a normal level. This review focuses on the impact factors, pathogenesis mechanisms, and therapeutic clues for intestinal EC cells hyperplasia, and showed that EC cell hyperplasia was observed under the condition of physiological stress, intestinal infection or intestinal inflammation, the disordered proliferation and/or differentiation of intestinal stem cells as well as their progenitor cells all contribute to the pathogenesis of intestinal EC cell hyperplasia. The altered intestinal niche, i.e. increased corticotrophin releasing factor (CRF) signal, elevated nerve growth factor (NGF) signal, and Th2-dominant cytokines production, has been found to have close correlation with intestinal EC cell hyperplasia. Currently, CRF receptor antagonist, nuclear factor-κB inhibitor, and NGF receptor neutralizing antibody have been proved useful to attenuate intestinal EC cell hyperplasia, which may provide a promising clue for the therapeutic strategy in EC cell hyperplasia related diseases.


Assuntos
Células Enterocromafins/metabolismo , Células Enterocromafins/fisiologia , Hiperplasia/patologia , Animais , Colo/metabolismo , Humanos , Hiperplasia/metabolismo , Infecções/metabolismo , Inflamação/metabolismo , Intestinos/patologia , Síndrome do Intestino Irritável/metabolismo , Serotonina/metabolismo , Estresse Fisiológico/fisiologia
11.
Nat Commun ; 10(1): 4427, 2019 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-31562314

RESUMO

Insulin and IGF-1 actions in vascular smooth muscle cells (VSMC) are associated with accelerated arterial intima hyperplasia and restenosis after angioplasty, especially in diabetes. To distinguish their relative roles, we delete insulin receptor (SMIRKO) or IGF-1 receptor (SMIGF1RKO) in VSMC and in mice. Here we report that intima hyperplasia is attenuated in SMIRKO mice, but not in SMIGF1RKO mice. In VSMC, deleting IGF1R increases homodimers of IR, enhances insulin binding, stimulates p-Akt and proliferation, but deleting IR decreases responses to insulin and IGF-1. Studies using chimeras of IR(extracellular domain)/IGF1R(intracellular-domain) or IGF1R(extracellular domain)/IR(intracellular-domain) demonstrate homodimer IRα enhances insulin binding and signaling which is inhibited by IGF1Rα. RNA-seq identifies hyaluronan synthase2 as a target of homo-IR, with its expression increases by IR activation in SMIGF1RKO mice and decreases in SMIRKO mice. Enhanced intima hyperplasia in diabetes is mainly due to insulin signaling via homo-IR, associated with increased Has2 expression.


Assuntos
Diabetes Mellitus/metabolismo , Hiperplasia/metabolismo , Resistência à Insulina/fisiologia , Receptor IGF Tipo 1/metabolismo , Receptor de Insulina/metabolismo , Animais , Modelos Animais de Doenças , Artéria Femoral/lesões , Artéria Femoral/metabolismo , Artéria Femoral/patologia , Homozigoto , Hialuronan Sintases/metabolismo , Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Músculo Liso Vascular/metabolismo , Receptor IGF Tipo 1/química , Receptor de Insulina/química , Transdução de Sinais
12.
Asian Pac J Cancer Prev ; 20(8): 2299-2302, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31450898

RESUMO

Toll-like receptor 9 (TLR9) is a cellular DNA receptor of the innate immune system which plays a pivotal role in inflammatory response. Recently, changing expression levels of TLR9 has been observed in a wide range of cancer cells; however, there is little information about colorectal polyps. Herein, we assessed the mRNA expression of TLR9 in different colorectal polyp types compared to normal group in order to investigate its expression level during CRC initiation. Fifty-four biopsy samples from colorectal polyp patients and from 20 healthy subjects were collected. The mucosal mRNA expression level of TLR9 gene was identified by real time PCR. Fold change of gene expression was evaluated by 2-ΔΔct method. There was a significant relationship between the lower expression of TLR9 gene in the polyp cases compared to normal individuals (P value = 0.0005), Also, decreased TLR9 mRNA expression was obtained in adenomas in contrast to hyperplastic and normal groups (P value = 0.0008). Based on the current results, we hypothesized that aberrant surface expression of TLR9 on tumor cells may promote the growth and invasion of colorectal polyps. Further, TLR9 modulation may have an important impact on the development of novel therapeutic strategies.


Assuntos
Adenocarcinoma/patologia , Biomarcadores Tumorais/genética , Pólipos do Colo/patologia , Neoplasias Colorretais/patologia , Hiperplasia/patologia , RNA Mensageiro/genética , Receptor Toll-Like 9/genética , Adenocarcinoma/genética , Adenocarcinoma/metabolismo , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Pólipos do Colo/genética , Pólipos do Colo/metabolismo , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Feminino , Seguimentos , Humanos , Hiperplasia/genética , Hiperplasia/metabolismo , Masculino , Estadiamento de Neoplasias , RNA Mensageiro/metabolismo , Receptor Toll-Like 9/metabolismo
13.
Biomed Pharmacother ; 117: 108986, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387172

RESUMO

Chemokine-like factor 1 (CKLF1) is a cytokine, which has a detrimental effect on the multiple disease progression. Our previous studies reported that arterial injury induced the upregulation of CKLF1 expression in artery at 7-14 days after injury. Here, using a rat carotid balloon injury model, we found that CKLF1 knockdown in the injured site abolished neointimal formation and even decreased medial area; contrarily, CKLF1 overexpression developed a thicker neointima than controls, demonstrating that CKLF1 exerted positive effects on neointimal hyperplasia and the accumulation of vascular smooth muscle cells (VSMC). The mechanism study indicated that CKLF1 reduced susceptibility to the cell cycle G2/M arrest and apoptosis, and thereby speeding up VSMC accumulation. This role of CKLF1 was tightly associated with phosphatidylinositol (PI) 3-kinase signaling pathway. CKLF1 increased the expression of four isoforms of the PI3-kinase catalytic subunits, which in turn activated its downstream targets Akt and an effector NF-κB accepted as critical transcription factors of cell survival and proliferation. Furthermore, RNA-sequencing analysis revealed that CKLF1 had wide-ranging roles in regulating the expression of genes that mainly engaged in cell apoptosis and innate immune response. Collectively, the data allow us to conclude that high level CKLF1 after artery injury switches the balance of VSMC proliferation and apoptosis through PI3K/AKT/NF-κB signaling and consequently leads to neointimal hyperplasia. The findings shed insight into new treatment strategies to limit restenosis based on CKLF1 as a future target.


Assuntos
Apoptose/fisiologia , Quimiocinas/metabolismo , Hiperplasia/metabolismo , Proteínas com Domínio MARVEL/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Neointima/metabolismo , Transdução de Sinais/fisiologia , Animais , Divisão Celular/fisiologia , Proliferação de Células/fisiologia , Células Cultivadas , Pontos de Checagem da Fase G2 do Ciclo Celular/fisiologia , Hiperplasia/patologia , Masculino , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , NF-kappa B/metabolismo , Neointima/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
14.
Pathol Int ; 69(5): 249-259, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31219232

RESUMO

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein and a member of the α2 -macroglobulin/C3,C4,C5 family of thioester-containing proteins first identified as being expressed on blood cells, including activated T cells and platelets, and a subset of CD34 + bone marrow cells containing megakaryocyte progenitors. Although CD109 carries the biallelic platelet-specific alloantigen Gov, the physiological functions or roles of CD109 in human disease remain largely unknown. It was recently demonstrated that CD109 is expressed in many malignant tumors, including various squamous cell carcinomas and adenocarcinomas, and plays a role as a multifunctional coreceptor. CD109 reportedly associates with transforming growth factor (TGF)-ß receptors and negatively regulates TGF-ß signaling in keratinocytes. Additionally, CD109 is potentially related to signal transducer and activator of transcription-3 signaling and aberrant cell proliferation. In this review, we describe recent evidence of CD109-specific significance in malignant tumors shown in mouse models and human tissues. Furthermore, we discuss the physiological functions of CD109 in vitro and in vivo, including results of phenotype analyses of CD109-deficient mice exhibiting epidermal hyperplasia and osteopenia.


Assuntos
Antígenos CD/metabolismo , Carcinogênese/metabolismo , Proteínas Ligadas por GPI/metabolismo , Proteínas de Neoplasias/metabolismo , Neoplasias , Adenocarcinoma/etiologia , Adenocarcinoma/metabolismo , Animais , Antígenos CD/genética , Doenças Ósseas Metabólicas/etiologia , Doenças Ósseas Metabólicas/metabolismo , Carcinogênese/imunologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Proteínas Ligadas por GPI/genética , Homeostase , Humanos , Hiperplasia/etiologia , Hiperplasia/metabolismo , Camundongos , Proteínas de Neoplasias/genética , Neoplasias/etiologia , Neoplasias/imunologia , Neoplasias/metabolismo , Fator de Transcrição STAT3/metabolismo , Fatores de Crescimento Transformadores/metabolismo
15.
Folia Biol (Praha) ; 65(1): 36-42, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31171080

RESUMO

Hypothermic incubation of chicken eggs leads to smaller embryos with enlarged hearts, originally described as hypertrophic. Over the years, however, accumulated evidence suggested that hyperplasia, rather than hypertrophy, is the predominant mechanism of cardiac growth during the prenatal period. We have thus set to re-evaluate the hypothermia model to precise the exact cellular mechanism behind cardiac enlargement. Fertilized chicken eggs were incubated at either 37.5 °C (normothermia) or 33.5 °C from embryonic day (ED) 13 onward (hypothermia). Sampling was performed at ED17, at which point wet embryo and heart weight were recorded, and the hearts were submitted to histological examination. In agreement with previous results, the hypothermic embryos were 29% smaller and had hearts 18% larger, translating into a 67% increase in the heart to body weight ratio (P < 0.05 for all parameters). The cell size was essentially the same between control and hypothermic hearts in all regions analysed. Likewise, there was no significant relationship between the cell size and heart weight; however, in the hypothermic hearts, there was a trend showing positive correlation between cell sizes in different cardiac regions and heart weight. Proliferation rate, determined on the basis of anti-phosphohistone H3 immunofluorescence, showed an overall increase in the hypothermic group, reaching statistical significance (P = 0.02, t-test) in the right ventricle. The proliferation rate was similar among different regions of the same heart. However, the correlation between the proliferation rate and heart weight was only small (r2 = 0.007 and r2 = 0.234 for the normothermic and hypothermic group, respectively). We thus conclude that hyperplasia is the predominant response mechanism in this volume-overload model; mechanistically, decreased heart rate at lower temperature increases the end-diastolic and stroke volume, minimizing the drop in cardiac output through the Frank- Starling mechanism.


Assuntos
Hiperplasia/metabolismo , Hipertrofia/fisiopatologia , Hipotermia Induzida/métodos , Animais , Proliferação de Células/fisiologia , Embrião de Galinha , Imunofluorescência , Hipertrofia/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos , Tamanho do Órgão/fisiologia , Volume Sistólico/fisiologia
16.
Mol Med Rep ; 20(2): 1436-1442, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31173198

RESUMO

Neointimal hyperplasia could be one of the most important complications after balloon angioplasty. Since calcium signaling has several physiologic effects on the regulation of the proliferation and migration of vascular smooth muscle cells (VSMCs), it was hypothesized that transmembrane protein 66 (TMEM66), a store operated calcium entry (SOCE)­associated regulatory factor, possesses vascular protection against balloon injury. The rat balloon­induced carotid artery injury model was performed. Histological analysis was used to check neointimal hyperplasia. TMEM66 expression was measured by PCR and immunoblotting. The results revealed that TMEM66 was expressed in the medial and neointimal layers of the injured artery, and the expression of TMEM66 was markedly decreased. TMEM66 overexpression attenuated neointimal hyperplasia via VSMC proliferation/migration inhibition, and restored expression of VSMC phenotypic markers. Moreover, TMEM66 overexpression reduced the increased expression of Stim1 and Orai1 and PDGF­BB treatment­enhanced [Ca2+]i. In conclusion, TMEM66 protects against balloon injury­induced neointimal hyperplasia, and may be a pharmacological target for the treatment of restenosis.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cálcio/metabolismo , Lesões das Artérias Carótidas/genética , Hiperplasia/genética , Proteínas Sensoras de Cálcio Intracelular/genética , Proteínas de Membrana/metabolismo , Neointima/genética , Angioplastia com Balão/efeitos adversos , Animais , Becaplermina/farmacologia , Sinalização do Cálcio , Proteínas de Ligação ao Cálcio/genética , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Lesões das Artérias Carótidas/etiologia , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Regulação da Expressão Gênica , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Proteínas Sensoras de Cálcio Intracelular/metabolismo , Transporte de Íons , Masculino , Proteínas de Membrana/genética , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Proteína ORAI1/genética , Proteína ORAI1/metabolismo , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Molécula 1 de Interação Estromal/genética , Molécula 1 de Interação Estromal/metabolismo
17.
Cell Tissue Res ; 378(2): 279-288, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31129720

RESUMO

Zebrafish (Danio rerio) is widely used as an animal model to understand the pathophysiology of cardiovascular diseases. Here, we present the adult cardiac phenotype of weak atrium, myh6-/-, which carry mutations in the zebrafish atrial myosin heavy chain. Homozygous mutants survive to adulthood and are fertile despite their initial weak atrial beat. In adult mutants, the atrium remains hypoplastic and shows elastin deposition while mutant ventricles exhibit increased size. In mammals, hypertrophy is the most common mechanism resulting in cardiomegaly. Using immunohistochemistry and confocal microscopy to measure cardiomyocyte cell size, density and proliferation, we show that the enlargement of the myh6-/- ventricle is predominantly due to hyperplasia. However, we identified similar transcriptional profiles to the mammalian hypertrophy response via RT-PCR of the hyperplastic ventricles. Furthermore, we show activation of the ER-stress pathway by western blot analysis. In conclusion, we can assume, based on our model, that molecular signaling pathways associated with hypertrophy in mammals, in combination with ER-stress activation, result in hyperplasia in zebrafish. In addition, to our knowledge, this is the first time to report elastin deposition in the atrium.


Assuntos
Modelos Animais de Doenças , Elastina/metabolismo , Átrios do Coração , Hiperplasia/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Direita/patologia , Cadeias Pesadas de Miosina/genética , Proteínas de Peixe-Zebra/genética , Animais , Átrios do Coração/metabolismo , Átrios do Coração/patologia , Mutação , Miócitos Cardíacos/patologia , Peixe-Zebra
18.
Int Immunopharmacol ; 73: 362-369, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31132731

RESUMO

Apigenin (API) is a plant flavone that is known to exert a protective effect in rheumatoid arthritis (RA), which is a chronic autoimmune disease. However, the molecular mechanism for API's protective effect against RA is still unclear. Here, a collagen-induced arthritis (CIA) mouse model was used to assess the protective effect of API on RA. Histomorphological studies, immunohistochemistry, RT-PCR, and western blot were conducted to elucidate the roles of synovial hyperplasia, angiogenesis, and osteoclastogenesis in the protective effect of API on RA. Fibroblast-like synoviocytes (FLSs) were isolated to measure the effect of API on FLS proliferation and apoptosis. API exhibited a significant protective effect in CIA mice in a dose- and time-dependent manner. An increase in apoptosis and decrease in proliferation were observed after the API treatment in FLSs, suggesting that API might inhibit synovial hyperplasia. Moreover, CIA angiogenesis was repressed by API via down-regulation of VEGF and VEGFR. Furthermore, API regulated the osteoclastogenesis-associated RANKL/RANK/OPG system in CIA mice. Therefore, API inhibits CIA by repressing synovial hyperplasia, angiogenesis, and osteoclastogenesis. This suggested that API might be a putative low toxicity candidate drug for RA treatment.


Assuntos
Antirreumáticos/uso terapêutico , Apigenina/uso terapêutico , Artrite Experimental/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Animais , Antirreumáticos/farmacologia , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Artrite Experimental/genética , Artrite Experimental/metabolismo , Artrite Experimental/patologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Hiperplasia/tratamento farmacológico , Hiperplasia/genética , Hiperplasia/metabolismo , Hiperplasia/patologia , Masculino , Camundongos Endogâmicos DBA , Neovascularização Fisiológica/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Ligante RANK/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Receptores de Fatores de Crescimento do Endotélio Vascular/genética , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Sinoviócitos/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
19.
Circ Res ; 125(2): 152-166, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31096851

RESUMO

RATIONALE: Neointimal hyperplasia is characterized by excessive accumulation of vascular smooth muscle cells (SMCs) leading to occlusive disorders, such as atherosclerosis and stenosis. Blood vessel injury increases growth factor secretion and matrix synthesis, which promotes SMC proliferation and neointimal hyperplasia via FAK (focal adhesion kinase). OBJECTIVE: To understand the mechanism of FAK action in SMC proliferation and neointimal hyperplasia. METHODS AND RESULTS: Using combined pharmacological FAK catalytic inhibition (VS-4718) and SMC-specific FAK kinase-dead (Myh11-Cre-ERT2) mouse models, we report that FAK regulates SMC proliferation and neointimal hyperplasia in part by governing GATA4- (GATA-binding protein 4) cyclin D1 signaling. Inhibition of FAK catalytic activity facilitates FAK nuclear localization, which is required for proteasome-mediated GATA4 degradation in the cytoplasm. Chromatin immunoprecipitation identified GATA4 binding to the mouse cyclin D1 promoter, and loss of GATA4-mediated cyclin D1 transcription diminished SMC proliferation. Stimulation with platelet-derived growth factor or serum activated FAK and redistributed FAK from the nucleus to cytoplasm, leading to concomitant increase in GATA4 protein and cyclin D1 expression. In a femoral artery wire injury model, increased neointimal hyperplasia was observed in parallel with elevated FAK activity, GATA4 and cyclin D1 expression following injury in control mice, but not in VS-4718-treated and SMC-specific FAK kinase-dead mice. Finally, lentiviral shGATA4 knockdown in the wire injury significantly reduced cyclin D1 expression, SMC proliferation, and neointimal hyperplasia compared with control mice. CONCLUSIONS: Nuclear enrichment of FAK by inhibition of FAK catalytic activity during vessel injury blocks SMC proliferation and neointimal hyperplasia through regulation of GATA4-mediated cyclin D1 transcription.


Assuntos
Proliferação de Células , Ciclina D1/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Fator de Transcrição GATA4/metabolismo , Miócitos de Músculo Liso/metabolismo , Túnica Íntima/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Ciclina D1/genética , Quinase 1 de Adesão Focal/antagonistas & inibidores , Hiperplasia/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/fisiologia , Túnica Íntima/patologia
20.
Colloids Surf B Biointerfaces ; 180: 168-176, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31048242

RESUMO

Due to their relatively good biocompatibility and inactivity, titanium oxide films (Ti-O) are used in the coating of coronary stents, which reduces metal corrosion, slows metal ion release, and improves endothelial cell (EC) compatibility. Here, we report further functionalizing Ti-O with biological cues for selective endothelialization. Selenocystine with an l- or a d-enantiomer was first immobilized on the Ti-O film via polydopamine to generate nitric oxide (NO) endogenously, which inhibited smooth muscle cell (SMC) proliferation, followed by the grafting of a functional KREDVC peptide to induce EC adhesion. The synergistic effects of the immobilized KREDVC, surface chirality, and NO generation on selective endothelialization were investigated. The results showed that the surface chirality of the l-enantiomer and KREDVC grafting significantly enhanced the attachment and growth of ECs compared to SMCs. An in vivo study showed von Willebrand factor expression was increased and neointimal hyperplasia was significantly decreased in samples with l-selenocystine immobilization and KREDVC grafting. In summary, these findings provide new insights on the surface modification of cardiovascular implants with selective endothelialization.


Assuntos
Cistina/análogos & derivados , Hiperplasia/prevenção & controle , Indóis/química , Neointima/prevenção & controle , Oligopeptídeos/química , Compostos Organosselênicos/química , Polímeros/química , Titânio/química , Animais , Prótese Vascular/efeitos adversos , Implante de Prótese Vascular , Proliferação de Células/efeitos dos fármacos , Técnicas de Cocultura , Cistina/química , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/citologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Hiperplasia/etiologia , Hiperplasia/metabolismo , Hiperplasia/patologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Neointima/etiologia , Neointima/metabolismo , Neointima/patologia , Óxido Nítrico/biossíntese , Óxido Nítrico/farmacologia , Cultura Primária de Células , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Titânio/farmacologia , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismo
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