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1.
BMC Immunol ; 19(1): 24, 2018 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-29996768

RESUMO

BACKGROUND: Macrophages are tissue resident immune cells important for host defence and homeostasis. During diabetes, macrophages and other innate immune cells are known to have a pro-inflammatory phenotype, which is believed to contribute to the pathogenesis of various diabetic complications. However, diabetic patients are highly susceptible to bacterial infections, and often have impaired wound healing. The molecular mechanism underlying the paradox of macrophage function in diabetes is not fully understood. Recent evidence suggests that macrophage functions are governed by metabolic reprograming. Diabetes is a disorder that affects glucose metabolism; dysregulated macrophage function in diabetes may be related to alterations in their metabolic pathways. In this study, we seek to understand the effect of high glucose exposure on macrophage phenotype and functions. RESULTS: Bone marrow cells were cultured in short or long term high glucose and normal glucose medium; the number and phenotype of bone marrow derived macrophages were not affected by long-term high glucose treatment. Short-term high glucose increased the expression of IL-1ß. Long-term high glucose increased the expression of IL-1ß and TNFα but reduced the expression of IL-12p40 and nitric oxide production in M1 macrophage. The treatment also increased Arg-1 and IL-10 expression in M2 macrophages. Phagocytosis and bactericidal activity was reduced in long-term high glucose treated macrophages and peritoneal macrophages from diabetic mice. Long-term high glucose treatment reduced macrophage glycolytic capacity and glycolytic reserve without affecting mitochondrial ATP production and oxidative respiration. CONCLUSION: Long-term high glucose sensitizes macrophages to cytokine stimulation and reduces phagocytosis and nitric oxide production, which may be related to impaired glycolytic capacity.


Assuntos
Células da Medula Óssea/imunologia , Diabetes Mellitus Experimental/imunologia , Glucose/metabolismo , Ativação de Macrófagos , Macrófagos Peritoneais/imunologia , Fagocitose , Animais , Células da Medula Óssea/citologia , Células Cultivadas , Interleucina-10/metabolismo , Subunidade p40 da Interleucina-12/metabolismo , Interleucina-1beta/metabolismo , Macrófagos Peritoneais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Óxido Nítrico/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
2.
Pathogens ; 12(8)2023 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-37624013

RESUMO

Pseudomonas aeruginosa (P. aeruginosa) is an opportunistic pathogen and the leading cause of infection in patients with cystic fibrosis (CF). The ability of P. aeruginosa to evade host responses and develop into chronic infection causes significant morbidity and mortality. Several mouse models have been developed to study chronic respiratory infections induced by P. aeruginosa, with the bead agar model being the most widely used. However, this model has several limitations, including the requirement for surgical procedures and high mortality rates. Herein, we describe novel and adapted biologically relevant models of chronic lung infection caused by P. aeruginosa. Three methods are described: a clinical isolate infection model, utilising isolates obtained from patients with CF; an incomplete antibiotic clearance model, leading to bacterial bounce-back; and the establishment of chronic infection; and an adapted water bottle chronic infection model. These models circumvent the requirement for a surgical procedure and, importantly, can be induced with clinical isolates of P. aeruginosa and in wild-type mice. We also demonstrate successful induction of chronic infection in the transgenic ßENaC murine model of CF. We envisage that the models described will facilitate the investigations of host and microbial factors, and the efficacy of novel antimicrobials, during chronic P. aeruginosa respiratory infections.

3.
J Biol Chem ; 286(5): 3915-24, 2011 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-21127042

RESUMO

Although members of the p63 family of transcription factors are known for their role in the development and differentiation of epithelial surfaces, their function in cancer is less clear. Here, we show that depletion of the ΔNp63α and ß isoforms, leaving only ΔNp63γ, results in epithelial to mesenchymal transition (EMT) in the normal breast cell line MCF10A. EMT can be rescued by the expression of the ΔNp63α isoform. We also show that ΔNp63γ expressed in a background where all the other ΔNp63 are knocked down causes EMT with an increase in TGFß-1, -2, and -3 and downstream effectors Smads2/3/4. In addition, a p63 binding site in intron 1 of TGFß was identified. Inhibition of the TGFß response with a specific inhibitor results in reversion of EMT in ΔNp63α- and ß-depleted cells. In summary, we show that p63 is involved in inhibiting EMT and reduction of certain p63 isoforms may be important in the development of epithelial cancers.


Assuntos
Transição Epitelial-Mesenquimal/genética , Regulação Neoplásica da Expressão Gênica , Proteínas Smad/genética , Transativadores/fisiologia , Fator de Crescimento Transformador beta/genética , Proteínas Supressoras de Tumor/fisiologia , Sítios de Ligação , Neoplasias da Mama/etiologia , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Humanos , Neoplasias Epiteliais e Glandulares/etiologia , Isoformas de Proteínas , Transativadores/metabolismo , Fatores de Transcrição , Proteínas Supressoras de Tumor/metabolismo , Regulação para Cima
4.
Environ Microbiol ; 10(3): 702-8, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18237305

RESUMO

The neurotoxic amino acid, beta-N-methylamino-L-alanine, was found to be present in all of 12 analysed samples of cyanobacterial blooms, scums and mats, which had been collected in seven years between 1990 and 2004 inclusive and stored at -20 degrees C. BMAA identification was by high performance liquid chromatography with fluorescence detection and by triple quadrapole mass spectrometry after derivatization. The samples originated from 11 freshwater lakes and 1 brackish waterbody, used either for drinking water, recreation, or both. BMAA was present at between 8 and 287 microg g(-1) cyanobacterial dry weight and was present as both the free amino acid and associated with precipitated proteins. Ten of the samples contained additional cyanotoxins (including microcystins, anatoxin-a, nodularin and saxitoxin) at the time of sample collection. Five of the samples were associated with animal deaths, attributable at the time of sample collection, to microcystins, nodularin or anatoxin-a. The data demonstrate the presence of BMAA by high performance liquid chromatography and mass spectrometry in a diverse range of cyanobacterial bloom samples from high resource waterbodies. Furthermore, samples collected over several years shows that BMAA can co-occur with other known cyanotoxins in such waterbodies. Health risk assessment of cyanobacterial BMAA in waterbodies is suggested.


Assuntos
Diamino Aminoácidos/biossíntese , Toxinas Bacterianas/biossíntese , Toxinas Bacterianas/química , Cianobactérias/metabolismo , Toxinas Marinhas/análise , Microcistinas/biossíntese , Microcistinas/química , Microbiologia da Água , Poluentes da Água/toxicidade , Diamino Aminoácidos/química , Cromatografia Líquida de Alta Pressão/métodos , Cianobactérias/química , Toxinas de Cianobactérias , Toxinas Marinhas/biossíntese , Toxinas Marinhas/química , Neurotoxinas/biossíntese , Neurotoxinas/toxicidade , Espectrofotometria Ultravioleta , Poluentes da Água/análise
5.
Mol Biol Cell ; 19(6): 2566-78, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18367547

RESUMO

The PC12 pheochromocytoma cell line responds to nerve growth factor (NGF) by exiting from the cell cycle and differentiating to induce extending neurites. Cyclin D1 is an important regulator of G1/S phase cell cycle progression, and it is known to play a role in myocyte differentiation in cultured cells. Herein, NGF induced cyclin D1 promoter, mRNA, and protein expression via the p21(RAS) pathway. Antisense- or small interfering RNA to cyclin D1 abolished NGF-mediated neurite outgrowth, demonstrating the essential role of cyclin D1 in NGF-mediated differentiation. Expression vectors encoding mutants of the Ras/mitogen-activated protein kinase pathway, and chemical inhibitors, demonstrated NGF induction of cyclin D1 involved cooperative interactions of extracellular signal-regulated kinase, p38, and phosphatidylinositol 3-kinase pathways downstream of p21(RAS). NGF induced the cyclin D1 promoter via Sp1, nuclear factor-kappaB, and cAMP-response element/activated transcription factor sites. NGF induction via Sp1 involved the formation of a Sp1/p50/p107 complex. Cyclin D1 induction by NGF governs differentiation and neurite outgrowth in PC12 cells.


Assuntos
Ciclina D1/genética , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , NF-kappa B/metabolismo , Fator de Crescimento Neural/farmacologia , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Fator de Transcrição Sp1/metabolismo , Animais , Sequência de Bases , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Ciclina D1/metabolismo , Humanos , Camundongos , Subunidade p50 de NF-kappa B/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/enzimologia , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Regiões Promotoras Genéticas/genética , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , RNA Interferente Pequeno/metabolismo , Ratos , Proteína p107 Retinoblastoma-Like/metabolismo , Transcrição Gênica/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno
6.
Clin Transl Sci ; 1(2): 107-15, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20443831

RESUMO

The ErbB2 (Her2/neu epidermal growth receptor family) oncogene is overexpressed in 30% to 40% of human breast cancers. Cyclin D1 is the regulatory subunit of the holoenzyme that phosphorylates and inactivates the retinoblastoma (pRb) tumor suppressor and is an essential downstream target of ErbB2-induced tumor growth. Herein, we demonstrate that ErbB2 induces the activity of the Notch signaling pathway. ErbB2 induction of DNA synthesis, contact-independent growth, and mammosphere induction required Notch1. ErbB2-induced cyclin D1 and cyclin D1 expression was suficient to induce Notch1 activity, and conversely, genetic deletion of Notch1 in mammary epithelial cells using foxed Notch (Notch(fl/fl)) mice demonstrated that cyclin D1 is induced by Notch1. Genetic deletion of cyclin D1 or small interfering RNA (siRNA) to cyclin D1-reduced Notch1 activity and reintroduction of cyclin D1 into cyclin D1-deficient cells restored Notch1 activity through the inhibition of Numb, an endogenous inhibitor of Notch1 activity. Thus, cyclin D1 functions downstream as a genetic target of Notch1, amplifies Notch1 activity by repressing Numb, and identifies a novel pathway by which ErbB2 induces Notch1 activity via the induction of cyclin D1.


Assuntos
Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor Notch1/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ciclina D1/metabolismo , DNA de Neoplasias/biossíntese , Feminino , Humanos , Camundongos , Neuregulina-1/metabolismo , Transdução de Sinais , Ensaio Tumoral de Célula-Tronco
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