Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 68.462
Filtrar
1.
Aquat Toxicol ; 226: 105568, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32791376

RESUMO

An emerging Multi-Ion Toxicity (MIT) model for assessment of environmental salt pollution is based on the premise that major ion toxicity to aquatic organisms is related to a critical disturbance of the trans-epithelial potential across the gills (ΔTEP), which can be predicted by electrochemical theory. However, the model has never been evaluated physiologically. We directly tested key assumptions by examining the individual effects of eight different salts (NaCl, Na2SO4, MgCl2, MgSO4, KCl, K2SO4, CaCl2, and CaSO4) on measured TEP in three different fish species (fathead minnow, Pimephales promelas = FHM; channel catfish, Ictalurus punctatus = CC; bluegill, Lepomis macrochirus = BG). A geometric concentration series based on previously reported 96-h LC50 values for FHM was used. All salts caused concentration-dependent increases in TEP to less negative/more positive values in a pattern well-described by the Michaelis-Menten equation. The ΔTEP responses for different salts were similar to one another within each species when concentrations were expressed as a percentage of the FHM LC50. A plateau was reached at or before 100 % of the LC50 where the ΔTEP values were remarkably consistent, with only 1.4 to 2.2-fold variation. This relative uniformity in the ΔTEP responses contrasts with 28-fold variation in salt concentration (in mmol L-1), 9.6-fold in total dissolved solids, and 7.9-fold in conductivity at the LC50. The Michaelis-Menten Km values (salt concentrations causing 50 % of the ΔTEPmax) were positively related to the 96-h LC50 values. ΔTEP responses were not a direct effect of osmolarity in all species and were related to specific cation rather than specific anion concentrations in FHM. These responses were stable for up to 24 h in CC. The results provide strong physiological support for the assumptions of the MIT model, are coherent with electrochemical theory, and point to areas for future research.


Assuntos
Cyprinidae/fisiologia , Epitélio/fisiologia , Brânquias/efeitos dos fármacos , Potenciais da Membrana/efeitos dos fármacos , Perciformes/fisiologia , Sais/toxicidade , Poluentes Químicos da Água/toxicidade , Animais , Eletrodos , Brânquias/fisiologia , Concentração Osmolar
2.
Nat Commun ; 11(1): 2767, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32488095

RESUMO

The pathophysiological nature of the common ABCG2 gout and hyperuricemia associated variant Q141K (rs2231142) remains undefined. Here, we use a human interventional cohort study (ACTRN12615001302549) to understand the physiological role of ABCG2 and find that participants with the Q141K ABCG2 variant display elevated serum urate, unaltered FEUA, and significant evidence of reduced extra-renal urate excretion. We explore mechanisms by generating a mouse model of the orthologous Q140K Abcg2 variant and find male mice have significant hyperuricemia and metabolic alterations, but only subtle alterations of renal urate excretion and ABCG2 abundance. By contrast, these mice display a severe defect in ABCG2 abundance and function in the intestinal tract. These results suggest a tissue specific pathobiology of the Q141K variant, support an important role for ABCG2 in urate excretion in both the human kidney and intestinal tract, and provide insight into the importance of intestinal urate excretion for serum urate homeostasis.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Gota/metabolismo , Hiperuricemia/metabolismo , Ácido Úrico/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Alelos , Animais , Modelos Animais de Doenças , Epitélio/metabolismo , Epitélio/patologia , Proteínas Facilitadoras de Transporte de Glucose/genética , Proteínas Facilitadoras de Transporte de Glucose/metabolismo , Gota/genética , Gota/patologia , Homeostase , Humanos , Intestinos/patologia , Rim/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas de Neoplasias , Fenótipo , Ácido Úrico/sangue
4.
PLoS Genet ; 16(6): e1008885, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32559217

RESUMO

Regulation of cell junctions is crucial for the integrity of epithelial tissues and organs. Cell junctions also play roles in controlling cell proliferation for organ growth. Translationally controlled tumor protein (TCTP) is a conserved protein involved in growth control, but its role in cell junctions is unknown. Here we show that Drosophila Tctp directly interacts with the septate junction protein Coracle (Cora) to regulate epithelial integrity and organ growth. Tctp localizes together with Cora in the epidermis of the embryo. Loss of Cora reduces the level of Tctp in the epidermis but not vice versa. cora/+ or Tctp/+ single heterozygotes develop normally to adulthood. However, double heterozygotes for cora and Tctp mutations show severe disruption of epithelia causing synthetic lethality in the embryo. Double knockdown of Cora and Tctp in eye imaginal disc synergistically leads to disruption of the eye disc, resulting in a severe reduction or loss of eye and head. Conversely, double knockdown of Cora and Tctp in wing disc causes overgrowth as well as cell death. Inhibition of cell death under this condition causes hyperplastic growth of the wing disc. Tctp also shows direct and functional interaction with Cora-associated factors like Yurt and Na+/K+-ATPase. This study suggests that proper levels of Tctp and Cora are essential for the maintenance of the Cora complex and the integrity of epithelia. Our data also provide evidence that both Cora and Tctp are required to suppress overgrowth in developing wing.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/fisiologia , Epitélio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Membrana/metabolismo , Asas de Animais/crescimento & desenvolvimento , Animais , Animais Geneticamente Modificados , Proliferação de Células/genética , Proteínas de Drosophila/genética , Embrião não Mamífero , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Técnicas de Silenciamento de Genes , Discos Imaginais/crescimento & desenvolvimento , Junções Intercelulares/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Proteínas de Membrana/genética , Morfogênese/genética , Mutações Sintéticas Letais , Asas de Animais/metabolismo
5.
Placenta ; 97: 1-5, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32501218

RESUMO

Although many pregnant women have been infected by coronavirus, the presence of intrauterine vertical transmission has not been conclusively reported yet. What prevents this highly contagious virus from reaching the fetus? Is it only the presence of a strong placental barrier, or is it the natural absence of the some receptor that the viruses use for transmission? We, therefore, need to comprehensively understand the mechanism of action of the mammalian epithelial barriers located in two different organs with functional similarity. The barriers selected as potential targets by SARS-CoV-2 are the alveolo-capillary barrier (ACB), and the syncytio-capillary barrier (SCB). Caveolae are omega-shaped structures located on the cell membrane. They consist of caveolin-1 protein (Cav-1) and are involved in the internalisation of some viruses. By activating leukocytes and nuclear factor-κB, Cav-1 initiates inflammatory reactions. The presence of more than one Cav-1 binding sites on coronavirus is an important finding supporting the possible relationship between SARS-CoV-2-mediated lung injury. While the ACB cells express Cav-1 there is no caveolin expression in syncytiotrophoblasts. In this short review, we will try to explain our hypothesis that the lack of caveolin expression in the SCB is one of the most important physiological mechanisms that prevents vertical transmission of SARS-CoV-2. Since the physiological Cav-1 deficiency appears to prevent acute cell damage treatment algorithms could potentially be developed to block this pathway in the non-pregnant population affected by SARS-CoV-2.


Assuntos
Betacoronavirus/fisiologia , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/transmissão , Doenças Fetais/prevenção & controle , Transmissão Vertical de Doença Infecciosa/prevenção & controle , Troca Materno-Fetal/imunologia , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/transmissão , Betacoronavirus/imunologia , Caveolina 1/fisiologia , Infecções por Coronavirus/imunologia , Epitélio/fisiologia , Epitélio/virologia , Feminino , Doenças Fetais/imunologia , Doenças Fetais/virologia , Células Gigantes/fisiologia , Células Gigantes/virologia , Humanos , Imunidade Inata/fisiologia , Pneumonia Viral/imunologia , Gravidez , Fatores de Risco , Internalização do Vírus
6.
Am J Physiol Lung Cell Mol Physiol ; 319(1): L115-L120, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32493030

RESUMO

COVID-19 can be divided into three clinical stages, and one can speculate that these stages correlate with where the infection resides. For the asymptomatic phase, the infection mostly resides in the nose, where it elicits a minimal innate immune response. For the mildly symptomatic phase, the infection is mostly in the pseudostratified epithelium of the larger airways and is accompanied by a more vigorous innate immune response. In the conducting airways, the epithelium can recover from the infection, because the keratin 5 basal cells are spared and they are the progenitor cells for the bronchial epithelium. There may be more severe disease in the bronchioles, where the club cells are likely infected. The devastating third phase is in the gas exchange units of the lung, where ACE2-expressing alveolar type II cells and perhaps type I cells are infected. The loss of type II cells results in respiratory insufficiency due to the loss of pulmonary surfactant, alveolar flooding, and possible loss of normal repair, since type II cells are the progenitors of type I cells. The loss of type I and type II cells will also block normal active resorption of alveolar fluid. Subsequent endothelial damage leads to transudation of plasma proteins, formation of hyaline membranes, and an inflammatory exudate, characteristic of ARDS. Repair might be normal, but if the type II cells are severely damaged alternative pathways for epithelial repair may be activated, which would result in some residual lung disease.


Assuntos
Células Epiteliais Alveolares/virologia , Betacoronavirus/patogenicidade , Infecções por Coronavirus/virologia , Células Epiteliais/virologia , Pneumonia Viral/virologia , Células Epiteliais Alveolares/metabolismo , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/terapia , Células Epiteliais/metabolismo , Epitélio/metabolismo , Epitélio/virologia , Humanos , Pulmão/metabolismo , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/terapia , Mucosa Respiratória/metabolismo , Mucosa Respiratória/virologia
7.
Nat Commun ; 11(1): 3068, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32555155

RESUMO

Surgical adhesions are bands of scar tissues that abnormally conjoin organ surfaces. Adhesions are a major cause of post-operative and dialysis-related complications, yet their patho-mechanism remains elusive, and prevention agents in clinical trials have thus far failed to achieve efficacy. Here, we uncover the adhesion initiation mechanism by coating beads with human mesothelial cells that normally line organ surfaces, and viewing them under adhesion stimuli. We document expansive membrane protrusions from mesothelia that tether beads with massive accompanying adherence forces. Membrane protrusions precede matrix deposition, and can transmit adhesion stimuli to healthy surfaces. We identify cytoskeletal effectors and calcium signaling as molecular triggers that initiate surgical adhesions. A single, localized dose targeting these early germinal events completely prevented adhesions in a preclinical mouse model, and in human assays. Our findings classifies the adhesion pathology as originating from mesothelial membrane bridges and offer a radically new therapeutic approach to treat adhesions.


Assuntos
Cálcio/química , Epitélio/metabolismo , Aderências Teciduais/metabolismo , Animais , Sinalização do Cálcio , Adesão Celular , Linhagem Celular , Membrana Celular/metabolismo , Biologia Computacional , Citoesqueleto/metabolismo , Citosol/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Complicações Pós-Operatórias , Análise de Componente Principal , RNA Interferente Pequeno/metabolismo , Análise de Célula Única
8.
Cell Host Microbe ; 27(5): 685-686, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32407703

RESUMO

Exfoliation is used as a mechanism to remove bacterially infected cells from the body. In this issue of Cell Host & Microbe, Muenzner and Hauck (2020) find that Neisseria gonorrhoeae blocks exfoliation by producing nitric oxide at the bacterial-host cell interface to promote tissue integrity. Uropathogenic Escherichia coli stimulates the same pathway, suggesting a common mechanism among bacterial pathogens.


Assuntos
Proteínas de Escherichia coli , Escherichia coli Uropatogênica , Animais , Epitélio , Camundongos , Neisseria gonorrhoeae , Óxido Nítrico
9.
Nat Genet ; 52(6): 604-614, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424351

RESUMO

During aging, progenitor cells acquire mutations, which may generate clones that colonize the surrounding tissue. By middle age, normal human tissues, including the esophageal epithelium (EE), become a patchwork of mutant clones. Despite their relevance for understanding aging and cancer, the processes that underpin mutational selection in normal tissues remain poorly understood. Here, we investigated this issue in the esophageal epithelium of mutagen-treated mice. Deep sequencing identified numerous mutant clones with multiple genes under positive selection, including Notch1, Notch2 and Trp53, which are also selected in human esophageal epithelium. Transgenic lineage tracing revealed strong clonal competition that evolved over time. Clone dynamics were consistent with a simple model in which the proliferative advantage conferred by positively selected mutations depends on the nature of the neighboring cells. When clones with similar competitive fitness collide, mutant cell fate reverts towards homeostasis, a constraint that explains how selection operates in normal-appearing epithelium.


Assuntos
Esôfago/citologia , Mutação , Proteína ADAM10/genética , Secretases da Proteína Precursora do Amiloide/genética , Animais , Linhagem da Célula , Dietilnitrosamina/toxicidade , Epitélio/efeitos dos fármacos , Epitélio/patologia , Epitélio/fisiologia , Esôfago/fisiologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Proteínas de Membrana/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptor Notch1/genética , Receptor Notch2/genética , Reprodutibilidade dos Testes , Proteína Supressora de Tumor p53/genética
10.
Obesity (Silver Spring) ; 28(9): 1586-1589, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32428380

RESUMO

OBJECTIVE: Mortality from coronavirus disease 2019 (COVID-19) is increased in patients with chronic obstructive pulmonary disease (COPD). Furthermore, higher BMI is related to severe disease. Severe acute respiratory syndrome coronavirus 2 utilizes angiotensin converting enzyme 2 (ACE2) to gain cellular entry. METHODS: Whether ACE2 bronchial epithelial expression is increased in COPD patients who have overweight compared with those who do not was investigated by RNA sequencing. RESULTS: Increased ACE2 expression was observed in patients with COPD with overweight (mean BMI, 29 kg/m2 ) compared with those without overweight (mean BMI, 21 kg/m2 ) (P = 0.004). CONCLUSIONS: Increased ACE2 expression may cause increased severe acute respiratory syndrome coronavirus 2 infection of the respiratory tract. Overweight COPD patients may be at greater risk for developing severe COVID-19.


Assuntos
Brônquios , Epitélio/metabolismo , Sobrepeso/complicações , Peptidil Dipeptidase A/genética , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Betacoronavirus , Infecções por Coronavirus , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral , Doença Pulmonar Obstrutiva Crônica/complicações
11.
Nat Commun ; 11(1): 2660, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32461556

RESUMO

High-grade serous ovarian cancer (HG-SOC)-often referred to as a "silent killer"-is the most lethal gynecological malignancy. The fallopian tube (murine oviduct) and ovarian surface epithelium (OSE) are considered the main candidate tissues of origin of this cancer. However, the relative contribution of each tissue to HG-SOC is not yet clear. Here, we establish organoid-based tumor progression models of HG-SOC from murine oviductal and OSE tissues. We use CRISPR-Cas9 genome editing to introduce mutations into genes commonly found mutated in HG-SOC, such as Trp53, Brca1, Nf1 and Pten. Our results support the dual origin hypothesis of HG-SOC, as we demonstrate that both epithelia can give rise to ovarian tumors with high-grade pathology. However, the mutated oviductal organoids expand much faster in vitro and more readily form malignant tumors upon transplantation. Furthermore, in vitro drug testing reveals distinct lineage-dependent sensitivities to the common drugs used to treat HG-SOC in patients.


Assuntos
Sistemas CRISPR-Cas/genética , Organoides , Neoplasias Ovarianas/etiologia , Animais , Antineoplásicos/farmacologia , Proteína BRCA1/genética , Proteína 9 Associada à CRISPR , Epitélio/patologia , Tubas Uterinas/patologia , Feminino , Edição de Genes/métodos , Camundongos , Mutação , Neurofibromatose 1/genética , Técnicas de Cultura de Órgãos/métodos , Organoides/efeitos dos fármacos , Organoides/fisiopatologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Ovário/patologia , PTEN Fosfo-Hidrolase/genética , Proteína Supressora de Tumor p53/genética
12.
Proc Natl Acad Sci U S A ; 117(21): 11503-11512, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32398375

RESUMO

To explain the evolutionary origin of vertebrate teeth from odontodes, it has been proposed that competent epithelium spread into the oropharyngeal cavity via the mouth and other possible channels such as the gill slits [Huysseune et al., 2009, J. Anat. 214, 465-476]. Whether tooth formation deep inside the pharynx in extant vertebrates continues to require external epithelia has not been addressed so far. Using zebrafish we have previously demonstrated that cells derived from the periderm penetrate the oropharyngeal cavity via the mouth and via the endodermal pouches and connect to periderm-like cells that subsequently cover the entire endoderm-derived pharyngeal epithelium [Rosa et al., 2019, Sci. Rep. 9, 10082]. We now provide conclusive evidence that the epithelial component of pharyngeal teeth in zebrafish (the enamel organ) is derived from medial endoderm, as hitherto assumed based on position deep in the pharynx. Yet, dental morphogenesis starts only after the corresponding endodermal pouch (pouch 6) has made contact with the skin ectoderm, and only after periderm-like cells have covered the prospective tooth-forming endodermal epithelium. Manipulation of signaling pathways shown to adversely affect tooth development indicates they act downstream of these events. We demonstrate that pouch-ectoderm contact and the presence of a periderm-like layer are both required, but not sufficient, for tooth initiation in the pharynx. We conclude that the earliest interactions to generate pharyngeal teeth encompass those between different epithelial populations (skin ectoderm, endoderm, and periderm-like cells in zebrafish), in addition to the epithelial-mesenchymal interactions that govern the formation of all vertebrate teeth.


Assuntos
Epitélio/fisiologia , Camadas Germinativas , Odontogênese/fisiologia , Faringe/fisiologia , Dente/crescimento & desenvolvimento , Animais , Evolução Biológica , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Camadas Germinativas/citologia , Camadas Germinativas/fisiologia , Transdução de Sinais/fisiologia , Peixe-Zebra
13.
Proc Natl Acad Sci U S A ; 117(21): 11531-11540, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32414916

RESUMO

A polarized architecture is central to both epithelial structure and function. In many cells, polarity involves mutual antagonism between the Par complex and the Scribble (Scrib) module. While molecular mechanisms underlying Par-mediated apical determination are well-understood, how Scrib module proteins specify the basolateral domain remains unknown. Here, we demonstrate dependent and independent activities of Scrib, Discs-large (Dlg), and Lethal giant larvae (Lgl) using the Drosophila follicle epithelium. Our data support a linear hierarchy for localization, but rule out previously proposed protein-protein interactions as essential for polarization. Cortical recruitment of Scrib does not require palmitoylation or polar phospholipid binding but instead an independent cortically stabilizing activity of Dlg. Scrib and Dlg do not directly antagonize atypical protein kinase C (aPKC), but may instead restrict aPKC localization by enabling the aPKC-inhibiting activity of Lgl. Importantly, while Scrib, Dlg, and Lgl are each required, all three together are not sufficient to antagonize the Par complex. Our data demonstrate previously unappreciated diversity of function within the Scrib module and begin to define the elusive molecular functions of Scrib and Dlg.


Assuntos
Polaridade Celular/fisiologia , Proteínas de Drosophila/fisiologia , Drosophila , Células Epiteliais , Proteínas de Membrana/fisiologia , Animais , Drosophila/citologia , Drosophila/fisiologia , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Epitélio/fisiologia , Feminino , Folículo Ovariano/citologia , Folículo Ovariano/fisiologia , Proteína Quinase C , Proteínas Supressoras de Tumor
14.
Cancer Sci ; 111(7): 2336-2348, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32437590

RESUMO

Dietary fat consumption during accelerated stages of mammary gland development, such as peripubertal maturation or pregnancy, is known to increase the risk for breast cancer. However, the underlying molecular mechanisms are not fully understood. Here we examined the gene expression profile of mouse mammary epithelial cells (MMECs) on exposure to a high-fat diet (HFD) or control diet (CD). Trp53-/- female mice were fed with the experimental diets for 5 weeks during the peripubertal period (3-8 weeks of age). The treatment showed no significant difference in body weight between the HFD-fed mice and CD-fed mice. However, gene set enrichment analysis predicted a significant enrichment of c-Myc target genes in animals fed HFD. Furthermore, we detected enhanced activity and stabilization of c-Myc protein in MMECs exposed to a HFD. This was accompanied by augmented c-Myc phosphorylation at S62 with a concomitant increase in ERK phosphorylation. Moreover, MMECs derived from HFD-fed Trp53-/- mouse showed increased colony- and sphere-forming potential that was dependent on c-Myc. Further, oleic acid, a major fatty acid constituent of the HFD, and TAK-875, an agonist to G protein-coupled receptor 40 (a receptor for oleic acid), enhanced c-Myc stabilization and MMEC proliferation. Overall, our data indicate that HFD influences MMECs by stabilizing an oncoprotein, pointing to a novel mechanism underlying dietary fat-mediated mammary carcinogenesis.


Assuntos
Dieta Hiperlipídica , Epitélio/metabolismo , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo , Maturidade Sexual , Animais , Linhagem Celular Tumoral , Feminino , Genes p53 , Humanos , Camundongos , Camundongos Knockout , Obesidade/etiologia , Obesidade/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Puberdade , Células Tumorais Cultivadas
15.
Nat Commun ; 11(1): 2366, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32398639

RESUMO

Epithelial bending is a fundamental process that shapes organs during development. Previously known mechanisms involve cells locally changing shape from columnar to wedge-shaped. Here we report a different mechanism that occurs without cell wedging. In mammalian salivary glands and teeth, we show that initial invagination occurs through coordinated vertical cell movement: cells towards the periphery of the placode move vertically upwards while their more central neighbours move downwards. Movement is achieved by active cell-on-cell migration: outer cells migrate with apical, centripetally polarised leading edge protrusions but remain attached to the basal lamina, depressing more central neighbours to "telescope" the epithelium downwards into underlying mesenchyme. Inhibiting protrusion formation by Arp2/3 protein blocks invagination. FGF and Hedgehog morphogen signals are required, with FGF providing a directional cue. These findings show that epithelial bending can be achieved by a morphogenetic mechanism of coordinated cell rearrangement quite distinct from previously recognised invagination processes.


Assuntos
Movimento Celular/fisiologia , Desenvolvimento Embrionário/fisiologia , Epitélio/embriologia , Dente Molar/embriologia , Glândulas Salivares/embriologia , Animais , Ectoderma/citologia , Ectoderma/embriologia , Embrião de Mamíferos/citologia , Células Epiteliais/fisiologia , Feminino , Microscopia Intravital , Masculino , Camundongos , Dente Molar/citologia , Glândulas Salivares/citologia , Técnicas de Cultura de Tecidos
16.
PLoS One ; 15(5): e0226233, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379832

RESUMO

Allergic asthma is the most common phenotype of the pathology, having an early-onset in childhood and producing a Th2-driven airways remodeling process that leads to symptoms and pathophysiological changes. The avoidance of aeroallergen exposure in early life has been shown to prevent asthma, but without repeated success and with the underlying preventive mechanisms at the beginning of asthma far to be fully recognized. In the present study, we aimed to evaluate if neonatal LPS-induced boost in epithelial host defenses contribute to prevent OVA-induced asthma in adult mice. To this, we focused on the response of bronchiolar club cells (CC), which are highly specialized in maintaining the epithelial homeostasis in the lung. In these cells, neonatal LPS administration increased the expression of TLR4 and TNFα, as well as the immunodulatory/antiallergic proteins: club cell secretory protein (CCSP) and surfactant protein D (SP-D). LPS also prevented mucous metaplasia of club cells and reduced the epidermal growth factor receptor (EGFR)-dependent mucin overproduction, with mice displaying normal breathing patterns after OVA challenge. Furthermore, the overexpression of the epithelial Th2-related molecule TSLP was blunted, and normal TSLP and IL-4 levels were found in the bronchoalveolar lavage. A lower eosinophilia was detected in LPS-pretreated mice, along with an increase in phagocytes and regulatory cells (CD4+CD25+FOXP3+ and CD4+IL-10+), together with higher levels of IL-12 and TNFα. In conclusion, our study demonstrates stable asthma-preventive epithelial effects promoted by neonatal LPS stimulation, leading to the presence of regulatory cells in the lung. These anti-allergic dynamic mechanisms would be overlaid in the epithelium, favored by an adequate epidemiological environment, during the development of asthma.


Assuntos
Asma/imunologia , Bronquíolos/efeitos dos fármacos , Bronquíolos/imunologia , Citocinas/metabolismo , Epitélio/imunologia , Imunidade Inata , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Alérgenos/imunologia , Animais , Animais Recém-Nascidos , Asma/prevenção & controle , Modelos Animais de Doenças , Epitélio/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/imunologia , Ovalbumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
17.
Proc Natl Acad Sci U S A ; 117(24): 13541-13551, 2020 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-32467168

RESUMO

Within developing embryos, tissues flow and reorganize dramatically on timescales as short as minutes. This includes epithelial tissues, which often narrow and elongate in convergent extension movements due to anisotropies in external forces or in internal cell-generated forces. However, the mechanisms that allow or prevent tissue reorganization, especially in the presence of strongly anisotropic forces, remain unclear. We study this question in the converging and extending Drosophila germband epithelium, which displays planar-polarized myosin II and experiences anisotropic forces from neighboring tissues. We show that, in contrast to isotropic tissues, cell shape alone is not sufficient to predict the onset of rapid cell rearrangement. From theoretical considerations and vertex model simulations, we predict that in anisotropic tissues, two experimentally accessible metrics of cell patterns-the cell shape index and a cell alignment index-are required to determine whether an anisotropic tissue is in a solid-like or fluid-like state. We show that changes in cell shape and alignment over time in the Drosophila germband predict the onset of rapid cell rearrangement in both wild-type and snail twist mutant embryos, where our theoretical prediction is further improved when we also account for cell packing disorder. These findings suggest that convergent extension is associated with a transition to more fluid-like tissue behavior, which may help accommodate tissue-shape changes during rapid developmental events.


Assuntos
Forma Celular , Drosophila/crescimento & desenvolvimento , Animais , Anisotropia , Drosophila/citologia , Drosophila/genética , Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Epitélio/metabolismo , Miosina Tipo II/genética , Miosina Tipo II/metabolismo
18.
Nanotoxicology ; 14(6): 740-756, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32401081

RESUMO

Despite numerous studies on the environmental health and safety (EHS) of silver nanoparticles (AgNPs), most studies looked into their gross toxicities with rather limited understanding on their labyrinthine implicit effects on the target sites, such as the endocrine system. Burgeoning evidence documents the disrupting effects of AgNPs on endocrine functions; however, little research has been invested to recognize the potential impacts on the mammary gland, a susceptible estrogen-responsive organ. Under this setting, we here aimed to scrutinize AgNP-induced effects on the development of pubertal mammary glands at various concentrations that bear significant EHS relevance. We unearthed that AgNPs could accumulate in mouse mammary glands and result in a decrease in the percentage of ducts and terminal ducts in the adult mice after chronic exposure. Strikingly, smaller sized AgNPs showed greater capability to alter the pubertal mammary development than larger sized particles. Intriguingly, mechanistic investigation revealed that the reduction of epithelial proliferation in response to AgNPs was ascribed to reduced ERα expression, which, at least partially, accounted for diseased epithelial morphology in mammary glands. Meanwhile, the decline in fibrous collagen deposition around the epithelium was found to contribute to the compromised development of mammary glands under the exposure of AgNPs. Moreover, as an extension of the mechanism, AgNPs diminished serum levels of estradiol in exposed animals. Together, these results uncovered a novel toxicity feature of AgNPs: compromised development of mouse pubertal mammary glands through the endocrine-disrupting actions. This study would open a new avenue to unveil the EHS impacts of AgNPs.


Assuntos
Disruptores Endócrinos/toxicidade , Estrogênios/metabolismo , Glândulas Mamárias Animais/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Prata/toxicidade , Animais , Relação Dose-Resposta a Droga , Disruptores Endócrinos/farmacocinética , Epitélio/efeitos dos fármacos , Epitélio/crescimento & desenvolvimento , Epitélio/metabolismo , Receptor alfa de Estrogênio/metabolismo , Estrogênios/farmacologia , Feminino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Transdução de Sinais , Prata/farmacocinética , Propriedades de Superfície , Distribuição Tecidual
19.
Rev Assoc Med Bras (1992) ; 66(2): 174-179, 2020 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-32428152

RESUMO

OBJECTIVE: Although estrogen therapy is widely used against post-menopausal symptoms, it can present adverse effects, including endometrial cancer. Soy isoflavones are considered a possible alternative to estrogen therapy. However, there are still concerns whether isoflavones exert trophic effects on the uterine cervix. To evaluate the histomorphometric and immunohistochemical alterations in the uterine cervix of ovariectomized rats treated with soy isoflavones (Iso). METHODS: Fifteen adult Wistar rats were ovariectomized (Ovx) and divided into three groups: Group I (Ovx), administered with vehicle solution; Group II (OVX-Iso), administered with concentrated extract of Iso (150 mg/kg) by gavage; and Group III (OVX-E2), treated with 17ß-estradiol (10 µg/kg), subcutaneously. After 30 days of treatments, the uterine cervix was fixed in 10% formaldehyde and processed for paraffin-embedding. Sections were stained with Hematoxylin and eosin for morphological and morphometric studies or subjected to immunohistochemistry for detections of Ki-67 and vascular endothelial growth factor-A (Vegf-A). The data obtained were subjected to statistical analysis (p ≤ 0.05). RESULTS: We noted an atrophic uterine cervix in GI, whereas it was more voluminous in GII and even more voluminous in GIII. The thickness of the cervical mucosa was significantly higher in GIII, as compared to GI and GII. The cell proliferation (Ki-67) was significantly elevated in the estradiol and isoflavones treated groups, whereas Vegf-A immunoexpression was significantly higher in GIII, as compared to groups GII and GI. CONCLUSIONS: Soy isoflavones cause less trophic and proliferative effects in the uterine cervix of rats as compared to estrogen.


Assuntos
Colo do Útero/efeitos dos fármacos , Estrogênios/farmacologia , Isoflavonas/farmacologia , Fitoestrógenos/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Colo do Útero/patologia , Epitélio/efeitos dos fármacos , Feminino , Imuno-Histoquímica , Antígeno Ki-67/análise , Membrana Mucosa/efeitos dos fármacos , Ovariectomia , Distribuição Aleatória , Ratos Wistar , Reprodutibilidade dos Testes , Fatores de Tempo , Fator A de Crescimento do Endotélio Vascular/análise
20.
Anticancer Res ; 40(5): 2627-2635, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32366407

RESUMO

BACKGROUND/AIM: Head and neck squamous cell carcinoma (HNSCC) is an aggressive head and neck malignancy. The aim of this study was to elucidate the role of periostin (POSTN) in the epithelial-to-mesenchymal transition (EMT) process mediating the acquisition of radioresistance in HNSCC. MATERIALS AND METHODS: The expression levels of EMT hallmark genes including POSTN and Erk/Akt signaling pathways were compared between radiosensitive and radioresistant HNSCC cells. RESULTS: POSTN mRNA expression was higher in radioresistant HNSCC cells, and silencing POSTN significantly impaired their invasiveness under the effect of EMT process represented by up-regulation of mesenchymal markers and down-regulation of an epithelial marker. Expression levels of Erk and Akt were higher in radioresistant cells. CONCLUSION: POSTN in association with the Erk and Akt signaling pathways was up-regulated during the EMT process, leading to the conversion of radiosensitive to radioresistant HNSCC cells. POSTN may be a key marker for predicting the radioresistance and therapeutic target of HNSCC.


Assuntos
Moléculas de Adesão Celular/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Tolerância a Radiação , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo , Epitélio/metabolismo , Epitélio/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Humanos , Mesoderma/patologia , Invasividade Neoplásica , Tolerância a Radiação/genética , Transdução de Sinais/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA