7-ketocholesterol and 7β-hydroxycholesterol: in vitro and animal models used to characterize their activities and to identify molecules preventing their toxicity

International audience; Oxysterols are molecules derived by the oxidation of cholesterol and can be formed either by auto-oxidation, enzymatically or by both processes. Among the oxysterols formed by auto-oxidation, 7-ketocholesterol and 7beta-hydroxycholesterol are the main forms generated. These oxysterols, formed endogenously and brought in large quantities by certain foods, have major cytotoxic properties. They are powerful inducers of oxidative stress, inducing dysfunction of organelles (mitochondria, lysosomes and peroxisomes) that can cause cell death. These molecules are often identified in increased amounts in common pathological states such as cardiovascular diseases, certain eye …

Prevention of 7-ketocholesterol-induced side effects by natural compounds

Cholesterol oxidation products, also named oxysterols, can be formed either by cholesterol auto-oxidation, enzymatically or both. Among these oxysterols, 7-ketocholesterol (7KC) is mainly formed during radical attacks that take place on the carbon 7 of cholesterol. As increased levels of 7KC have been found in the tissues, plasma and/or cerebrospinal fluid of patients with major diseases, especially age-related diseases (cardiovascular diseases, eye diseases, neurodegenerative diseases), some cancers, and chronic inflammatory diseases, it is suspected that 7KC, could contribute to their development. Since 7KC, provided by the diet or endogenously formed, is not or little efficiently metabol…

Absence of correlation between oxysterol accumulation in lipid raft microdomains, calcium increase, and apoptosis induction on 158N murine oligodendrocytes.

There is some evidence that oxidized derivatives of cholesterol, 7-ketocholesterol (7KC) and 7β-hydroxycholesterol (7βOHC), are increased in the plasma of patients with neurodegenerative diseases associated with demyelinization of the central nervous system (CNS). It was therefore of interest to investigate the effects of these oxysterols on oligodendrocytes, the myelin-forming cells in the CNS. To this end, 158N murine oligodendrocytes were treated with 7KC or 7βOHC inducing an apoptotic mode of cell death characterized by condensation/fragmentation of the nuclei, dephosphorylation of Akt and GSK3, mitochondrial depolarization involving Mcl-1, and caspase-3 activation. In contrast, under t…

Argan oil prevents down-regulation induced by endotoxin on liver fatty acid oxidation and gluconeogenesis and on peroxisome proliferator-activated receptor gamma coactivator-1 alpha, (PGC-1alpha), peroxisome proliferator-activated receptor gamma (PPARgamma) and estrogen related receptor alpha (ERRalpha)

In patients with sepsis, liver metabolism and its capacity to provide other organs with energetic substrates are impaired. This and many other pathophysiological changes seen in human patients are reproduced in mice injected with purified endotoxin (lipopolysaccharide, LPS). In the present study, down-regulation of genes involved in hepatic fatty acid oxidation (FAOx) and gluconeogenesis in mice exposed to LPS was challenged by nutritional intervention with Argan oil. Mice given a standard chow supplemented or not with either 6% (w/w) Argan oil (AO) or 6% (w/w) olive oil (OO) prior to exposure to LPS were explored for liver gene expressions assessed by mRNA transcript levels and/or enzyme a…

Prevention of 7-Ketocholesterol-Induced Overproduction of Reactive Oxygen Species, Mitochondrial Dysfunction and Cell Death with Major Nutrients (Polyphenols, ω3 and ω9 Unsaturated Fatty Acids) of the Mediterranean Diet on N2a Neuronal Cells

The brain, which is a cholesterol-rich organ, can be subject to oxidative stress in a variety of pathophysiological conditions, age-related diseases and some rare pathologies. This can lead to the formation of 7-ketocholesterol (7KC), a toxic derivative of cholesterol mainly produced by auto-oxidation. So, preventing the neuronal toxicity of 7KC is an important issue to avoid brain damage. As there are numerous data in favor of the prevention of neurodegeneration by the Mediterranean diet, this study aimed to evaluate the potential of a series of polyphenols (resveratrol, RSV

Evidence of oxidative stress in very long chain fatty acid--treated oligodendrocytes and potentialization of ROS production using RNA interference-directed knockdown of ABCD1 and ACOX1 peroxisomal proteins.

X-linked adrenoleukodystrophy (X-ALD) and pseudo neonatal adrenoleukodystrophy (P-NALD) are neurodegenerative demyelinating diseases resulting from the functional loss of the peroxisomal ATP-binding cassette transporter D (ABCD1) and from single peroxisomal enzyme deficiency (Acyl-CoA oxidase1: ACOX1), respectively. As these proteins are involved in the catabolism of very long chain fatty acids (VLCFA: C24:0, C26:0), X-ALD and P-NALD patients are characterized by the accumulation of VLCFA in plasma and tissues. Since peroxisomes are involved in the metabolism of reactive oxygen species (ROS) and nitrogen species (RNS), we examined the impact of VLCFA on the oxidative status of 158N murine o…

Comparison of chemical composition and biological activities of Algerian seed oils of Pistacia lentiscus L., Opuntia ficus indica (L.) mill. and Argania spinosa L. Skeels

Abstract Many parameters can influence the chemical profiles and the biological activities of seed oils. It was therefore of interest to study Algerian seed oils, whose caharacteristics are not well known. So, the physicochemical properties and nutrient profiles (fatty acids, phytosterols, polyphenols) of seed oils from Pistacia lentiscus L. (PL), Opuntia ficus-indica (L.) mill. (OFI), and Argania spinosa L. Skeels (AS) were determined. The antioxidant and antimicrobial activities of the oils were also characterized. The physicochemical parameters of the oils are closely related to the standard values. PL oil is distinguished by its high content of pigments. AS and OFI oils were dominated b…

Prevention by Dietary Polyphenols (Resveratrol, Quercetin, Apigenin) Against 7-Ketocholesterol-Induced Oxiapoptophagy in Neuronal N2a Cells: Potential Interest for the Treatment of Neurodegenerative and Age-Related Diseases.

The Mediterranean diet is associated with health benefits due to bioactive compounds such as polyphenols. The biological activities of three polyphenols (quercetin (QCT), resveratrol (RSV), apigenin (API)) were evaluated in mouse neuronal N2a cells in the presence of 7-ketocholesterol (7KC), a major cholesterol oxidation product increased in patients with age-related diseases, including neurodegenerative disorders. In N2a cells, 7KC (50 &micro

Impact of 7-Ketocholesterol and Very Long Chain Fatty Acids on Oligodendrocyte Lipid Membrane Organization: Evaluation Via LAURDAN and FAMIS Spectral Image Analysis

International audience; In the context of multiple sclerosis and X-linked adrenoleukodystrophy, 7-ketocholesterol (7KC) and very long chain fatty acids (C24:0, C26:0) are supposed to induce side effects respectively on oligodendrocytes which are myelin (which is a lipoproteic complex) synthesizing cells. The effects of 7KC (25, 50 mu M), C24:0 and C26:0 (10, 20 mu M) on cell viability and lipid membrane organization were investigated on 158N murine oligodendrocytes. Concerning 7KC and fatty acids (at 20 mu M only):1) cell growth was strongly inhibited; 2) marked induction of cell death was revealed with propidium iodide (PI); 3) no apoptotic cells were found with C24:0 and C26:0 (absence of…

Antiproliferative activities of resveratrol and related compounds in human hepatocyte derived HepG2 cells are associated with biochemical cell disturbance revealed by fluorescence analyses.

International audience; Resveratrol is a well known polyphenol largely produced in grapevine. It is a strong antioxidant and a free radical scavenger. It exhibits several beneficial effects for health including cancer. Resveratrol antioxidant activity is essential in the prevention of chemical-induced cancer by inhibiting initiation step of carcinogenesis process but it is also considered to inhibit cancer promotion and progression steps. While the effects of resveratrol on cancer cells are widely described, the data available on the antiproliferative potential of resveratrol derivatives remain weak. Nevertheless, resveratrol analogs could exhibit stronger potentials than the parent molecul…

The Inflammatory Response in Acyl-CoA Oxidase 1 Deficiency (Pseudoneonatal Adrenoleukodystrophy)

Among several peroxisomal neurodegenerative disorders, the pseudoneonatal adrenoleukodystrophy (P-NALD) is characterized by the acyl-coenzyme A oxidase 1 (ACOX1) deficiency, which leads to the accumulation of very-long-chain fatty acids ( VLCFA) and inflammatory demyelination. However, the components of this inflammatory process in P-NALD remain elusive. In this study, we used transcriptomic profiling and PCR array analyses to explore inflammatory gene expression in patient fibroblasts. Our results show the activation of IL-1 inflammatory pathway accompanied by the increased secretion of two IL-1 target genes, IL-6 and IL-8 cytokines. Human fibroblasts exposed to very-long-chain fatty acids…

Activation of a caspase-3-independent mode of cell death associated with lysosomal destabilization in cultured human retinal pigment epithelial cells (ARPE-19) exposed to 7beta-hydroxycholesterol

International audience; Purpose: To characterize the possible cytotoxic effects of oxysterols (7-hydroxycholesterol (7-OH), 25-hydroxycholesterol (25-OH)) in human retinal pigment epithelial cells (ARPE-19) and to detail the relationships between some of these effects. Methods: ARPE-19 cells were treated with 7-OH and 25-OH. Cell viability was measured with the MTT assay. Membrane permeability, mitochondrial potential, and lysosomal integrity were measured by flow cytometry with propidium iodide, DiOC6(3), and acridine orange, respectively. Cell death was characterized by staining with Hoechst 33342, transmission electron microscopy, and analysis of the DNA fragmentation pattern. Caspase ac…

Immunohistochemical analysis of vascular endothelial growth factor (VEGF) and p53 expression in pterygium from Tunisian patients.

A pterygium is characterized by abnormal fibrovascular corneoconjunctival tissue. A number of investigations have attempted to elucidate this incompletely understood pathology. Since vascular endothelial growth factor (VEGF) and p53 are known to participate in tumor vascularization, our purpose was to study VEGF and p53 expression in active primary and recurrent pterygium from Tunisian patients. To this end, 15 cases of active primary pterygium and five cases of recurrent pterygium from Tunisia were studied by immunohistochemistry. Antibodies raised against VEGF and p53 were used to analyze the distribution and expression of these markers in pterygium and normal human conjunctiva were used …

Flow Cytometric Analysis of the Expression Pattern of Peroxisomal Proteins, Abcd1, Abcd2, and Abcd3 in BV-2 Murine Microglial Cells

Microglial cells play important roles in neurodegenerative diseases including peroxisomal leukodystrophies. The BV-2 murine immortalized cells are widely used in the context of neurodegenerative researches. It is therefore important to establish the expression pattern of peroxisomal proteins by flow cytometry in these cells. So, the expression pattern of various peroxisomal transporters (Abcd1, Abcd2, Abcd3) contributing to peroxisomal β-oxidation was evaluated on BV-2 cells by flow cytometry and complementary methods (fluorescence microscopy, and RT-qPCR). By flow cytometry a strong expression of peroxisomal proteins (Abcd1, Abcd2, Abcd3) was observed. These data were in agreement with tho…

Cytométrie en flux, microbilles et analyses biomoléculaires multiplexes

Resume En cytometrie en flux, les microbilles constituent des outils importants. Initialement developpees pour optimiser les signaux de diffraction et de fluorescence detectes par les cytometres, les microbilles sont maintenant largement utilisees pour la quantification d'antigenes. Actuellement, leur utilisation comme support reactionnel permet aussi de detecter et de quantifier simultanement par cytometrie en flux plusieurs analytes tels que des proteines, des nucleotides, et des ions, mais aussi des agents infectieux dans quelques microlitres d'echantillon. Pour cela, des microbilles de fluorescences et/ou de tailles differentes couplees a des proteines ou a des oligonucleotides sont le …

An expeditious synthesis of spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, and evaluation of their biological activities on cells of the central nervous system

International audience; Spinasterol and schottenol, two phytosterols present in argan oil and in cactus pear seed oil, were synthesized from commercially available stigmasterol by a four steps reactions. In addition, the effects of these phytosterols on cell growth and mitochondrial activity were evaluated on 158N murine oligodendrocytes, C6 rat glioma cells, and SK-N-BE human neuronal cells with the crystal violet test and the MTT test, respectively. The effects of spinasterol and schottenol were compared with 7-ketocholesterol (71CC) and ferulic acid, which is also present in argan and cactus pear seed oil. Whatever the cells considered, dose dependent cytotoxic effects of 71CC were obser…

Assessment of the toxicity of cholesterol oxides on retinal pigment epithelial cultured cells

International audience; Purpose: Among the retinal lipid deposits found in AMD (age related macular degeneration), esterified and unesterified cholesterol have been identified. Cholesterol that accumulates in Bruch's membrane could be oxidized and lead to cholesterol oxides known as oxysterols. These compounds have cytotoxic activities on many vascular cell types, and we conducted this study to evaluate the cytotoxics effects of oxysterols on retinal pigment epithelial (RPE) cells. Methods: Human RPE cells (ARPE–19) were cultured and treated by 7–ketocholesterol (7–keto), 7–betahydroxycholesterol (7–beta) and 25–hydroxycholesterol (25–OH). ARPE–19 cells viability was determined with MTT ana…

Phase I study of OM-174, a lipid A analogue, with assessment of immunological response, in patients with refractory solid tumors.

International audience; BACKGROUND: Lipids A, the lipophilic partial structure of lipopolysaccharides, induce regression of several tumor types in animal models. Rather than exerting direct cytotoxic effect, these compounds trigger the immune system which in turn stimulates secretion of cytokines, and activates the inducible nitric oxide synthase, as well as immune cell infiltration of tumors. OM-174 is an analogue of lipid A with dual action on toll-like receptors 2 and 4. In an experimental model of peritoneal carcinomatosis induced in BDIX rats by intraperitoneal injection of syngeneic PROb colon cancer cells, it induced a complete regression of tumors. The present phase I trial was cond…

Improved synthesis and in vitro evaluation of the cytotoxic profile of oxysterols oxidized at C4 (4α- and 4β-hydroxycholesterol) and C7 (7-ketocholesterol, 7α- and 7β-hydroxycholesterol) on cells of the central nervous system

Whereas the biological activities of oxysterols oxidized at C7 (7-ketocholesterol (7KC), 7β-hydroxycholesterol (7β-OHC), 7α-hydroxycholesterol (7α-OHC)) are well documented, those of oxysterols oxidized at C4 (4β-hydroxycholesterol (4β-OHC), 4α-hydroxycholesterol (4α-OHC)) are not well known, especially on the cells of the central nervous system. Therefore, an improved methodology has been validated for 4β-OHC and 4α-OHC synthesis, and the effects on cell viability and cell growth of these molecules were studied on immortalized, tumoral and normal brain cells (158N, C6 and SK-N-BE cells, and mixed primary cultures of astrocytes and oligodendrocytes). Whereas inhibition of cell growth with 7…

Attenuation of 7-ketocholesterol- and 7β-hydroxycholesterol-induced oxiapoptophagy by nutrients, synthetic molecules and oils: Potential for the prevention of age-related diseases.

Age-related diseases for which there are no effective treatments include cardiovascular diseases; neurodegenerative diseases such as Alzheimer's disease; eye disorders such as cataract and age-related macular degeneration; and, more recently, Severe Acute Respiratory Syndrome (SARS-CoV-2). These diseases are associated with plasma and/or tissue increases in cholesterol derivatives mainly formed by auto-oxidation: 7-ketocholesterol, also known as 7-oxo-cholesterol, and 7β-hydroxycholesterol. The formation of these oxysterols can be considered as a consequence of mitochondrial and peroxisomal dysfunction, leading to increased in oxidative stress, which is accentuated with age. 7-ketocholester…

Tunisian Milk Thistle: An Investigation of the Chemical Composition and the Characterization of Its Cold-Pressed Seed Oils

In this study, milk thistle seeds growing in different areas in Tunisia were cold pressed and the extracted oils were examined for their chemical and antioxidant properties. The major fatty acids were linoleic acid (C18:2) (57.0%, 60.0%, and 60.3% for the milk thistle seed oils native to Bizerte, Zaghouan and Sousse, respectively) and oleic acid (C18:1) (15.5%, 21.5%, and 22.4% for the milk thistle seed oils originating from Bizerte, Zaghouan and Sousse, respectively). High performance liquid chromatography (HPLC) analysis showed the richness of the milk thistle seed oils (MTSO) in α-tocopherol. The highest content was recorded for that of the region of Zaghouan (286.22 mg/kg). The total ph…

Peroxisomal and mitochondrial status of two murine oligodendrocytic cell lines (158N, 158JP): potential models for the study of peroxisomal disorders associated with dysmyelination processes.

International audience; In some neurodegenerative disorders (leukodystrophies) characterized by myelin alterations, the defect of peroxisomal functions on myelin-producing cells (oligodendrocytes) are poorly understood. The development of in vitro models is fundamental to understanding the physiopathogenesis of these diseases. We characterized two immortalized murine oligodendrocyte cell lines: a normal (158N) and a jimpy (158JP) cell line mutated for the proteolipid protein PLP/DM20. Fluorescence microscopy, flow cytometry, and western blotting analysis allow to identify major myelin proteins (PLP colocalizing with mitochondria; myelin basic protein), oligodendrocyte (CNPase and myelin oli…

Induction of oxiapoptophagy, a mixed mode of cell death associated with oxidative stress, apoptosis and autophagy, on 7-ketocholesterol-treated 158N murine oligodendrocytes: impairment by α-tocopherol.

7-Ketocholesterol (7KC) has been suggested to induce a complex mode of cell death on monocytic cells: oxiapoptophagy (OXIdation, APOPTOsis, and autoPHAGY) (Monier et al. (2003) [12]). The aim of the present study, realized on 158N murine oligodendrocytes, was to bring new evidence on this mixed form of cell death. On 158N cells, 7KC induces an overproduction of reactive oxygen species (ROS) revealed by dihydroethidium staining, a loss of transmembrane mitochondrial potential measured with DiOC6(3), caspase-3 activation, and condensation and/or fragmentation of the nuclei which are typical criteria of oxidative stress and apoptosis. Moreover, 7KC enhances cytoplamic membrane permeability to …

Prophylaxis of Non-communicable Diseases: Why fruits and vegetables may be better chemopreventive agents than dietary supplements based on isolated phytochemicals?

The World Health Organization (WHO) report from 2014 documented that non-communicable socalled civilization diseases such as cardiovascular disease, chronic respiratory diseases, cancer or type 2 diabetes are responsible for over 50% of all premature deaths in the world. Research carried out over the past 20 years has provided data suggesting that diet is an essential factor influencing the risk of development of these diseases. The increasing knowledge on chemopreventive properties of certain food ingredients, in particular, those of plant origin, opened the discussion on the possibility to use edible plants or their active components in the prevention of these chronic diseases. Health-pro…

α-Tocopherol impairs 7-ketocholesterol-induced caspase-3-dependent apoptosis involving GSK-3 activation and Mcl-1 degradation on 158N murine oligodendrocytes

Abstract In important and severe neurodegenerative pathologies, 7-ketocholesterol, mainly resulting from cholesterol autoxidation, may contribute to dys- or demyelination processes. On various cell types, 7-ketocholesterol has often been shown to induce a complex mode of cell death by apoptosis associated with phospholipidosis. On 158N murine oligodendrocytes treated with 7-ketocholesterol (20 μg/mL corresponding to 50 μM, 24–48 h), the induction of a mode of cell death by apoptosis characterised by the occurrence of cells with condensed and/or fragmented nuclei, caspase activation (including caspase-3) and internucleosomal DNA fragmentation was observed. It was associated with a loss of tr…

Polyphenols of the Mediterranean Diet and Their Metabolites in the Prevention of Colorectal Cancer.

The Mediterranean diet is a central element of a healthy lifestyle, where polyphenols play a key role due to their anti-oxidant properties, and for some of them, as nutripharmacological compounds capable of preventing a number of diseases, including cancer. Due to the high prevalence of intestinal cancer (ranking second in causing morbidity and mortality), this review is focused on the beneficial effects of selected dietary phytophenols, largely present in Mediterranean cooking: apigenin, curcumin, epigallocatechin gallate, quercetin-rutine, and resveratrol. The role of the Mediterranean diet in the prevention of colorectal cancer and future perspectives are discussed in terms of food polyp…

Induction of Mitochondrial Changes Associated with Oxidative Stress on Very Long Chain Fatty Acids (C22:0, C24:0, or C26:0)-Treated Human Neuronal Cells (SK-NB-E)

In Alzheimer's disease, lipid alterations point towards peroxisomal dysfunctions. Indeed, a cortical accumulation of saturated very long chain fatty acids (VLCFAs: C22:0, C24:0, C26:0), substrates for peroxisomalβ-oxidation, has been found in Alzheimer patients. This study was realized to investigate the effects of VLCFAs at the mitochondrial level since mitochondrial dysfunctions play crucial roles in neurodegeneration. On human neuronal SK-NB-E cells treated with C22:0, C24:0, or C26:0 (0.1–20 μM; 48 h), an inhibition of cell growth and mitochondrial dysfunctions were observed by cell counting with trypan blue, MTT assay, and measurement of mitochondrial transmembrane potential (Δψm) with…

Aza- and Azo-Stilbenes: Bio-Isosteric Analogs of Resveratrol

Several series of natural polyphenols are described for their biological and therapeutic potential. Natural stilbenoid polyphenols, such as trans-resveratrol, pterostilbene and piceatannol are well-known for their numerous biological activities. However, their moderate bio-availabilities, especially for trans-resveratrol, prompted numerous research groups to investigate innovative and relevant synthetic resveratrol derivatives. This review is focused on isosteric resveratrol analogs aza-stilbenes and azo-stilbenes in which the C=C bond between both aromatic rings was replaced with C=N or N=N bonds, respectively. In each series, synthetic ways will be displayed, and structural sights will be…

Incidence of Abcd1 level on the induction of cell death and organelle dysfunctions triggered by very long chain fatty acids and TNF-alpha on oligodendrocytes and astrocytes

X-linked adrenoleukodystrophy (X-ALD) is characterized by ABCD1 deficiency. This disease is associated with elevated concentrations of very long chain fatty acids (C24:0 and C26:0) in the plasma and tissues of patients. Under its severe form, brain demyelination and inflammation are observed. Therefore, we determined the effects of C24:0 and C26:0 on glial cells:oligodendrocytes, which synthesize myelin, and astrocytes, which participate in immune response. So, 158N murine oligodendrocytes, rat C6 glioma cells, rat primary cultures of neuronal-glial cells, and of oligodendrocytes were treated for various periods of time in the absence or presence of C24:0 and C26:0 used at plasmatic concent…

Effects of caspase inhibitors (z-VAD-fmk, z-VDVAD-fmk) on Nile Red fluorescence pattern in 7-ketocholesterol-treated cells: Investigation by flow cytometry and spectral imaging microscopy.

Background: The 7-ketocholesterol (7KC)-induced cell death has some characteristics of apoptosis and is associated with polar lipid accumulation. So, we investigated the effects of the broad-spectrum caspase inhibitor z-VAD-fmk and of the caspase-2 inhibitor z-VDVAD-fmk on lipid profile evaluated by staining with Nile Red (NR). Methods: The 7KC-treated human monocytic U937 cells were cultured in the absence or in the presence of the caspase inhibitors z-VAD-fmk or z-VDVAD-fmk. When staining with NR is performed, neutral and polar lipids have yellow and orange/red emission, respectively, and fluorescence was then analyzed by flow cytometry (FCM) and by confocal laser scanning microscopy (CLS…

Contribution of cholesterol and oxysterols to the pathophysiology of Parkinson's disease

International audience; Neurodegenerative diseases are a major public health issue worldwide. Some countries, including France, have engaged in research into the causes of Parkinson's disease, Alzheimer's disease, and multiple sclerosis and the management of these patients. It should lead to a better understanding of the mechanisms leading to these diseases including the possible involvement of lipids in their pathogenesis. Parkinson's disease is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (Lewy bodies). Several in vivo studies have shown a relationship between the lipid profile [chole…

Effects of resveratrol analogs on cell cycle progression, cell cycle associated proteins and 5fluoro-uracil sensitivity in human derived colon cancer cells.

International audience; Epidemiological studies suggested that trans-resveratrol, a wine grape component, could prevent malignant tumor development. This compound also demonstrated cytostatic and cytotoxic effects on tumor cells in vitro. To obtain trans-resveratrol derivatives with a better cellular uptake and enhanced antiproliferative effects, we synthesized a triacetate derivative as well as an oligomer, epsilon-viniferin and its acetylated form, epsilon-viniferin penta-acetate. We also obtained vineatrol, a wine grape shoot extract that associates several polyphenols that may act synergistically, including trans-resveratrol and epsilon-viniferin. We show here that resveratrol triacetat…

DNA and neutral lipid contents of peripheral cells as predictive biomarkers of mild cognitive impairment and Alzheimer's disease: Highlights on the interest of a cytomic approach for the characterization of dementia

Fatty Acid Profiles in Demented Patients: Identification of Hexacosanoic Acid (C26:0) as a Blood Lipid Biomarker of Dementia

Background: Several lipid metabolism alterations have been described in the brain and plasma of Alzheimer’s disease (AD) patients, suggesting a relation between lipid metabolism alteration and dementia. 15 16 Objective: We attempted to identify blood fatty acids as biomarkers of dementia. 17 Methods: Fatty acid profiles were established using gas chromatography with or without mass spectrometry on matched plasma and red blood cells (RBCs) of demented patients diagnosed with AD, vascular dementia, or other dementia, and compared with a control group of elderly individuals. The severity of dementia was evaluated with the Mini-Mental State Examination test. 18 19 20 Results: Fatty acid analysi…

Contribution of Cholesterol and Oxysterols in the Physiopathology of Cataract: Implication for the Development of Pharmacological Treatments

The development of cataract is associated with some lipid changes in human lens fibers, especially with increased accumulation and redistribution of cholesterol inside these cells. Some direct and indirect lines of evidence, also suggest an involvement of cholesterol oxide derivatives (also named oxysterols) in the development of cataract. Oxysterol formation can result either from nonenzymatic or enzymatic processes, and some oxysterols can induce a wide range of cytotoxic effects (overproduction of reactive oxygen species (ROS); phospholipidosis) which might contribute to the initiation and progression of cataract. Thus, the conception of molecules capable of regulating cholesterol homeos…

Nopal Cactus (Opuntia ficus-indica) as a Source of Bioactive Compounds for Nutrition, Health and Disease

Opuntia ficus-indica, commonly referred to as prickly pear or nopal cactus, is a dicotyledonous angiosperm plant. It belongs to the Cactaceae family and is characterized by its remarkable adaptation to arid and semi-arid climates in tropical and subtropical regions of the globe. In the last decade, compelling evidence for the nutritional and health benefit potential of this cactus has been provided by academic scientists and private companies. Notably, its rich composition in polyphenols, vitamins, polyunsaturated fatty acids and amino acids has been highlighted through the use of a large panel of extraction methods. The identified natural cactus compounds and derivatives were shown to be e…

Toxicity of Branched-Chain Fatty Acids in Conjunctival Cell Line

International audience; Purpose:: Tear film lipid composition is modified in patients suffering from chronic blepharitis. We previously found that branched chain fatty acids (BCFA) were significantly increased in tears of these patients, suggesting that BCFA may be involved in the disease. The toxicity of different BCFA as potent inducers of apoptosis has already been established in various cell lines but not in the conjunctiva. The aim of this work was to assess the toxic effects of BCFA in cultures of Chang conjunctival cells. Methods:: Chang’s human conjunctival cells were cultured during 4 or 24h with various concentrations of IsoC16 and IsoC20 as BCFA (from 50 to 200µM), by comparison …

Potential Roles of Peroxisomes in Alzheimer's Disease and in Dementia of the Alzheimer's Type

In Alzheimer's disease (AD) and dementia of the Alzheimer's type (DAT), the role played by peroxisomes is not well known. Peroxisomes are present in all eukaryotic cells, with the exception of erythrocytes. They are involved in the β-oxidation process of long-chain fatty acids, very-long-chain fatty acids, and branched-chain fatty acids. They participate in the α-oxidation of phytanic acid, the biosynthesis of bile acids, and the breakdown of eicosanoids. Peroxisomes are also involved in the synthesis of specific fatty acids such as docosahexaenoic acid (DHA), which is essential for the brain and retina, and plasmalogens (PLGN), which play crucial roles in neural cells and are essential com…

Major sulfation pathway for resveratrol metabolism in human hepatic derived cells and resveratrol –dependent inducibility of conjugating enzymes. Perspective in nutritional prevention

7-Ketocholesterol effects on survival and growth in Drosophila melanogaster

International audience

Prédiction de la réponse aux traitements de fond antirhumatismaux (DMARD) dans la polyarthrite rhumatoïde

Resume Objectif Examiner les facteurs potentiels predictifs de la reponse aux traitements de fond (DMARD) classiques dans la polyarthrite rhumatoide (PR). Methodes (1) design de l’etude : etude prospective sur six mois de suivi. Participants  : patients avec une PR active ; (2) intervention et suivi : introduction d’un DMARD. Reponse au traitement evaluee a six mois (criteres ACR20) ; (3) analyse : facteurs potentiels predictifs de la reponse : criteres demographiques, activite de la maladie, pourcentages de sous-populations de cellules mononucleees du sang peripherique (CMSP) exprimant la glycoproteine P, taux d’interleukine 1 beta (IL-1β) serique, IL-6, IL-8, IL-10, IL-12 et de facteur de…

Phytosterols: to be or not to be toxic; that is the question

Plant sterols (phytosterols) are membrane constituents of all plants with a structure analogous to that of cholesterol. Thus, phytosterols have either an additional methyl or ethyl group on the carbon-24 position or an additional double bond in the side chain (1) . Noteworthy, in patients with the rare inherited disease of phytosterolaemia characterized by a hyperabsorption and diminished biliary secretion of cholesterol and phytosterols as well as by tendon and tuberous xanthoma, elevated plasma concentrations of phytosterols (campesterol, sitosterol) have been shown to constitute a risk factor for premature atherosclerosis (2) . However, whether plasma concentrations of campesterol and si…

Highlight on transient activation of red/ox-dependent survival signals involving MEK/ERK and PI3/Akt signaling pathways in 27-hydroxycholesterol treated-U937 Human monocytic cells: Commentary on “Survival signaling elicited by 27-hydroxycholesterol through the combined modulation of cellular redox state and ERK/Akt phosphorylation,” by Beyza Vurusaner et al.

Protective effects of bezafibrate against elaidic acid-induced accumulation of lipid droplets in monocytic cells

Some factors related to diet, such as trans fatty acids (TFA), are known to be involved in the progression of atherosclerosis in humans. Thus, the aim of our study was (i) to evaluate the effects of three dietary free fatty acids (FFA) (elaidic (EA), oleic (OA) and palmitic acid (PA)) on U937 human monocytes, and (ii) to study the eventual benefits of bezafibrate (BZF), a pan-agonist for PPAR isoforms (α, γ and δ) in U937 cells treated with FFA. Morphologic and functional changes were investigated by microscopic and flow cytometric methods. Cellular lipid content, lipid droplets and FA composition were identified and studied. All analyses were also realized in association with or without BZ…

Correlational selection on pro- and anti-inflammatory effectors.

9 pages; International audience; Parasites impose a permanent threat for hosts. As a consequence, immune defenses are important for host fitness. However, the immune response can also produce self-damage and impair host fitness if not properly regulated. Effectors that up- and downregulate the immune response should, therefore, evolve in concert, and be under the action of correlational selection. To address this issue, we assessed the shape of the selection operating on pro- and anti-inflammatory effectors following an inflammatory challenge in laboratory mice. We found that selection acts on the combination of these two traits as individuals that produced large amount of pro-inflammatory …

Determination of heavy metal content and lipid profiles in mussel extracts from two sites on the moroccan atlantic coast and evaluation of their biological activities on MIN6 pancreatic cells

Mussels may concentrate pollutants, with possibly significant side effects on human health. Therefore, mussels (Mytilus galloprovincialis) from two sites of the Moroccan Atlantic coast (Jorf Lasfar [JL], an industrial site, and Oualidia [OL], a vegetable-growing area), were subjected to biochemical analyses to quantify the presence of heavy metals (Cd, Cr, and Pb) and to establish the lipid profile: fatty acid, cholesterol, oxysterol, phytosterol and phospholipid content. In addition, mussel lipid extracts known to accumulate numerous toxic components were tested on murine pancreatic β-cells (MIN6), and their biological activities were measured with various flow cytometric and biochemical m…

Biological activities of the LXRα and β agonist, 4β-hydroxycholesterol, and of its isomer, 4α-hydroxycholesterol, on oligodendrocytes: effects on cell growth and viability, oxidative and inflammatory status.

The biochemical and biological properties of 4β-hydroxycholesterol and of its isomer, 4α-hydroxycholesterol, are not well known. So, we determined the ability of 4α- and 4β-hydroxycholesterol to react with LXRα and LXRβ, and we characterized the activities of these oxysterols on oligodendrocytes which are myelin synthesizing cells. The effects of 4α- and 4β-hydroxycholesterol were studied on 158N murine oligodendrocytes to assess their activities on cell growth and viability, oxidative and inflammatory status. To this end different parameters were used: cell counting with trypan blue; identification of dead cells and cell cycle analysis with propidium iodide; evaluation of mitochondrial dep…

Protecting group-free radical decarboxylation of bile acids: Synthesis of novel steroidal substituted maleic anhydrides and maleimides and evaluation of their cytotoxicity on C6 rat glioma cells.

Abstract We report the first Barton radical decarboxylation of unprotected bile acids via in situ irradiation of their thiohydroxamic esters in the presence of citraconic anhydride and citracoimide, leading to the synthesis a series of steroidal maleic anhydrides and maleimides as novel hybrid bile acids. The cytotoxic activities were evaluated on C6 rat glioma cells.

Evaluation of Antioxidant, Anti-Inflammatory and Cytoprotective Properties of Ethanolic Mint Extracts from Algeria on 7-Ketocholesterol-Treated Murine RAW 264.7 Macrophages

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 …

LXR antagonists induce ABCD2 expression

X-linked adrenoleukodystrophy (X-ALD) is a rare neurodegenerative disorder characterized by the accumulation of very-long-chain fatty acids resulting from a beta-oxidation defect. Oxidative stress and inflammation are also key components of the pathogenesis. X-ALD is caused by mutations in the ABCDI gene, which encodes for a peroxisomal half ABC transporter predicted to participate in the entry of VLCFA-CoA into the peroxisome, the unique site of their beta-oxidation. Two homologous peroxisomal ABC transporters, ABCD2 and ABCD3 have been proven to compensate for ABCD1 deficiency when overexpressed. Pharmacological induction of these target genes could therefore represent an alternative ther…

Analogies between atherosclerosis and age-related maculopathy: expected roles of oxysterols

The pathogenesis of age-related macular degeneration (ARMD) is not clearly understood. Like other age-related diseases, it is associated with abnormal deposits called drusen. These drusens are localized in Bruch's membrane. Recent investigations have shown a link between drusen formation and inflammatory and immunologic reactions. The involvement of oxidative stress is supported by available data as an important contributing factor in the developement of ARMD. The data regarding the nature and the source of the deposits suggest that ARMD may share similar pathways with atherosclerosis. The role of oxydized products of cholesterol, the oxysterols, in the pathogenesis of atherosclerosis is we…

Cytotoxic effects of oxysterols associated with human diseases: Induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis.

Oxysterols resulting from spontaneous or enzymatic oxidation of cholesterol are present in numerous foodstuffs and have been identified at increased levels in the plasma and the vascular walls of patients with cardiovascular diseases, especially in atherosclerotic lesions. Consequently, their role in lipid disorders is widely suspected, but they may also contribute to the development of important degenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, osteoporosis, age-related macular degeneration, and cataract. Since these pathologies can be associated with the presence of apoptotic cells, oxidative and inflammatory processes, and lipid disorders, the ab…

Side effects of oxysterols: cytotoxicity, oxidation, inflammation, and phospholipidosis.

Oxysterols are 27-carbon atom molecules resulting from autoxidation or enzymatic oxidation of cholesterol. They are present in numerous foodstuffs and have been demonstrated to be present at increased levels in the plasma of patients with cardiovascular diseases and in atherosclerotic lesions. Thus, their role in lipid disorders is widely suspected, and they might also be involved in important degenerative diseases such as Alzheimer's disease, osteoporosis, and age-related macular degeneration. Since atherosclerosis is associated with the presence of apoptotic cells and with oxidative and inflammatory processes, the ability of some oxysterols, especially 7-ketocholesterol and 7β-hydrox…

Transporteurs ABC peroxysomaux et adrénoleucodystrophie liée au chromosome X

X-linked adrenoleukodystrophy (X-ALD) is a complex neurodegenerative disease associated with mutations in the ABCD1 gene, which encodes for a peroxisomal ABC transporter. Thanks to the efforts of the ELA foundation and to the recent successes of gene therapy published in Science in 2009, X-ALD is better known but still remains poorly understood. The exact role of ABCD1 and its homologs, as well as the exact link between the biochemical and metabolic peroxisomal defects and the clinical symptoms of the disease remain to be elucidated. This review summarizes the knowledge concerning the subfamily D of the ABC transporter family and concerning X-ALD, the most frequent peroxisomal disorder.

Protective Effect of Cactus Cladode Extracts on Peroxisomal Functions in Microglial BV-2 Cells Activated by Different Lipopolysaccharides

International audience; In this study, we aimed to evaluate the antioxidant and anti-inflammatory properties of Opuntia ficus-indica cactus cladode extracts in microglia BV-2 cells. Inflammation associated with microglia activation in neuronal injury can be achieved by LPS exposure. Using four different structurally and biologically well-characterized LPS serotypes, we revealed a structure-related differential effect of LPS on fatty acid β-oxidation and antioxidant enzymes in peroxisomes: Escherichia coli-LPS decreased ACOX1 activity while Salmonella minnesota-LPS reduced only catalase activity. Different cactus cladode extracts showed an antioxidant effect through microglial catalase activ…

Immunohistochemical analysis of cellular adhesion molecules (ICAM-1, VCAM-1) and VEGF in fibrovascular membranes of patients with proliferative diabetic retinopathy: preliminary study.

Abstract Purpose Diabetic fibrovascular membranes are the main pathological changes of proliferative diabetic retinopathy that can cause serious complications leading to blindness. Since the mechanism of fibrovascular membrane development is still unknown, the aim of our study was to identify potential biomarkers for this pathology. To this end, we analyzed the simultaneous expression of ICAM-1, VCAM-1 and VEGF within tissues of diabetic fibrovascular membranes. Patients and methods Fibrovascular membranes were taken from nine diabetic patients with proliferative diabetic retinopathy. The fibrovascular membrane specimens were analyzed by immunohistochemistry to determine ICAM-1, VCAM-1 and …

Generation of oxysterols formed by free radicals and enzymes by electrochemical oxidation

International audience; It is commonly accepted that cholesterol oxide derivatives, also named oxysterols, are 27 carbon-atom molecules deriving either from enzymatic and non-enzymatic oxidation of cholesterol. Most of these compounds can be synthesized by more or less difficult and time consuming chemical reactions, and some of them have been discovered before the identification of the enzymes [mainly cytochrome P450 enzymes (CYP enzymes)] involved in their biosynthesis. A wide range of biological activities depends on oxysterols. Some oxysterols are also involved in the synthesis of cholesterol metabolites which have various properties. The paper by Weber et al. in this issue of European …

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

Seuls les 100 premiers auteurs dont les auteurs INRA ont été entrés dans la notice. La liste complète des auteurs et de leurs affiliations est accessible sur la publication.; International audience; In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues…

Major sulfation pathway for resveratrol metabolism in human hepatic derived cells and resveratrol –dependent inducibility of conjugating enzymes. Perspective in nutritional prevention

Lipids Nutrients in Parkinson and Alzheimer’s Diseases: Cell Death and Cytoprotection

Neurodegenerative diseases, particularly Parkinson’s and Alzheimer’s, have common features: protein accumulation, cell death with mitochondrial involvement and oxidative stress. Patients are treated to cure the symptoms, but the treatments do not target the causes; so, the disease is not stopped. It is interesting to look at the side of nutrition which could help prevent the first signs of the disease or slow its progression in addition to existing therapeutic strategies. Lipids, whether in the form of vegetable or animal oils or in the form of fatty acids, could be incorporated into diets with the aim of preventing neurodegenerative diseases. These different lipids can inhibit the cytotoxi…

Flow cytometry analyses and bioinformatics: interest in new softwares to optimize novel technologies and to favor the emergence of innovative concepts in cell research.

Profile of Fatty Acids, Tocopherols, Phytosterols and Polyphenols in Mediterranean Oils (Argan Oils, Olive Oils, Milk Thistle Seed Oils and Nigella Seed Oil) and Evaluation of their Antioxidant and Cytoprotective Activities

Background: The effects of vegetable oils on human health depend on their components. Therefore, their profiles of lipid nutrients and polyphenols were determined. Objective: To establish and compare the fatty acid, tocopherol, phytosterol and polyphenol profiles of Mediterranean oils: cosmetic and dietary argan oils (AO; Morocco: Agadir, Berkane); olive oils (OO; Morocco, Spain, Tunisia); milk thistle seed oils (MTSO; Tunisia: Bizerte, Sousse, Zaghouane); nigella seed oil (NSO). Methods: The biochemical profiles were determined by gas chromatography-flame ionization, high performance liquid chromatography and gas chromatography, coupled with mass spectrometry as required. The antioxidant …

Biological activities of Schottenol and Spinasterol, two natural phytosterols present in argan oil and in cactus pear seed oil, on murine miroglial BV2 cells

International audience; The objective of this study was to evaluate the biological activities of the major phytosterols present in argan oil (AO) and in cactus seed oil (CSO) in BV2 microglial cells. Accordingly, we first determined the sterol composition of AO and CSO, showing the presence of Schottenol and Spinasterol as major sterols in AO. While in CSO, in addition to these two sterols, we found mainly another sterol, the Sitosterol. The chemical synthesis of Schottenol and Spinasterol was performed. Our results showed that these two phytosterols, as well as sterol extracts from AO or CSO, are not toxic to microglial BV2 cells. However, treatments by these phytosterols impact the mitoch…

Modulation of peroxisomes abundance by argan oil and lipopolysaccharides in acyl-CoA oxidase 1-deficient fibroblasts

Pseudo-neonatal adrenoleukodystrophy (P-NALD) is a neurodegenerative disorder caused by acyl-CoA oxidase 1 (ACOX1) deficiency with subsequent impairment of peroxisomal fatty acid β-oxidation, accumulation of very long chain fatty acids (VLCFAs) and strong reduction in peroxisome abundance. Increase in peroxisome number has been previously suggested to improve peroxisomal disorders, and in this perspective, the present work was aimed at exploring whether modulation of peroxisomes abundance could be achieved in P-NALD fibroblasts. Here we showed that treatment with the natural Argan oil induced peroxisome proliferation in P-NALD fibroblasts. This induction was independent on activations of bo…

Impact of phytosterols on mitochondrial functions

Involvement of Microglia in Neurodegenerative Diseases: Beneficial Effects of Docosahexahenoic Acid (DHA) Supplied by Food or Combined with Nanoparticles

Neurodegenerative diseases represent a major public health issue and require better therapeutic management. The treatments developed mainly target neuronal activity. However, an inflammatory component must be considered, and microglia may constitute an important therapeutic target. Given the difficulty in developing molecules that can cross the blood–brain barrier, the use of food-derived molecules may be an interesting therapeutic avenue. Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid (22:6 omega-3), has an inhibitory action on cell death and oxidative stress induced in the microglia. It also acts on the inflammatory activity of microglia. These data obtained in vitro or…

Early mitochondrial dysfunction, superoxide anion production, and DNA degradation are associated with non-apoptotic death of human airway epithelial cells induced by Pseudomonas aeruginosa exotoxin A.

It has been shown that bacterial exoproducts may induce airway epithelium injury. During the epithelial repair process, the respiratory epithelial cells no more establish tight junctional intercellular complexes and may be particularly susceptible to bacterial virulence factors. In this study, we analyzed the effect of Pseudomonas aeruginosa exotoxin A (ETA) at different periods of time and concentrations on 16 HBE 14o(-) human bronchial epithelial cells in culture conditions inducing a phenotype of repairing cells. ETA treatment for 24 and 48 h led to the killing of 40.0 +/- 5.7% and 79.0 +/- 1.4% of the cells, respectively, as determined by the dimethylthiazole 2,5 diphenyl tetrazolium br…

Absence of oxysterol-like side effects in human monocytic cells treated with phytosterols and oxyphytosterols

Oxysterols, found in some commonly consumed foods, can induce a wide range of cytotoxic effects, which have been extensively studied. On the other hand, the side effects of phytosterols and oxyphytosterols are less well-known. Over the past few years, different types of foods have been enriched with phytosterols on the basis of the properties of these compounds that reduce circulating cholesterol levels in certain experimental conditions. It is therefore important to gain better knowledge of the risks and benefits of this type of diet. In this study, conducted in human monocytic U937 cells, the ability of phytosterols (sitosterol, campesterol) and oxyphytosterols (7 beta-hydroxysitosterol, …

Protective function of autophagy during VLCFA-induced cytotoxicity in a neurodegenerative cell model

Abstract In recent years, a particular interest has focused on the accumulation of fatty acids with very long chains (VLCFA) in the occurrence of neurodegenerative diseases such as Alzheimer's disease, multiple sclerosis or dementia. Indeed, it seems increasingly clear that this accumulation of VLCFA in the central nervous system is accompanied by a progressive demyelination resulting in death of neuronal cells. Nevertheless, molecular mechanisms by which VLCFA result in toxicity remain unclear. This study highlights for the first time in 3 different cellular models (oligodendrocytes 158 N, primary mouse brain culture, and patient fibroblasts) the types of cell death involved where VLCFA-in…

The role of reactive oxygen species and subsequent DNA-damage response in the emergence of resistance towards resveratrol in colon cancer models

AbstractIn spite of the novel strategies to treat colon cancer, mortality rates associated with this disease remain consistently high. Tumour recurrence has been linked to the induction of resistance towards chemotherapy that involves cellular events that enable cancer cells to escape cell death. Treatment of colon cancer mainly implicates direct or indirect DNA-damaging agents and increased repair or tolerances towards subsequent lesions contribute to generate resistant populations. Resveratrol (RSV), a potent chemosensitising polyphenol, might share common properties with chemotherapeutic drugs through its indirect DNA-damaging effects reported in vitro. In this study, we investigated how…

Diagnosing HIV infection using flow cytometry: From antigenic analyses to a specifically dedicated bead-based assay to measure viral load.

SINCE the discovery of HIV in 1984 (1,2), millions have been infected and have died of AIDS. In 2006, the World Health Organization identified 40 million HIV-infected subjects, noting that antiretroviral therapy was required throughout the world (Fig. 1; http://www.who.int/hiv/data/en/index.html). Today, the situation is very similar and the HIV pandemic remains a major world health problem (3). The treatment of AIDS with highly active antiretroviral therapy (HAART) involves regular monitoring of different blood parameters, requiring the development of convenient and accurate methods that can evaluate HIV infection even in resource-poor countries (4,5). In addition to CD4 cell count, which …

Elaboration of Trans-Resveratrol Derivative-Loaded Superparamagnetic Iron Oxide Nanoparticles for Glioma Treatment

In this work, new nanohybrids based on superparamagnetic iron oxide nanoparticles (SPIONs) were elaborated and discussed for the first time as nanovectors of a derivative molecule of trans-resveratrol (RSV), a natural antioxidant molecule, which can be useful for brain disease treatment. The derivative molecule was chemically synthesized (4&rsquo

Erratum

Author(s): Klionsky, DJ; Abdelmohsen, K; Abe, A; Abedin, MJ; Abeliovich, H; Arozena, AA; Adachi, H; Adams, CM; Adams, PD; Adeli, K; Adhihetty, PJ; Adler, SG; Agam, G; Agarwal, R; Aghi, MK; Agnello, M; Agostinis, P; Aguilar, PV; Aguirre-Ghiso, J; Airoldi, EM; Ait-Si-Ali, S; Akematsu, T; Akporiaye, ET; Al-Rubeai, M; Albaiceta, GM; Albanese, C; Albani, D; Albert, ML; Aldudo, J; Algul, H; Alirezaei, M; Alloza, I; Almasan, A; Almonte-Beceril, M; Alnemri, ES; Alonso, C; Altan-Bonnet, N; Altieri, DC; Alvarez, S; Alvarez-Erviti, L; Alves, S; Amadoro, G; Amano, A; Amantini, C; Ambrosio, S; Amelio, I; Amer, AO; Amessou, M; Amon, A; An, Z; Anania, FA; Andersen, SU; Andley, UP; Andreadi, CK; Andrieu-Ab…

Prediction of response to disease modifying antirheumatic drugs in rheumatoid arthritis.

Abstract Aim To investigate potential predictors of response to conventional DMARDs in RA. Methods Study design – 6-month follow-up prospective study. Participants RA patients with active disease. Intervention and follow-up Introduction of one DMARD. Response to treatment evaluated at 6 months (ACR20 criteria). Analysis Potential predictors of response, patients’ demographics, disease activity, percentages of PBMC subsets expressing P-gp, serum IL-1β, IL-6, IL-8, IL-10, IL-12, TNF-α levels, were evaluated using univariate and multivariate logistic regression analysis. ROC curve analyses were performed in order to obtain thresholds allowing the prediction of response. Results Forty-two patie…

Phospholipidosis and down-regulation of the PI3-K/PDK-1/Akt signalling pathway are vitamin E inhibitable events associated with 7-ketocholesterol-induced apoptosis

International audience; Among the oxysterols accumulating in atherosclerotic plaque, 7-ketocholesterol (7KC) is a potent apoptotic inducer, which favours myelin figure formation and polar lipid accumulation. This investigation performed on U937 cells consisted in characterizing the myelin figure formation process; determining the effects of 7KC on the PI3-K/PDK-1/Akt signalling pathway; evaluating the activities of vitamin E (Vit-E) (α-tocopherol) on the formation of myelin figures and the PI3-K/PDK-1/Akt signalling pathway and assessing the effects of PI3-K inhibitors (LY-294002, 3-methyladenine) on the activity of Vit-E on cell death and polar lipid accumulation. The ultrastructural and b…

Docosahexaenoic Acid Attenuates Mitochondrial Alterations and Oxidative Stress Leading to Cell Death Induced by Very Long-Chain Fatty Acids in a Mouse Oligodendrocyte Model

In the case of neurodegenerative pathologies, the therapeutic arsenal available is often directed towards the consequences of the disease. The purpose of this study is, therefore, to evaluate the ability of docosahexaenoic acid (DHA), a molecule present in certain foods and considered to have health benefits, to inhibit the cytotoxic effects of very long-chain fatty acids (C24:0, C26:0), which can contribute to the development of some neurodegenerative diseases. The effect of DHA (50 &micro

Inhibitory effects oftrans-resveratrol analogs molecules on the proliferation and the cell cycle progression of human colon tumoral cells

International audience; Resveratrol may function as a cancer chemopreventive agent. However, few data are available on the antitumoral activities of its dimer, epsilon-viniferin, also present in human diet. So, the effects of resveratrol, epsilon-viniferin, of their acetylated forms (resveratrol triacetate, epsilon-viniferin pentaacetate) and of vineatrol (a wine grape extract) were compared on human adenocarcinoma colon cells. Resveratrol and resveratrol triacetate inhibit cell proliferation and arrest cell cycle. epsilon-Viniferin and epsilon-viniferin pentaacetate slightly reduce cell proliferation. Vineatrol inhibits cell proliferation and favors an accumulation in the S phase of the ce…

Flow cytometric investigation of neutrophil oxidative burst and apoptosis in physiological and pathological situations

Flow cytometric analysis provides a rapid screen for abnormalities of polymorphonuclear neutrophils (PMN) function and reflect their behavior in vivo more accurately. This review summarizes the major fluorescent probes used to study PMN oxidative burst and apoptosis using flow cytometry (FCM). We also provide examples of FCM studies in physiological and pathological situations, illustrating the advantages of FCM for assessment of PMN oxidative burst and PMN apoptosis. These data point to the role of FCM in detecting primary immunodeficiencies such as IRAK4 deficiency and support the use of the assessment of the PMN oxidative burst for routine testing in patients with bacterial infections. W…

Data from: Correlational selection on pro- and anti-inflammatory effectors

Parasites impose a permanent threat for hosts. As a consequence, immune defenses are important for host fitness. However, the immune response can also produce self-damage and impair host fitness if not properly regulated. Effectors that up- and down-regulate the immune response should, therefore, evolve in concert, and be under the action of correlational selection. To address this issue, we assessed the shape of the selection operating on pro- and anti-inflammatory effectors following an inflammatory challenge in laboratory mice. We found that selection acts on the combination of these two traits as individuals that produced large amount of pro-inflammatory cytokines could achieve relative…