Regulation of COX-2 protein expression by Akt in endometrial cancer cells is mediated through NF-κB/IκB pathway

BACKGROUND: Cyclooxygenase-2 (COX-2) has been shown to be highly expressed in a broad series of primary endometrial tumors and its expression may be closely associated with parameters of tumor aggressiveness. In human endometrial cancer, tumor suppressor phosphatase tensin homologue (PTEN) is frequently mutated. In the presence of a mutated PTEN protein, Akt phosphorylation levels increase leading to the activation of this survival pathway. The nuclear transcription factor κB (NF-κB) is a well establish regulator of genes encoding cytokines, cytokine receptors, and cell adhesion molecules that drive immune and inflammatory responses. More recently, NF-κB activation has been connected with multiple aspects of oncogenesis, including the control of apoptosis, cell cycle, differentiation, and cell migration. It is known that Akt may act through NF-κB pathway and that COX-2 gene has been shown to be regulated at the promoter level by NF-κB. Recently, we showed that Akt regulates COX-2 gene and protein expressions in phospho-Akt expressing endometrial cancer cells. The present study was undertaken to determine the involvement of NF-κB pathway and IκB (an inhibitor of NF-κB) in the regulation of COX-2 expression and to determine more precisely the downstream targets of Akt involved in this process. RESULTS: Three different human endometrial cancer cell lines known to have wild type PTEN (HEC 1-A) or a mutated inactive PTEN protein (RL 95-2 and Ishikawa) were used for these studies. Expression IκB and Phospho-IκB were evaluated by Western analysis. The presence of IκB phosphorylation was found in all cell lines studied. There was no difference between cell lines in term of NF-κB abundance. Inhibition of PI 3-K with Wortmannin and LY294002 blocked IκB phosphorylation, reduced NF-κB nuclear activity, reduced COX-2 expression and induced apoptosis. Transfection studies with a dominant negative Akt vector blocked IκB phosphorylation and reduced COX-2 expression. On the opposite, constitutively active Akt transfections resulted in the induction of IκB phosphorylation and up-regulation of COX-2. CONCLUSION: These results demonstrate that Akt signals through NF-κB/IκB pathway to induce COX-2 expression in mutated PTEN endometrial cancer cells

Natural killer cell behavior in lymph nodes revealed by static and real-time imaging

Natural killer (NK) cells promote dendritic cell (DC) maturation and influence T cell differentiation in vitro. To better understand the nature of the putative interactions among these cells in vivo during the early phases of an adaptive immune response, we have used immunohistochemical analysis and dynamic intravital imaging to study NK cell localization and behavior in lymph nodes (LNs) in the steady state and shortly after infection with Leishmania major. In the LNs of naive mice, NK cells reside in the medulla and the paracortex, where they closely associate with DCs. In contrast to T cells, intravital microscopy revealed that NK cells in the superficial regions of LNs were slowly motile and maintained their interactions with DCs over extended times in the presence or absence of immune-activating signals. L. major induced NK cells to secrete interferon-γ and to be recruited to the paracortex, where concomitant CD4 T cell activation occurred. Therefore, NK cells form a reactive but low mobile network in a strategic area of the LN where they can receive inflammatory signals, interact with DCs, and regulate colocalized T cell responses

The mitochondrial peptidase, neurolysin, regulates respiratory chain supercomplex formation and is necessary for AML viability

Neurolysin (NLN) is a zinc metallopeptidase whose mitochondrial function is unclear. We found that NLN was overexpressed in almost half of patients with acute myeloid leukemia (AML), and inhibition of NLN was selectively cytotoxic to AML cells and stem cells while sparing normal hematopoietic cells. Mechanistically, NLN interacted with the mitochondrial respiratory chain. Genetic and chemical inhibition of NLN impaired oxidative metabolism and disrupted the formation of respiratory chain supercomplexes (RCS). Furthermore, NLN interacted with the known RCS regulator, LETM1, and inhibition of NLN disrupted LETM1 complex formation. RCS were increased in patients with AML and positively correlated with NLN expression. These findings demonstrate that inhibiting RCS formation selectively targets AML cells and stem cells and highlights the therapeutic potential of pharmacologically targeting NLN in AML

A three-dimensional atlas of human dermal leukocytes, lymphatics, and blood vessels.

Dendritic cells (DCs), macrophages (Mφ), and T cells are major components of the skin immune system, but their interstitial spatial organization is poorly characterized. Using four-channel whole-mount immunofluorescence staining of the human dermis, we demonstrated the three-dimensional distribution of CD31(+) blood capillaries, LYVE-1(+) lymphatics, discrete populations of CD11c(+) myeloid DCs, FXIIIa(+) Mφ, and lymphocytes. We showed phenotypic and morphological differences in situ between DCs and Mφ. DCs formed the first dermal cellular layer (0-20 μm beneath the dermoepidermal junction), Mφ were located deeper (40-60 μm), and CD3(+) lymphocytes were observed throughout (0-60 μm). Below this level, DCs, T cells, and the majority of Mφ formed stable perivascular sheaths. Whole-mount imaging revealed the true extent of dermal leukocytes previously underestimated from cross-section views. The total area of apical dermis (0-30 μm) contained approximately 10-fold more myeloid DCs than the entire blood volume of an average individual. Surprisingly, <1% of dermal DCs occupied lymphatics in freshly isolated skin. Dermal DCs rapidly accumulated within lymphatics, but Mφ remained fixed in skin explants cultured ex vivo. The leukocyte architecture observed in normal skin was distorted in inflammation and disease. These studies illustrate the micro-anatomy of dermal leukocytes and provide further insights into their functional organization

DC mobilization from the skin requires docking to immobilized CCL21 on lymphatic endothelium and intralymphatic crawling

Dermal DC mobilization requires docking to CCL21 on lymphatic endotheliu

Anxiolytic and Antiepileptic Properties of the Aqueous Extract of Cissus quadrangularis (Vitaceae) in Mice Pilocarpine Model of Epilepsy

Cissus quadrangularis (C. quadrangularis) is a plant of the Vitaceae family known for its anticonvulsant effects in traditional medicine. The objective of this study was to elucidate the anxiolytic and antiepileptic effects of aqueous extract of C. quadrangularis. The mice were divided into different groups and treated for seven consecutive days as follows: a negative control group that received distilled water, po, four test groups that received four doses of the plant (37.22, 93.05, 186.11, and 372.21 mg/kg, po), and a positive control group that received sodium valproate (300 mg/kg, ip). One hour after the first treatment (first day), epilepsy was induced by intraperitoneal administration of a single dose of pilocarpine (360 mg/kg). On the seventh day, the anxiolytic effects of the extract were evaluated in the epileptic mice using the elevated plus maze (EPM) and open field (OP) paradigms. Antioxidant activities and the involvement of gabaergic neurotransmission were determined by measuring the levels of malondialdehyde, reduced glutathione (GSH), GABA, and GABA-transaminase (GABA-T) in the hippocampus of sacrificed epileptic mice. The results show that the extract of C. quadrangularis significantly and dose-dependently increased the latency to clonic and generalized tonic–clonic seizures and decreased the number and duration of seizures. In the EPM, the extract of C. quadrangularis significantly increased the number of entries and the time spent into the open arms and reduced the number of entries and the time spent into the closed arms as well as the number of rearing. The extract of C. quadrangularis also increased the number of crossing, and the time spent in the center of the OP. The level of MDA and the activity of GABA-T were significantly decreased by the extract of C. quadrangularis while reduced GSH and GABA levels were increased. The results suggest that the anticonvulsant activities of C. quadrangularis are accompanied by its anxiolytics effects. These effects may be supported by its antioxidant properties and mediated at least in part by the GABA neurotransmission

La récupération du nom propre d'une personne : éléments fondamentaux sur les informations sémantiques en mémoire et éléments appliqués pour la prise en charge de la maladie d'Elzheimer.

Pouvoir identifier la personne en face de soi et être capable de retrouver son nom apparaissent des activités indispensables aux interactions sociales quotidiennes. Or, le nom propre s‟avère être une information spécifique comparée aux autres informations disponibles sur une personne. La récupération de cette information est souvent décrite comme difficile. Pour autant, si les auteurs s‟accordent sur la spécificité du nom propre, l‟examen de l‟organisation en mémoire du nom propre et des informations sémantiques liées aux personnes sera l‟objet de ce travail. De plus, l‟accès aux informations sémantiques s‟avère déficitaire dans la maladie d‟Alzheimer.Une première expérience a permis d‟élaborer un matériel normé sur 210 visages/noms, permettant la sélection précise de stimuli. Afin d'étudier la question de l‟organisation en mémoire des informations sémantiques et plus particulièrement l‟information nom propre, deux études comportementales et trois études électrophysiologiques ont été menées. Dans les deux dernières études, nous avons travaillé sur l‟apprentissage et le maintien en mémoire de l‟information spécifique nom propre auprès d‟une population Alzheimer. La discussion des différents résultats s‟appuie sur les connaissances théoriques actuelles sur le sujet.Being able to identify the person in front of us and being able to remember his or her name appear to be essential activities to daily social interactions. However, compared to other available information related to a person, the proper name seems to be specific information. Proper name retrieval has been very often described as particularly difficult. Although this work aims to study the organization of semantic information in memory, and more specifically the proper name information. Moreover, access to semantic information is known be deficient for Alzheimer disease.A first study has allowed to develope out a standardized material of 210 faces/names, permitting an accurate selection of stimuli. Two behavioural and three electrophysiological studies have been carried out to study the organization of semantic information in memory, and more specifically the proper name. For the last two experiments, we have worked on learning and how to keep specific information « proper name » into memory for Alzheimer‟s disease patients. Discussion of the different results is based on current theorical knowledge on the subject

Functional analysis of PTEN-like gene homologues from Arabidopsis thaliana

National audienc

Functional analysis of mammalian PTEn-like homologs from Arabidopsis thaliana : which roles in plants ?

National audienc