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1.
Am J Trop Med Hyg ; 2020 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-32157994

RESUMO

The genitourinary tract was recently identified as a potential site of complications related to the congenital Zika syndrome (CZS). We provide the first report of a series of cryptorchidism cases in 3-year-old children with Zika-related microcephaly who underwent consultations between October 2018 and April 2019 as part of the follow-up of the children cohort of the Microcephaly Epidemic Research Group, Pernambuco, Brazil. Of the 22 males examined, eight (36.4%) presented with cryptorchidism. Among 14 undescended testis cases, 11 (78.6%) could be palpated in the inguinal region. Seven of the eight children had severe microcephaly. Conventional risk factors for cryptorchidism were relatively infrequent in these children. We hypothesize that cryptorchidism is an additional manifestation of CZS present in children with severe microcephaly. As in our cases, for most of the children, the testes were located in the inguinal region, and the possible mechanisms for cryptorchidism were gubernaculum disturbance or cremasteric abnormality.

2.
J Ocul Pharmacol Ther ; 36(1): 30-41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31140899

RESUMO

The blood-retinal barrier (BRB) protects the retina by maintaining an adequate microenvironment for neuronal function. Alterations of the junctional complex of the BRB and consequent BRB breakdown in disease contribute to a loss of neuronal signaling and vision loss. As new therapeutics are being developed to prevent or restore barrier function, it is critical to implement physiologically relevant in vitro models that recapitulate the important features of barrier biology to improve disease modeling, target validation, and toxicity assessment. New directions in organ-on-a-chip technology are enabling more sophisticated 3-dimensional models with flow, multicellularity, and control over microenvironmental properties. By capturing additional biological complexity, organs-on-chip can help approach actual tissue organization and function and offer additional tools to model and study disease compared with traditional 2-dimensional cell culture. This review describes the current state of barrier biology and barrier function in ocular diseases, describes recent advances in organ-on-a-chip design for modeling the BRB, and discusses the potential of such models for ophthalmic drug discovery and development.

3.
Biomater Sci ; 7(12): 5338-5349, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31620727

RESUMO

Laminin incorporation into biological or synthetic hydrogels has been explored to recapitulate the dynamic nature and biological complexity of neural stem cell (NSC) niches. However, the strategies currently explored for laminin immobilization within three-dimensional (3D) matrices do not address a critical aspect influencing cell-matrix interactions, which is the control over laminin conformation and orientation upon immobilization. This is a key feature for the preservation of the protein bioactivity. In this work, we explored an affinity-based approach to mediate the site-selective immobilization of laminin into a degradable synthetic hydrogel. Specifically, a four-arm maleimide terminated poly(ethylene glycol) (PEG-4MAL) macromer was functionalized with a mono-PEGylated recombinant human N-terminal agrin (NtA) domain, to promote high affinity binding of laminin. Different NtA concentrations (10, 50 and 100 µM) were used to investigate the impact of NtA density on laminin incorporation, hydrogel biophysical properties, and biological outcome. Laminin was efficiently incorporated for all the conditions tested (laminin incorporation >95%), and the developed hydrogels revealed mechanical properties (average storage modulus (G') ranging from 187 to 256 Pa) within the values preferred for NSC proliferation and neurite branching and extension. Affinity-bound laminin PEG-4MAL hydrogels better preserve laminin bioactivity, compared to unmodified hydrogels and hydrogels containing physically entrapped laminin, this effect being dependent on NtA concentration. This was evidenced by the 10 µM NtA-functionalized PEG-4MAL gels incorporating laminin that support enhanced human NSC proliferation and neurite extension, compared to the latter. Overall, this work highlights the potential of the proposed engineered matrices to be used as defined 3D platforms for the establishment of artificial NSC niches and as extracellular matrix-mimetic microenvironments to support human NSC transplantation.

4.
Life Sci ; 234: 116738, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31398418

RESUMO

AIMS: Oxidative stress has been linked to the development and progression of diabetic nephropathy (DN). The present study evaluated whether the dipeptidyl peptidase-4 inhibitor sitagliptin attenuates glomerular lesions and oxidative stress evoked by chronic hyperglycemia, by a mechanism independent of insulin secretion and glycemia normalization. MAIN METHODS: A rat model of DN caused by streptozotocin injection was established and the effects of sitagliptin (5 mg/kg/day) were evaluated after two weeks of treatment. KEY FINDINGS: Sitagliptin treatment did not change body weight, glycemic and lipid profiles. However, histopathological observation revealed that sitagliptin attenuates diabetes-induced glomerular lesions on diabetic rats. Sitagliptin also ameliorated the increase in DPP-4 content and promoted the stabilization of GLP-1 in the diabetic kidney. Furthermore, sitagliptin treatment significantly attenuated the increase of free-radical formation and the decrease of antioxidant defenses, attenuating therefore the oxidative stress in the kidneys of diabetic animals. SIGNIFICANCE: The results suggest that sitagliptin treatment alleviates kidney oxidative stress in type 1 diabetic rats, which could play a key role in reducing the progression of DN.


Assuntos
Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Glomérulos Renais/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Nefropatias Diabéticas/etiologia , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Inibidores da Dipeptidil Peptidase IV/farmacologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Masculino , Ratos , Ratos Wistar , Fosfato de Sitagliptina/farmacologia
5.
Nat Metab ; 1(5): 519-531, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31276102

RESUMO

Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.

6.
Biomed Pharmacother ; 102: 833-838, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29605771

RESUMO

Diabetic retinopathy is considered a low-grade chronic inflammatory disease and several inflammatory molecules, including tumor necrosis factor (TNF)-α, are known to play a major role in the degeneration of retinal capillaries. Previous studies have reported that sitagliptin, a DPP-4 inhibitor, prevents the increase in blood-retinal barrier (BRB) permeability and inhibits the tight junction disassembly induced by diabetes. AIM: Our goal was to investigate whether sitagliptin is able to prevent retinal endothelial cells (EC) dysfunction triggered by the pro-inflammatory cytokine TNF-α. MAIN METHODS: The effects of TNF-α and/or sitagliptin on primary cultures of bovine retinal EC were tested. The EC monolayer permeability was analyzed by using 70 kDa rhodamine isothiocyanate (RITC) dextran. The cellular distribution profile of claudin-5 was examined by immunofluorescence staining, and DPP-4 activity was evaluated by using a fluorogenic substrate. Cell viability was assessed by MTT assay, and cell proliferation by the BrdU incorporation assay. Retinal EC migration and angiogenesis were evaluated by a scratch assay and a capillary tube formation in matrigel assay, respectively. KEY FINDINGS: TNF-α increased the permeability of EC monolayer and induced the loss of claudin-5 immunostaining at the cell borders. This impairment was associated with decreased migration and capillary morphogenesis of retinal EC. Sitagliptin was unable to prevent the effect of TNF-α on EC permeability. However, it decreased DPP-4 activity in bovine retinal EC exposed to TNF-α, without affecting cell viability. Moreover, sitagliptin enhanced the migration and capillary morphogenesis in bovine retinal EC challenged with TNF-α. SIGNIFICANCE: These results suggest that sitagliptin is able to positively modulate vascular EC function under conditions of retinal inflammation.


Assuntos
Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Células Endoteliais/patologia , Inflamação/tratamento farmacológico , Inflamação/patologia , Retina/patologia , Fosfato de Sitagliptina/uso terapêutico , Animais , Capilares/crescimento & desenvolvimento , Bovinos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Morfogênese/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Fator de Necrose Tumoral alfa/farmacologia
7.
Biomed Mater ; 13(3): 035009, 2018 03 14.
Artigo em Inglês | MEDLINE | ID: mdl-29363620

RESUMO

Barrier membranes for guided bone regeneration (GBR) mainly promote mechanical maintenance of bone defect space and induce osteopromotion. Additionally, biopolymer-based membranes may provide greater bioactivity and biocompatibility due to their similarity to extracellular matrix (ECM). In this study, biopolymers-based membranes from bacterial cellulose (BC) and collagen (COL) associated with osteogenic growth peptide (OGP(10-14)) were evaluated to determine in vitro osteoinductive potential in early osteogenesis; moreover, histological study was performed to evaluate the BC-COL OGP(10-14) membranes on bone healing after GBR in noncritical defects in rat femur. The results showed that the BC-COL and BC-COL OGP(10-14) membranes promoted cell proliferation and alkaline phosphatase activity in osteoblastic cell cultures. However, ECM mineralization was similar between cultures grown on BC OGP(10-14) and BC-COL OGP(10-14) membranes. In vivo results showed that all the membranes tested, including the peptide-free BC membrane, promoted better bone regeneration than control group. Furthermore, the BC-COL OGP(10-14) membranes induced higher radiographic density in the repaired bone than the other groups at 1, 4 and 16 weeks. Histomorphometric analyses revealed that the BC-COL OGP(10-14) induced higher percentage of bone tissue in the repaired area at 2 and 4 weeks than others membranes. In general, these biopolymer-based membranes might be potential candidates for bone regeneration applications.


Assuntos
Biopolímeros/química , Regeneração Óssea , Histonas/química , Peptídeos e Proteínas de Sinalização Intercelular/química , Osteogênese/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Osso e Ossos/patologia , Técnicas de Cultura de Células , Membrana Celular/metabolismo , Proliferação de Células , Colágeno/química , Masculino , Osteoblastos/citologia , Peptídeos/química , Polímeros/química , Ratos , Ratos Wistar
8.
Hum Immunol ; 78(11-12): 752-757, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28941745

RESUMO

Human leukocyte antigen (HLA) G and E, programmed cell death 1 ligand 1 (PD-L1), IL-10 and TGF-ß are proteins involved in failure of the antitumor immune response. We investigated the expression of these immunomodulatory mediators in oral precancerous lesions (oral leukoplakia-OL; n=80) and whether these molecules were related to the risk of malignant transformation. Samples of normal mucosa (n=20) and oral squamous cells carcinoma (OSCC, n=20) were included as controls. Tissue and saliva samples were analyzed by immunohistochemistry and ELISA respectively. Fifteen OL samples showed severe dysplasia (18.7%) and 40 samples (50%) presented combined high Ki-67/p53. Irrespective of the degree of epithelial dysplasia and the proliferation/apoptosis index of OL, the expression of HLA-G, -E, PD-L1, IL-10, TGF-ß2 and -ß3 was higher to control (P<0.05) and similar to OSCC (P>0.05). The number of granzyme B+ cells in OL was similar to control (P=0.28) and lower compared to OSCC (P<0.01). Salivary concentrations of sHLA-G, IL-10 and TGF-ß did not allow for a distinction between OL and healthy individuals. Overexpression of immunosuppressive mediators in the OL reflects the immune evasion potential of this lesion, which is apparently independent of at cytological and proliferation/apoptosis status.


Assuntos
Carcinoma de Células Escamosas/genética , Células Epiteliais/patologia , Leucoplasia Oral/genética , Mucosa Bucal/fisiologia , Neoplasias Bucais/genética , Lesões Pré-Cancerosas/genética , Adulto , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proliferação de Células , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica , Antígenos HLA-G/genética , Antígenos HLA-G/metabolismo , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Fatores Imunológicos/genética , Fatores Imunológicos/metabolismo , Interleucina-10/genética , Interleucina-10/metabolismo , Masculino , Pessoa de Meia-Idade , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo
9.
Arch Oral Biol ; 83: 55-62, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28711734

RESUMO

OBJECTIVE: To identify the expression of nonclassical human leukocyte antigen G and E (HLA-G and -E), programmed cell death ligand-1 (PD-L1) and granzyme B (GB) in intraoral mucoepidermoid carcinomas (MECs), and to assess whether such expressions are related to metastasis, survival, staging, tumor grade and number of GB-positive cells. DESIGN: For this cross-sectional study, samples of MEC (n=30) were selected and classified as low-grade (LG), intermediate-grade (IG) or high-grade (HG), according to the WHO grading system. HLA-G, -E and PD-L1 were identified by immunohistochemistry and quantified as the proportion of positive neoplastic cells. The density of GB+ cells was also evaluated. The Kruskal-Wallis test was used with a 5% significance level. RESULTS: Expressions of HLA-G, -E and PD-L1 were identified in the majority of epidermoid, intermediate and clear cells, but not in the mucous cells of the MECs. The quantitative analysis of the total percentage of positive neoplastic cells showed overexpression of this set of proteins in all MEC samples. The expression of these proteins and histological grading were positively correlated [HLA-G (LG=79% positive cells, IG=96%, HG=99%; p=0.0004), HLA-E (LG=70%, IG=96%, HG=99%; p<0.0001) and PD-L1 (LG=34%, IG=79%, HG=80%; p=0.01)]. No relationship was observed between the immunosuppressive proteins and other clinicopathological parameters. Low GB density was found in all MEC samples. CONCLUSIONS: The augmented expression of HLA-G, -E and PD-L1 in the intraoral MEC might suggest a role of these molecules in the scape of neoplastic cells from immunosurveillance.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma Mucoepidermoide/metabolismo , Granzimas/metabolismo , Antígenos HLA-G/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Imuno-Histoquímica/métodos , Neoplasias Bucais/metabolismo , Adolescente , Adulto , Idoso , Carcinoma Mucoepidermoide/patologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Taxa de Sobrevida
10.
BMC Res Notes ; 10(1): 253, 2017 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-28683764

RESUMO

BACKGROUND: Publication retraction is a mechanism to preserve the scientific literature against publications that contain seriously flawed or erroneous data, redundant publication, plagiarism, unethical research, and other features that compromise the integrity of science. An increase in the occurrence of retractions in recent years has been reported. Nevertheless, there is scarce information on this topic concerning publications in dentistry and related specialties. Thus, this study aimed to investigate retracted papers published in dental journals. METHODS: Data collection included an exploratory search in PubMed and a specific search in SCImago Journal Rank indexed journals, complemented by the cases reported on the Retraction Watch website and in PubMed. All 167 dental journals included in SCImago were searched for identification of retracted articles up to March 2016. The selected retracted articles and their corresponding retraction notices were recorded and assessed for classification according to the reason for retraction and other additional information. RESULTS: Forty of the 167 journals scrutinised at SCImago (23.9%) had at least one retracted article, and four additional journals were identified from the Retraction Watch website. A total of 72 retracted found were retracted for the reasons: redundant publication (20.8%), plagiarism (18.1%), misconduct (13.8%), overlap (13.6%) and honest error (9.7%). Higher number of retractions were reported in those journals with cites/doc <2.0-n = 49 (74.2%). The types of studies were mainly laboratory studies (34.7%), case reports (22.2%) and review articles (13.9%). CONCLUSIONS: The approach to ethical problems in papers published in dental scientific journals is still incipient; retractions were mostly due to the authors' malpractice and were more frequently related to journals with less impact.


Assuntos
Pesquisa Biomédica/estatística & dados numéricos , Bases de Dados Bibliográficas/estatística & dados numéricos , Odontologia/estatística & dados numéricos , Publicações Periódicas como Assunto/estatística & dados numéricos , Retratação de Publicação como Assunto , Humanos
11.
Oral Surg Oral Med Oral Pathol Oral Radiol ; 123(6): e188-e196, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28159587

RESUMO

OBJECTIVE: The aim of this study was to investigate the expression of human leukocyte antigens (HLAs) G and E and programmed death-ligand 1 (PD-L1) in oral osteosarcoma (OO) (n = 13). The relationship between the expression of these molecules and histologic grading and metastasis was also evaluated. STUDY DESIGN: HLA-G, HLA-E, and PD-L1 were identified by immunohistochemistry. Samples of normal bone tissue (n = 6) were used as controls. The sections were evaluated using a semiquantitative scoring system with an immunoreactive score, where a score of 0 was considered absent, ≤2 was low, and >2 was high expression. RESULTS: We identified high expression of HLA-G, HLA-E, and PD-L1 by malignant osteoblastic cells in 69.2% of OO cases, which was statistically higher than that in controls (P < .05). Overexpression of these proteins was identified in 8 of 11 samples of high-grade and 1 of 2 samples of low-grade OO. Additionally, 66.6% of patients with metastases (n = 4) and 71.4% of patients without metastases (n = 5) had high expression of HLA-G, HLA-E, and PD-L1 in tumor samples (P > .05). CONCLUSION: OO had high expression of HLA-G, HLA-E, and PD-L1 irrespective of clinicopathologic parameters, including histologic grading and metastasis.


Assuntos
Antígeno B7-H1/imunologia , Antígenos HLA-G/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Neoplasias Maxilomandibulares/imunologia , Osteossarcoma/imunologia , Adulto , Idoso , Biomarcadores Tumorais/imunologia , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Maxilomandibulares/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Osteossarcoma/patologia
12.
Redox Biol ; 11: 157-169, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27936457

RESUMO

BACKGROUND AND AIMS: In hereditary hemochromatosis, iron deposition in the liver parenchyma may lead to fibrosis, cirrhosis and hepatocellular carcinoma. Most cases are ascribed to a common mutation in the HFE gene, but the extent of clinical expression is greatly influenced by the combined action of yet unidentified genetic and/or environmental modifying factors. In mice, transcription factor NRF2 is a critical determinant of hepatocyte viability during exposure to acute dietary iron overload. We evaluated if the genetic disruption of Nrf2 would prompt the development of liver damage in Hfe-/- mice (an established model of human HFE-hemochromatosis). METHODS: Wild-type, Nrf2-/-, Hfe-/- and double knockout (Hfe/Nrf2-/-) female mice on C57BL/6 genetic background were sacrificed at the age of 6 (young), 12-18 (middle-aged) or 24 months (old) for evaluation of liver pathology. RESULTS: Despite the parenchymal iron accumulation, Hfe-/- mice presented no liver injury. The combination of iron overload (Hfe-/-) and defective antioxidant defences (Nrf2-/-) increased the number of iron-related necroinflammatory lesions (sideronecrosis), possibly due to the accumulation of toxic oxidation products such as 4-hydroxy-2-nonenal-protein adducts. The engulfment of dead hepatocytes led to a gradual accumulation of iron within macrophages, featuring large aggregates. Myofibroblasts recruited towards the injury areas produced substantial amounts of collagen fibers involving the liver parenchyma of double-knockout animals with increased hepatic fibrosis in an age-dependent manner. CONCLUSIONS: The genetic disruption of Nrf2 promotes the transition from iron accumulation (siderosis) to liver injury in Hfe-/- mice, representing the first demonstration of spontaneous hepatic fibrosis in the long term in a mouse model of hereditary hemochromatosis displaying mildly elevated liver iron.


Assuntos
Proteína da Hemocromatose/genética , Hemocromatose/genética , Cirrose Hepática/genética , Fator 2 Relacionado a NF-E2/genética , Animais , Sobrevivência Celular/genética , Modelos Animais de Doenças , Hemocromatose/metabolismo , Hemocromatose/patologia , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Ferro/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/patologia , Camundongos , Camundongos Knockout , Mutação
13.
Invest Ophthalmol Vis Sci ; 57(6): 2584-92, 2016 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-27163772

RESUMO

PURPOSE: Inflammation associated with blood-retinal barrier (BRB) breakdown is a common feature of several retinal diseases. Therefore, the development of novel nonsteroidal anti-inflammatory approaches may provide important therapeutic options. Previous studies demonstrated that inhibition of dipeptidyl peptidase-IV, the enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1), led to insulin-independent prevention of diabetes-induced increases in BRB permeability, suggesting that incretin-based drugs may have beneficial pleiotropic effects in the retina. In the current study, the barrier protective and anti-inflammatory properties of exendin-4 (Ex-4), an analog of GLP-1, after ischemia-reperfusion (IR) injury were examined. METHODS: Ischemia-reperfusion injury was induced in rat retinas by increasing the intraocular pressure for 45 minutes followed by 48 hours of reperfusion. Rats were treated with Ex-4 prior to and following IR. Blood-retinal barrier permeability was assessed by Evans blue dye leakage. Retinal inflammatory gene expression and leukocytic infiltration were measured by qRT-PCR and immunofluorescence, respectively. A microglial cell line was used to determine the effects of Ex-4 on lipopolysaccharide (LPS)-induced inflammatory response. RESULTS: Exendin-4 dramatically reduced the BRB permeability induced by IR injury, which was associated with suppression of inflammatory gene expression. Moreover, in vitro studies showed that Ex-4 also reduced the inflammatory response to LPS and inhibited NF-κB activation. CONCLUSIONS: The present work suggests that Ex-4 can prevent IR injury-induced BRB breakdown and inflammation through inhibition of inflammatory cytokine production by activated microglia and may provide a novel option for therapeutic intervention in diseases involving retinal inflammation.


Assuntos
Barreira Hematorretiniana/efeitos dos fármacos , Peptídeo 1 Semelhante ao Glucagon/análogos & derivados , Inflamação/prevenção & controle , Isquemia/prevenção & controle , Peptídeos/farmacologia , Traumatismo por Reperfusão/complicações , Doenças Retinianas/prevenção & controle , Peçonhas/farmacologia , Animais , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Exenatida , Immunoblotting , Imuno-Histoquímica , Incretinas/farmacologia , Inflamação/metabolismo , Isquemia/etiologia , Isquemia/metabolismo , Masculino , Ratos , Ratos Long-Evans , Traumatismo por Reperfusão/metabolismo , Doenças Retinianas/etiologia , Doenças Retinianas/metabolismo
14.
Hum Immunol ; 77(9): 785-90, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26723902

RESUMO

HLA-G, HLA-E and IL-10 are molecules which can provide tumor immunosuppression as well as the capacity of evasion to the immune system host. This study set out to evaluate HLA-G, HLA-E and IL-10 expression in lip squamous cell carcinoma (LSCC) and in a potentially malignant disorder (actinic cheilitis - AC), correlating the expression of these proteins with the degree of epithelial dysplasia. Immunohistochemistry was undertaken to identify HLA-G, HLA-E and IL-10 in samples from patients with LSCC (n=20), AC (n=30) and healthy lip mucosa (control) (n=10). A semiquantitative scoring system was used for analysis. Differences between the groups were evaluated using the Pearson Chi-Squared test. The percentage of LSCC samples showing high immunoreactivity (IRS>2) for HLA-G, HLA-E and IL-10 (neoplastic/epithelial cells) and HLA-E (stroma/connective tissue) was significantly higher that of the control (P<0.05). A tendency for a progressive increase in the proteins analyzed was observed from the control to AC and to LSCC. The degree of dysplasia in the AC samples was not significantly associated with the proteins evaluated (P>0.05). The high expression of HLA-G, HLA-E and IL-10 in AC and LSCC reflects the capacity that these pathologies have for evasion and progression.


Assuntos
Carcinoma de Células Escamosas/metabolismo , Queilite/metabolismo , Antígenos HLA-G/metabolismo , Antígenos de Histocompatibilidade Classe I/metabolismo , Interleucina-10/metabolismo , Neoplasias Labiais/metabolismo , Mucosa Bucal/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese , Carcinoma de Células Escamosas/patologia , Queilite/patologia , Feminino , Antígenos HLA-G/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Imuno-Histoquímica , Interleucina-10/imunologia , Neoplasias Labiais/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
15.
Biom J ; 58(3): 623-34, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26455826

RESUMO

In longitudinal studies of disease, patients may experience several events through a follow-up period. In these studies, the sequentially ordered events are often of interest and lead to problems that have received much attention recently. Issues of interest include the estimation of bivariate survival, marginal distributions, and the conditional distribution of gap times. In this work, we consider the estimation of the survival function conditional to a previous event. Different nonparametric approaches will be considered for estimating these quantities, all based on the Kaplan-Meier estimator of the survival function. We explore the finite sample behavior of the estimators through simulations. The different methods proposed in this article are applied to a dataset from a German Breast Cancer Study. The methods are used to obtain predictors for the conditional survival probabilities as well as to study the influence of recurrence in overall survival.


Assuntos
Biometria/métodos , Modelos Estatísticos , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Análise Multivariada , Probabilidade , Recidiva , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo
16.
J Oral Pathol Med ; 45(6): 418-24, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26514660

RESUMO

BACKGROUND: There may be differences in the antitumor immunity induced by dendritic cells (DCs) during the development of squamous cell carcinoma (SCC) located in the lip rather than in the oral cavity. The aim of this study was to evaluate the number of immature and mature DCs in SCC and potentially malignant disorders of the oral cavity and lip. METHODS: Immunohistochemistry was used to identify the number (cells/mm(2) ) of immature (CD1a(+) ) or mature (CD83(+) ) DCs in samples of oral cavity SCC (OCSCC) (n = 39), lip SCC (LSCC) (n = 23), leukoplakia (LK) (n = 21), actinic cheilitis (AC) (n = 13), and normal mucosa of the oral cavity (OC control, n = 12) and the lip (lip control, n = 11). RESULTS: The number of CD1a(+) cells tended to be higher in the OC control samples compared with the LK (P = 0.04) and OCSCC (P = 0.21). Unlike, this cell population was lower in the lip control than in AC or LSCC (P < 0.05). The number of CD83(+) cells was increased in the LSCC samples compared with the AC and lip control (P = 0.0001) and in OCSCC compared with both the LK (P = 0.001) and OC control (P = 0.0001) samples. LSCC showed an elevated number of CD1a(+) and CD83(+) cells compared with OCSCC (P = 0.03). The population of mature DCs was lower than the population of immature DCs in all of the tested groups (P < 0.05). CONCLUSION: There were a greater number of both mature and immature DC populations in the LSCC samples than in the OCSCC, which could contribute to establishing a more effective immune antitumor response for this neoplasm.


Assuntos
Carcinoma de Células Escamosas/patologia , Células Dendríticas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias Labiais/patologia , Neoplasias Bucais/patologia , Antígenos CD/metabolismo , Antígenos CD1/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/metabolismo , Queilite/metabolismo , Queilite/patologia , Estudos Transversais , Células Dendríticas/metabolismo , Feminino , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imunoglobulinas/metabolismo , Leucoplasia/metabolismo , Leucoplasia/patologia , Neoplasias Labiais/diagnóstico , Neoplasias Labiais/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Mucosa Bucal/metabolismo , Mucosa Bucal/patologia , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida
17.
Biomed Res Int ; 2015: 597134, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26120584

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH), which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment.


Assuntos
Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Fator 2 Relacionado a NF-E2/genética , Hepatopatia Gordurosa não Alcoólica/genética , Antioxidantes/metabolismo , Ácidos Graxos/metabolismo , Humanos , Fígado/patologia , Fator 2 Relacionado a NF-E2/biossíntese , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo
18.
Hum Immunol ; 76(1): 52-8, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25500427

RESUMO

The goal of this study was to compare the salivary concentrations of IL-10, TGF-ß1 and soluble HLA-G (sHLA-G) in patients with oral squamous cell carcinoma (OSCC) to those in healthy individuals (control group), and to correlate the expression of these mediators in saliva with that in the tumour microenvironment. Neoplastic tissue and saliva samples from patients with OSCC (n=22) were analysed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA) respectively. We detected high expression of IL-10 and HLA-G in the tumour microenvironment when compared to healthy oral mucosa samples. Determination of IL-10 salivary concentration enabled us to distinguish patients with OSCC from healthy individuals (P=0.038), which showed correlation with tissue expression of this cytokine. HLA-G salivary release was similar in both groups (P=0.17) and no correlation with tumour expression was observed. TGF-ß1 expression was low or absent in tumours, and salivary concentration was similar between groups. Our results suggest that of the three markers analysed, IL-10 is a potential salivary biomarker. Furthermore, the elevated expression of HLA-G and IL-10 in tumour sites could favour the escape of tumour cells from immune defense mechanisms.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Antígenos HLA-G/genética , Interleucina-10/genética , Neoplasias Bucais/genética , Fator de Crescimento Transformador beta1/genética , Biomarcadores Tumorais/imunologia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Antígenos HLA-G/imunologia , Humanos , Imunidade Inata , Interleucina-10/imunologia , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/química , Neoplasias Bucais/diagnóstico , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Saliva/química , Fator de Crescimento Transformador beta1/imunologia , Evasão Tumoral/genética , Microambiente Tumoral/imunologia
19.
Mediators Inflamm ; 2014: 538737, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24817793

RESUMO

This study aimed to evaluate the efficacy of sitagliptin, a dipeptidyl peptidase IV (DPP-IV) inhibitor, in preventing the deleterious effects of diabetes on the kidney in an animal model of type 2 diabetes mellitus; the Zucker diabetic fatty (ZDF) rat: 20-week-old rats were treated with sitagliptin (10 mg/kg bw/day) during 6 weeks. Glycaemia and blood HbA1c levels were monitored, as well as kidney function and lesions. Kidney mRNA and/or protein content/distribution of DPP-IV, GLP-1, GLP-1R, TNF-α, IL-1ß, BAX, Bcl-2, and Bid were evaluated by RT-PCR and/or western blotting/immunohistochemistry. Sitagliptin treatment improved glycaemic control, as reflected by the significantly reduced levels of glycaemia and HbA1c (by about 22.5% and 1.2%, resp.) and ameliorated tubulointerstitial and glomerular lesions. Sitagliptin prevented the diabetes-induced increase in DPP-IV levels and the decrease in GLP-1 levels in kidney. Sitagliptin increased colocalization of GLP-1 and GLP-1R in the diabetic kidney. Sitagliptin also decreased IL-1ß and TNF-α levels, as well as, prevented the increase of BAX/Bcl-2 ratio, Bid protein levels, and TUNEL-positive cells which indicates protective effects against inflammation and proapoptotic state in the kidney of diabetic rats, respectively. In conclusion, sitagliptin might have a major role in preventing diabetic nephropathy evolution due to anti-inflammatory and antiapoptotic properties.


Assuntos
Apoptose/efeitos dos fármacos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inflamação/prevenção & controle , Pirazinas/uso terapêutico , Triazóis/uso terapêutico , Animais , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Ratos , Ratos Zucker , Fosfato de Sitagliptina , Fator de Necrose Tumoral alfa/metabolismo
20.
Biochim Biophys Acta ; 1842(9): 1454-63, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24769045

RESUMO

Diabetic retinopathy, a leading cause of vision loss in working-age population, is often associated with inflammation and apoptosis. We have previously reported that sitagliptin, a DPP-IV inhibitor, exerts beneficial effects in the retina of type 2 diabetic animals. The present study aimed to evaluate whether sitagliptin can exert protective effects in the retina of type 1 diabetic animals by a mechanism independent of insulin secretion and glycemia normalization. Streptozotocin-induced diabetic rats were treated orally with sitagliptin (5mg/kg/day) for the last two weeks of 4 weeks of diabetes. Sitagliptin treatment did not change the weight and glucose, HbA1c or insulin levels. However, it prevented the diabetes-induced increase in DPP-IV/CD26 activity and levels in serum and retina. Sitagliptin also prevented the increase in blood-retinal barrier (BRB) permeability and inhibited the changes in immunoreactivity and endothelial subcellular distribution of occludin, claudin-5 and ZO-1 proteins induced by diabetes. Furthermore, sitagliptin decreased the retinal inflammatory state and neuronal apoptosis. Sitagliptin inhibited the BRB breakdown in a type 1 diabetic animal model, by a mechanism independent of normalization of glycemia, by preventing changes in tight junctions (TJs) organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used to prevent or delay some of the alterations associated with the development of diabetic retinopathy.


Assuntos
Barreira Hematorretiniana/efeitos dos fármacos , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Dipeptidil Peptidase 4/química , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inflamação/tratamento farmacológico , Neurônios/efeitos dos fármacos , Retina/efeitos dos fármacos , Animais , Apoptose , Biomarcadores/análise , Barreira Hematorretiniana/metabolismo , Western Blotting , Morte Celular , Células Cultivadas , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/patologia , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/metabolismo , Retinopatia Diabética/patologia , Dipeptidil Peptidase 4/metabolismo , Ensaio de Imunoadsorção Enzimática , Técnicas Imunoenzimáticas , Inflamação/metabolismo , Inflamação/patologia , Masculino , Neurônios/metabolismo , Neurônios/patologia , Pirazinas/farmacologia , Ratos , Ratos Wistar , Retina/metabolismo , Retina/patologia , Fosfato de Sitagliptina , Triazóis/farmacologia
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