Curcumin induces heme oxygenase-1 in normal human skin fibroblasts through redox signaling: relevance for anti-aging intervention

Scope: Curcumin, a component of the spice turmeric, was tested for its potential hormetic anti-aging effects as an inducer of mild stress. Methods and results: Early passage young human skin fibroblasts treated with low doses of curcumin (below 20μM) showed a time- and concentration-dependent induction of heme oxygenase-1 (HO-1), followed by compensatory increase in glutathione-S-transferase activity, GSH levels and GSH/GSSG ratio. These effects were preceded by induction of oxidative stress (increased levels of reactive oxygen species and DNA damage) and impairment of cells' GSH redox state. Curcumin also induced nuclear factor-erythroid-2-related factor 2 accumulation in the nuclei. The use of the antioxidant N-acetyl cysteine prevented the induction of HO-1 by curcumin. Pharmacological inhibition of phosphatidylinositol 3-kinase, but not other kinases, significantly prevented curcumin-induced HO-1 levels, which was corroborated by the induction of phospho-Akt levels by curcumin. Late passage senescent cells already had higher HO-1 levels, and further induction of HO-1 by curcumin was considerably impaired. The induction of stress responses by curcumin in human cells led to protective hormetic effects to further oxidant challenge. Conclusion: Curcumin induces cellular stress responses in normal human skin fibroblasts through phosphatidylinositol 3-kinase/Akt pathway and redox signaling, supporting the view that curcumin-induced hormetic stimulation of cellular antioxidant defenses can be a useful approach toward anti-aging intervention.União Europeia. Fundo Europeu de Desenvolvimento Regional (FEDER) - programa COMPETE (QREN)Fundação para a Ciência e a Tecnologia (FCT) - bolsa PTDC/QUI-BIQ/101392/2008 (NaturAge)

A potent nonporphyrin class of photodynamic therapeutic agent: cellular localisation, cytotoxic potential and influence of hypoxia

We have developed a totally new class of nonporphyrin photodynamic therapeutic agents with a specific focus on two lead candidates azadipyrromethene (ADPM)01 and ADPM06. Confocal laser scanning microscopy imaging showed that these compounds are exclusively localised to the cytosolic compartment, with specific accumulation in the endoplasmic reticulum and to a lesser extent in the mitochondria. Light-induced toxicity assays, carried out over a broad range of human tumour cell lines, displayed EC50 values in the micro-molar range for ADPM01 and nano-molar range for ADPM06, with no discernable activity bias for a specific cell type. Strikingly, the more active agent, ADPM06, even retained significant activity under hypoxic conditions. Both photosensitisers showed low to nondeterminable dark toxicity. Flow cytometric analysis revealed that ADPM01 and ADPM06 were highly effective at inducing apoptosis as a mode of cell death. The photophysical and biological characteristics of these PDT agents suggest that they have potential for the development of new anticancer therapeutics

The multifaceted role of curcumin in cancer prevention and treatment

Despite significant advances in treatment modalities over the last decade, neither the incidence of the disease nor the mortality due to cancer has altered in the last thirty years. Available anti-cancer drugs exhibit limited efficacy, associated with severe side effects, and are also expensive. Thus identification of pharmacological agents that do not have these disadvantages is required. Curcumin, a polyphenolic compound derived from turmeric (Curcumin longa), is one such agent that has been extensively studied over the last three to four decades for its potential anti-inflammatory and/or anti-cancer effects. Curcumin has been found to suppress initiation, progression, and metastasis of a variety of tumors. These anti-cancer effects are predominantly mediated through its negative regulation of various transcription factors, growth factors, inflammatory cytokines, protein kinases, and other oncogenic molecules. It also abrogates proliferation of cancer cells by arresting them at different phases of the cell cycle and/or by inducing their apoptosis. The current review focuses on the diverse molecular targets modulated by curcumin that contribute to its efficacy against various human cancers

Curcumin―The Paradigm of a Multi-Target Natural Compound with Applications in Cancer Prevention and Treatment

As cancer is a multifactor disease, it may require treatment with compounds able to target multiple intracellular components. We summarize here how curcumin is able to modulate many components of intracellular signaling pathways implicated in inflammation, cell proliferation and invasion and to induce genetic modulations eventually leading to tumor cell death. Clinical applications of this natural compound were initially limited by its low solubility and bioavailability in both plasma and tissues but combination with adjuvant and delivery vehicles was reported to largely improve bio-availability of curcumin. Moreover, curcumin was reported to act in synergism with several natural compounds or synthetic agents commonly used in chemotherapy. Based on this, curcumin could thus be considered as a good candidate for cancer prevention and treatment when used alone or in combination with other conventional treatments

Curcuminoid Binding to Embryonal Carcinoma Cells: Reductive Metabolism, Induction of Apoptosis, Senescence, and Inhibition of Cell Proliferation

Curcumin preparations typically contain a mixture of polyphenols, collectively referred to as curcuminoids. In addition to the primary component curcumin, they also contain smaller amounts of the co-extracted derivatives demethoxycurcumin and bisdemethoxycurcumin. Curcuminoids can be differentially solubilized in serum, which allows for the systematic analysis of concentration-dependent cellular binding, biological effects, and metabolism. Technical grade curcumin was solubilized in fetal calf serum by two alternative methods yielding saturated preparations containing either predominantly curcumin (60%) or bisdemethoxycurcumin (55%). Continual exposure of NT2/D1 cells for 4–6 days to either preparation in cell culture media reduced cell division (1–5 µM), induced senescence (6–7 µM) or comprehensive cell death (8–10 µM) in a concentration-dependent manner. Some of these effects could also be elicited in cells transiently exposed to higher concentrations of curcuminoids (47 µM) for 0.5–4 h. Curcuminoids induced apoptosis by generalized activation of caspases but without nucleosomal fragmentation. The equilibrium binding of serum-solubilized curcuminoids to NT2/D1 cells incubated with increasing amounts of curcuminoid-saturated serum occurred with apparent overall dissociation constants in the 6–10 µM range. However, the presence of excess free serum decreased cellular binding in a hyperbolic manner. Cellular binding was overwhelmingly associated with membrane fractions and bound curcuminoids were metabolized in NT2/D1 cells via a previously unidentified reduction pathway. Both the binding affinities for curcuminoids and their reductive metabolic pathways varied in other cell lines. These results suggest that curcuminoids interact with cellular binding sites, thereby activating signal transduction pathways that initiate a variety of biological responses. The dose-dependent effects of these responses further imply that distinct cellular pathways are sequentially activated and that this activation is dependent on the affinity of curcuminoids for the respective binding sites. Defined serum-solubilized curcuminoids used in cell culture media are thus suitable for further investigating the differential activation of signal transduction pathways

Evaluation des prises en charge des méningites aigués communautaires au CHU de Brest chez les patients de plus de 16 ans du 20 novembre 2008 au 31decembre 2010

Nous avons conduit une étude rétrospective observationnelle de la prise en charge des méningites aigües communautaires au CHU de Brest : analyse épidémiologique et évaluation de la prise en charge initiale selon la conférence de consensus de 2008. Soixante deux patients ont été colligés. Les résultats montrent une variabilité clinique et biologique rendant le diagnostic de méningite bactérienne difficile. L'instauration de l'antibiothérapie urgente est retardée par un excès de prescriptions de scanners cérébraux avant ponction lombaire. Les modalités de prescription de la corticothérapie adjuvante aux méningites purulentes sont mal connues. L'utilisation d'aides para-cliniques au diagnostic (score de Hoen, lactates dans le LCR) ne sont jamais utilisées permettraient d'éviter des antibiothérapies inutiles (40%). Les posologies à dose méningée des antibiotiques et antiviraux sont respectées. Cette étude démontre la nécessité de diffuser les recommandations de 2008 en informant le personnel des urgences pour optimiser leur prises en charge.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF