Search results for " alpha"
showing 10 items of 1610 documents
A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Can…
2017
AbstractSomatic mutations of the Estrogen Receptor α (ERα) occur with an up to 40% incidence in ER sensitive breast cancer (BC) patients undergoing prolonged endocrine treatments. These polymorphisms are implicated in acquired resistance, disease relapse, and increased mortality rates, hence representing a current major clinical challenge. Here, multi-microseconds (12.5 µs) molecular dynamics simulations revealed that recurrent ERα polymorphisms (i. e. L536Q, Y537S, Y537N, D538G) (mERα) are constitutively active in their apo form and that they prompt the selection of an agonist (active)-like conformation even upon antagonists binding. Interestingly, our simulations rationalize, for the firs…
TRAIL–NP hybrids for cancer therapy: a review
2017
IF 7.367; International audience; Cancer is a worldwide health problem. It is now considered as a leading cause of morbidity and mortality in developed countries. In the last few decades, considerable progress has been made in anti-cancer therapies, allowing the cure of patients suffering from this disease, or at least helping to prolong their lives. Several cancers, such as those of the lung and pancreas, are still devastating in the absence of therapeutic options. In the early 90s, TRAIL (Tumor Necrosis Factor-related apoptosis-inducing ligand), a cytokine belonging to the TNF superfamily, attracted major interest in oncology owing to its selective anti-tumor properties. Clinical trials u…
Estradiol, acting through ERα, induces endothelial non-classic renin-angiotensin system increasing angiotensin 1–7 production
2016
Intracellular renin-angiotensin system (RAS) can operate independently of the circulating RAS. Estrogens provide protective effects by modulating the RAS. Our aim was to investigate the effect of estradiol (E2) on angiotensin converting enzymes (ACE) 1 and ACE2 expression and activities in human endothelial cells (HUVEC), and the role of estrogen receptors (ER). The results confirmed the presence of active intracellular RAS in HUVEC. Physiological concentrations of E2 induced a concentration-dependent increase of ACE1 and ACE2 mRNA expression and ACE1, but not ACE2, protein levels. ACE1 and ACE2 enzymatic activities were also induced with E2. These effects were mediated through ERα activati…
The Role of Osteoprotegerin and Its Ligands in Vascular Function
2019
International audience; The superfamily of tumor necrosis factor (TNF) receptors includes osteoprotegerin (OPG) and its ligands, which are receptor activators of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL). The OPG/RANKL/RANK system plays an active role in pathological angiogenesis and inflammation as well as cell survival. It has been demonstrated that there is crosstalk between endothelial cells and osteoblasts during osteogenesis, thus establishing a connection between angiogenesis and osteogenesis. This OPG/RANKL/RANK/TRAIL system acts on specific cell surface receptors, which are then able to transmit their signals to other intracellular comp…
Crosstalk between angiotensin and the nonamyloidogenic pathway of Alzheimer's amyloid precursor protein.
2017
The association between hypertension and an increased risk for Alzheimer's disease (AD) and dementia is well established. Many data suggest that modulation of the renin-angiotensin system may be meaningful for the prevention and therapy of neurodegenerative disorders, in particular AD. Proteolytic cleavage of the amyloid precursor protein (APP) by α-secretase precludes formation of neurotoxic Aβ peptides and is expected to counteract the development of AD. An established approach for the up-regulation of α-secretase cleavage is the activation of G protein-coupled receptors (GPCRs). Therefore, our study aimed to analyze whether stimulation of angiotensin AT1 or AT2 receptors stably expressed…
Pinolenic acid ameliorates oleic acid-induced lipogenesis and oxidative stress via AMPK/SIRT1 signaling pathway in HepG2 cells
2019
Pinolenic acid (PLA), a natural compound isolated from pine nut oil, has been reported to exert bioactivity against lipid anabolism. Nonetheless, the underlying mechanisms still poorly elucidated. The aim of this study is to comprehensively demonstrate the effects of PLA on oleic acid (OA)-induced non-alcoholic fatty liver disease (NAFLD) and their relationship with the lipid metabolic regulation. The results demonstrated that treatment with PLA dramatically inhibited lipid accumulation, oxidative stress as well as inflammatory responses induced by oleic acid in HepG2 cells. PLA also obviously decreased the levels of cellular triglyceride (TG), total cholesterol (TC), malondialdehyde (MDA),…
Evaluation of Antioxidant, Anti-Inflammatory and Cytoprotective Properties of Ethanolic Mint Extracts from Algeria on 7-Ketocholesterol-Treated Murin…
2018
The present study consisted in evaluating the antioxidant, anti-inflammatory and cytoprotective properties of ethanolic extracts from three mint species (Mentha spicata L. (MS), Mentha pulegium L. (MP) and Mentha rotundifolia (L.) Huds (MR)) with biochemical methods on murine RAW 264.7 macrophages (a transformed macrophage cell line isolated from ascites of BALB/c mice infected by the Abelson leukemia virus). The total phenolic, flavonoid and carotenoid contents were determined with spectrophotometric methods. The antioxidant activities were quantified with the Kit Radicaux Libres (KRLTM), the ferric reducing antioxidant power (FRAP) and the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assays. The …
Mutant p53 induces Golgi tubulo-vesiculation driving a prometastatic secretome
2020
TP53 missense mutations leading to the expression of mutant p53 oncoproteins are frequent driver events during tumorigenesis. p53 mutants promote tumor growth, metastasis and chemoresistance by affecting fundamental cellular pathways and functions. Here, we demonstrate that p53 mutants modify structure and function of the Golgi apparatus, culminating in the increased release of a pro-malignant secretome by tumor cells and primary fibroblasts from patients with Li-Fraumeni cancer predisposition syndrome. Mechanistically, interacting with the hypoxia responsive factor HIF1α, mutant p53 induces the expression of miR-30d, which in turn causes tubulo-vesiculation of the Golgi apparatus, leading …
H-ferritin and proinflammatory cytokines are increased in the bone marrow of patients affected by macrophage activation syndrome
2017
Summary Macrophage activation syndrome (MAS) is hyperinflammatory life-threatening syndrome, associated typically with high levels of serum ferritin. This is an iron storage protein including heavy (H) and light (L) subunits, categorized on their molecular weight. The H-/L subunits ratio may be different in tissues, depending on the specific tissue and pathophysiological status. In this study, we analysed the bone marrow (BM) biopsies of adult MAS patients to assess the presence of: (i) H-ferritin and L-ferritin; (ii) CD68+/H-ferritin+ and CD68+/L-ferritin+; and (iii) interleukin (IL)-1β, tumour necrosis factor (TNF) and interferon (IFN)-γ. We also explored possible correlations of these re…
Mast cells contribute to autoimmune diabetes by releasing interleukin-6 and failing to acquire a tolerogenic IL-10+ phenotype
2017
Mast cells (MCs) are innate immune cells that exert positive and negative immune modulatory functions capable to enhance or limit the intensity and/or duration of adaptive immune responses. Although MCs are crucial to regulate T cell immunity, their action in the pathogenesis of autoimmune diseases is still debated. Here we demonstrate that MCs play a crucial role in T1D pathogenesis so that their selective depletion in conditional MC knockout NOD mice protects them from the disease. MCs of diabetic NOD mice are overly inflammatory and secrete large amounts of IL-6 that favors differentiation of IL-17-secreting T cells at the site of autoimmunity. Moreover, while MCs of control mice acquire…