Evaluation of the metallic contamination impact on 'Mytilus Edulis' mussel at the level of the mouth of Sebou's estuary, Marocco

International audienceThe understanding of the bioaccumulation phenomenon of heavy metals in the living substance is of an extreme complexity. This is due to the interpenetration of several parameters which influence this bioaccumulation such as: the physico-chemical characteristics of the study area, the chemical properties of the contaminant and the biologic factors of the organism. This work constitutes, using Mytilus edulis as bioindicator, a contribution to study the metal contamination at different points of the mouth of Sebou's estuary. The samples were collected during the spring and the summer of the year 2005. The obtained results reveal a contamination of the study area by all the measured metals especially by lead, cadmium and chromium. This study allowed also discerning the existence of a variation in the accumulation of heavy metals according to Mytilus edulis size, as it was reported in the literature. Indeed, it showed that the small mussels accumulate heavy metals more than the big, mainly for manganese, chromium and cadmium. Seven trace metals (Mn, Cu, Cr, Pb, Co, Fe and Cd) were detected in the four studied organs (hepatopancreas, gills, gonads and muscle); the variations was least or more significant according to the organ. So, we conclude that the bioaccumulation does not make in a strictly selective way

Cytoprotective and Antioxidants in Peroxisomal Neurodegenerative Diseases

Several of the peroxisomal neurodegenerative disorders are the consequence of a specific deficiency of an enzyme or a transporter involved in peroxisomal beta-oxidation of very long chain fatty acids [1,2]. One of the hallmarks in these peroxisomal rare neurodegenerative diseases and in other common demyelinating disorders is the accompanying oxidative damage and neuroinflammation [3]. Compelling data indicates that oxidative stress can activate microglia leading to the overproduction of pro-inflammatory molecules [4,5]. Thus, targeting oxidative stress to limit neuroinflammation may open a new pharmacological therapy window for these still incurable devastating peroxisomal diseases. Here, we present different natural (resveratrol) [6] and synthetic (organoselenides) [7] antioxidant compounds for their capacity of scavenging oxidative stress and in the perspective therapeutic use against oxidative damage in peroxisomal disorders

Peroxisomal defects in microglial cells induce a disease-associated microglial signature

Microglial cells ensure essential roles in brain homeostasis. In pathological condition, microglia adopt a common signature, called disease-associated microglial (DAM) signature, characterized by the loss of homeostatic genes and the induction of disease-associated genes. In X-linked adrenoleukodystrophy (X-ALD), the most common peroxisomal disease, microglial defect has been shown to precede myelin degradation and may actively contribute to the neurodegenerative process. We previously established BV-2 microglial cell models bearing mutations in peroxisomal genes that recapitulate some of the hallmarks of the peroxisomal β-oxidation defects such as very long-chain fatty acid (VLCFA) accumulation. In these cell lines, we used RNA-sequencing and identified large-scale reprogramming for genes involved in lipid metabolism, immune response, cell signaling, lysosome and autophagy, as well as a DAM-like signature. We highlighted cholesterol accumulation in plasma membranes and observed autophagy patterns in the cell mutants. We confirmed the upregulation or downregulation at the protein level for a few selected genes that mostly corroborated our observations and clearly demonstrated increased expression and secretion of DAM proteins in the BV-2 mutant cells. In conclusion, the peroxisomal defects in microglial cells not only impact on VLCFA metabolism but also force microglial cells to adopt a pathological phenotype likely representing a key contributor to the pathogenesis of peroxisomal disorders

Immune response of BV-2 microglial cells is impacted by peroxisomal beta-oxidation

Microglia are crucial for brain homeostasis, and dysfunction of these cells is a key driver in most neurodegenerative diseases, including peroxisomal leukodystrophies. In X-linked adrenoleukodystrophy (X-ALD), a neuroinflammatory disorder, very long-chain fatty acid (VLCFA) accumulation due to impaired degradation within peroxisomes results in microglial defects, but the underlying mechanisms remain unclear. Using CRISPR/Cas9 gene editing of key genes in peroxisomal VLCFA breakdown (Abcd1, Abcd2, and Acox1), we recently established easily accessible microglial BV-2 cell models to study the impact of dysfunctional peroxisomal β-oxidation and revealed a disease-associated microglial-like signature in these cell lines. Transcriptomic analysis suggested consequences on the immune response. To clarify how impaired lipid degradation impacts the immune function of microglia, we here used RNA-sequencing and functional assays related to the immune response to compare wild-type and mutant BV-2 cell lines under basal conditions and upon pro-inflammatory lipopolysaccharide (LPS) activation. A majority of genes encoding proinflammatory cytokines, as well as genes involved in phagocytosis, antigen presentation, and co-stimulation of T lymphocytes, were found differentially overexpressed. The transcriptomic alterations were reflected by altered phagocytic capacity, inflammasome activation, increased release of inflammatory cytokines, including TNF, and upregulated response of T lymphocytes primed by mutant BV-2 cells presenting peptides. Together, the present study shows that peroxisomal β-oxidation defects resulting in lipid alterations, including VLCFA accumulation, directly reprogram the main cellular functions of microglia. The elucidation of this link between lipid metabolism and the immune response of microglia will help to better understand the pathogenesis of peroxisomal leukodystrophies

Etude des effets protecteurs de substances naturelles issues du cactus sur le stress oxydant et l'inflammation liés à l'absence de la β-oxydation peroxysomale

The objective of my thesis work was to better understand the role of microglial cells in neuroinflammation initiated in several neurovegetative peroxisomal leukodystrophies and to explore the protective effects of substances from the cactus Opuntia ficus indica. To this end, we used as an in vitro model microglial cells deficient in ATP Binding Cassette D transporters (ABCD 1 and ABCD 2) or acyl-CoA oxidase 1 (ACOX1). These are two BV-2 murine cell lines, deficient in Abcd1/Abcd2-/- or deficient in Acox1-/-, obtained elsewhere by gene editing using the CRISPR/Cas9 methodology. Our results made it possible to: (i) characterize, by differential centrifugation and isopycnic ultracentrifugation analysis, the impact of these deficiencies (Acox1- /- or Abcd1/d2-/-) on the size and/or the density of peroxisomes and other cellular organelles thanks to the activities of marker enzymes. We also revealed a change in the phagocytic capacity of these mutant microglial cells; (ii) to explore the protective effect of cactus seed oil (CSO), Opuntia ficus-indica, in vivo in mice, treated or not with lipopolysaccharides (LPS), thus showing anti-inflammatory activity of CSO by reducing both cerebral expression of iNos and at the hepatic level the expressions of Il-1β and Il-6. CSO was also able to restore peroxisomal activities, antioxidant of catalase and -oxidative of ACOX1, respectively affected by LPS treatment; (iii) to evaluate, in wild and deficient in Acox1 cells, the protective potential of two families of cactus substances (flavanols: isorhamnetin, isorhamnetin-rutinoside, quercetin; and polyphenols: ferulaldehyde, syringaldehyde, vanillin) against inflammation and oxidative stress generated by the absence of ACOX1 activity and/or LPS treatment. These cactus-derived substances can reduce the expression of pro-inflammatory mediators (TNFα, NLRP3, IL-1β) and the production of NO, increase the expression of peroxisomal antioxidant enzymes (Catalase and SOD1), and restore the lysosomal functions impacted by cellular stress induced by the absence of ACOX1 activity or by LPS treatment.L’objectif de mes travaux de thèse était de mieux comprendre le rôle des cellules microgliales dans la neuroinflammation initiée dans plusieurs leucodystrophies peroxysomales neurovégétatives et d’explorer les effets protecteurs de substances issues du cactus Opuntia ficus indica. Pour ce faire, nous avons utilisé comme modèle in vitro des cellules microgliales déficientes en transporteurs ATP Binding Cassette D (ABCD1 et ABCD2) ou en acyl-CoA oxydase 1 (ACOX1). Il s’agit de deux lignées cellulaires murines BV-2, déficiente en Abcd1/Abcd2 - /- ou déficiente en Acox1-/-, obtenues par ailleurs par édition génique grâce à la méthodologie CRISPR/Cas9. Nos résultats ont permis : (i) de caractériser, par analyse en centrifugation différentielle et ultracentrifugation isopycnique, l’impact de ces déficiences (Acox1 -/- ou Abcd1/d2-/-) sur la taille et /ou la densité des peroxysomes et les autres organites cellulaires grâce aux activités des enzymes marqueurs. De plus, nous avons démontré une modification de la capacité phagocytaire de ces cellules microgliales mutantes ; (ii) d’explorer l’effet protecteur de l’huile de graines de cactus (CSO), Opuntia ficus-indica, in vivo chez les souris, traitées ou non par des lipopolysaccharides (LPS), montrant ainsi une activité anti-inflammatoire de la CSO en réduisant aussi bien au niveau cérébrale l’expression d’iNos qu’au niveau hépatique les expressions de l’Il- 1β et l’Il-6. La CSO est capable également de rétablir les activités peroxysomales respectivement, antioxydante de la catalase et -oxydative de l’ACOX1 affectées par le traitement aux LPS ; (iii) d’évaluer, dans les cellules sauvages et déficientes en Acox1, le potentiel protecteur de deux familles de substances issues de cactus (flavanols :isorhamnétine, isorhamnétine-rutinoside, quercétine ; et polyphénols : férulaldéhyde, syringaldéhyde, vanilline) contre l’inflammation et le stress oxydatif générés par l’absence de l’activité ACOX1 et/ou par les LPS. Ces substances issues de cactus sont capables de réduire l’expression des médiateurs pro-inflammatoires (TNFα, NLRP3, IL-1β) et la production de NO, d’augmenter l’expression des enzymes antioxydantes peroxysomales (Catalase et SOD1), et de restaurer les fonctions lysosomales impactées par le stress cellulaire induit par l’absence de l’activité ACOX1 ou par le traitement aux LPS

Etude des effets protecteurs de substances naturelles issues du cactus sur le stress oxydant et l'inflammation liés à l'absence de la β-oxydation peroxysomale

The objective of my thesis work was to better understand the role of microglial cells in neuroinflammation initiated in several neurovegetative peroxisomal leukodystrophies and to explore the protective effects of substances from the cactus Opuntia ficus indica. To this end, we used as an in vitro model microglial cells deficient in ATP Binding Cassette D transporters (ABCD 1 and ABCD 2) or acyl-CoA oxidase 1 (ACOX1). These are two BV-2 murine cell lines, deficient in Abcd1/Abcd2-/- or deficient in Acox1-/-, obtained elsewhere by gene editing using the CRISPR/Cas9 methodology. Our results made it possible to: (i) characterize, by differential centrifugation and isopycnic ultracentrifugation analysis, the impact of these deficiencies (Acox1- /- or Abcd1/d2-/-) on the size and/or the density of peroxisomes and other cellular organelles thanks to the activities of marker enzymes. We also revealed a change in the phagocytic capacity of these mutant microglial cells; (ii) to explore the protective effect of cactus seed oil (CSO), Opuntia ficus-indica, in vivo in mice, treated or not with lipopolysaccharides (LPS), thus showing anti-inflammatory activity of CSO by reducing both cerebral expression of iNos and at the hepatic level the expressions of Il-1β and Il-6. CSO was also able to restore peroxisomal activities, antioxidant of catalase and -oxidative of ACOX1, respectively affected by LPS treatment; (iii) to evaluate, in wild and deficient in Acox1 cells, the protective potential of two families of cactus substances (flavanols: isorhamnetin, isorhamnetin-rutinoside, quercetin; and polyphenols: ferulaldehyde, syringaldehyde, vanillin) against inflammation and oxidative stress generated by the absence of ACOX1 activity and/or LPS treatment. These cactus-derived substances can reduce the expression of pro-inflammatory mediators (TNFα, NLRP3, IL-1β) and the production of NO, increase the expression of peroxisomal antioxidant enzymes (Catalase and SOD1), and restore the lysosomal functions impacted by cellular stress induced by the absence of ACOX1 activity or by LPS treatment.L’objectif de mes travaux de thèse était de mieux comprendre le rôle des cellules microgliales dans la neuroinflammation initiée dans plusieurs leucodystrophies peroxysomales neurovégétatives et d’explorer les effets protecteurs de substances issues du cactus Opuntia ficus indica. Pour ce faire, nous avons utilisé comme modèle in vitro des cellules microgliales déficientes en transporteurs ATP Binding Cassette D (ABCD1 et ABCD2) ou en acyl-CoA oxydase 1 (ACOX1). Il s’agit de deux lignées cellulaires murines BV-2, déficiente en Abcd1/Abcd2 - /- ou déficiente en Acox1-/-, obtenues par ailleurs par édition génique grâce à la méthodologie CRISPR/Cas9. Nos résultats ont permis : (i) de caractériser, par analyse en centrifugation différentielle et ultracentrifugation isopycnique, l’impact de ces déficiences (Acox1 -/- ou Abcd1/d2-/-) sur la taille et /ou la densité des peroxysomes et les autres organites cellulaires grâce aux activités des enzymes marqueurs. De plus, nous avons démontré une modification de la capacité phagocytaire de ces cellules microgliales mutantes ; (ii) d’explorer l’effet protecteur de l’huile de graines de cactus (CSO), Opuntia ficus-indica, in vivo chez les souris, traitées ou non par des lipopolysaccharides (LPS), montrant ainsi une activité anti-inflammatoire de la CSO en réduisant aussi bien au niveau cérébrale l’expression d’iNos qu’au niveau hépatique les expressions de l’Il- 1β et l’Il-6. La CSO est capable également de rétablir les activités peroxysomales respectivement, antioxydante de la catalase et -oxydative de l’ACOX1 affectées par le traitement aux LPS ; (iii) d’évaluer, dans les cellules sauvages et déficientes en Acox1, le potentiel protecteur de deux familles de substances issues de cactus (flavanols :isorhamnétine, isorhamnétine-rutinoside, quercétine ; et polyphénols : férulaldéhyde, syringaldéhyde, vanilline) contre l’inflammation et le stress oxydatif générés par l’absence de l’activité ACOX1 et/ou par les LPS. Ces substances issues de cactus sont capables de réduire l’expression des médiateurs pro-inflammatoires (TNFα, NLRP3, IL-1β) et la production de NO, d’augmenter l’expression des enzymes antioxydantes peroxysomales (Catalase et SOD1), et de restaurer les fonctions lysosomales impactées par le stress cellulaire induit par l’absence de l’activité ACOX1 ou par le traitement aux LPS

Study of the natural cactus extracts protective effects on oxidative stress and inflammation related to peroxisomal β-oxidation deficiencies

L’objectif de mes travaux de thèse était de mieux comprendre le rôle des cellules microgliales dans la neuroinflammation initiée dans plusieurs leucodystrophies peroxysomales neurovégétatives et d’explorer les effets protecteurs de substances issues du cactus Opuntia ficus indica. Pour ce faire, nous avons utilisé comme modèle in vitro des cellules microgliales déficientes en transporteurs ATP Binding Cassette D (ABCD1 et ABCD2) ou en acyl-CoA oxydase 1 (ACOX1). Il s’agit de deux lignées cellulaires murines BV-2, déficiente en Abcd1/Abcd2 - /- ou déficiente en Acox1-/-, obtenues par ailleurs par édition génique grâce à la méthodologie CRISPR/Cas9. Nos résultats ont permis : (i) de caractériser, par analyse en centrifugation différentielle et ultracentrifugation isopycnique, l’impact de ces déficiences (Acox1 -/- ou Abcd1/d2-/-) sur la taille et /ou la densité des peroxysomes et les autres organites cellulaires grâce aux activités des enzymes marqueurs. De plus, nous avons démontré une modification de la capacité phagocytaire de ces cellules microgliales mutantes ; (ii) d’explorer l’effet protecteur de l’huile de graines de cactus (CSO), Opuntia ficus-indica, in vivo chez les souris, traitées ou non par des lipopolysaccharides (LPS), montrant ainsi une activité anti-inflammatoire de la CSO en réduisant aussi bien au niveau cérébrale l’expression d’iNos qu’au niveau hépatique les expressions de l’Il- 1β et l’Il-6. La CSO est capable également de rétablir les activités peroxysomales respectivement, antioxydante de la catalase et -oxydative de l’ACOX1 affectées par le traitement aux LPS ; (iii) d’évaluer, dans les cellules sauvages et déficientes en Acox1, le potentiel protecteur de deux familles de substances issues de cactus (flavanols :isorhamnétine, isorhamnétine-rutinoside, quercétine ; et polyphénols : férulaldéhyde, syringaldéhyde, vanilline) contre l’inflammation et le stress oxydatif générés par l’absence de l’activité ACOX1 et/ou par les LPS. Ces substances issues de cactus sont capables de réduire l’expression des médiateurs pro-inflammatoires (TNFα, NLRP3, IL-1β) et la production de NO, d’augmenter l’expression des enzymes antioxydantes peroxysomales (Catalase et SOD1), et de restaurer les fonctions lysosomales impactées par le stress cellulaire induit par l’absence de l’activité ACOX1 ou par le traitement aux LPS.The objective of my thesis work was to better understand the role of microglial cells in neuroinflammation initiated in several neurovegetative peroxisomal leukodystrophies and to explore the protective effects of substances from the cactus Opuntia ficus indica. To this end, we used as an in vitro model microglial cells deficient in ATP Binding Cassette D transporters (ABCD 1 and ABCD 2) or acyl-CoA oxidase 1 (ACOX1). These are two BV-2 murine cell lines, deficient in Abcd1/Abcd2-/- or deficient in Acox1-/-, obtained elsewhere by gene editing using the CRISPR/Cas9 methodology. Our results made it possible to: (i) characterize, by differential centrifugation and isopycnic ultracentrifugation analysis, the impact of these deficiencies (Acox1- /- or Abcd1/d2-/-) on the size and/or the density of peroxisomes and other cellular organelles thanks to the activities of marker enzymes. We also revealed a change in the phagocytic capacity of these mutant microglial cells; (ii) to explore the protective effect of cactus seed oil (CSO), Opuntia ficus-indica, in vivo in mice, treated or not with lipopolysaccharides (LPS), thus showing anti-inflammatory activity of CSO by reducing both cerebral expression of iNos and at the hepatic level the expressions of Il-1β and Il-6. CSO was also able to restore peroxisomal activities, antioxidant of catalase and -oxidative of ACOX1, respectively affected by LPS treatment; (iii) to evaluate, in wild and deficient in Acox1 cells, the protective potential of two families of cactus substances (flavanols: isorhamnetin, isorhamnetin-rutinoside, quercetin; and polyphenols: ferulaldehyde, syringaldehyde, vanillin) against inflammation and oxidative stress generated by the absence of ACOX1 activity and/or LPS treatment. These cactus-derived substances can reduce the expression of pro-inflammatory mediators (TNFα, NLRP3, IL-1β) and the production of NO, increase the expression of peroxisomal antioxidant enzymes (Catalase and SOD1), and restore the lysosomal functions impacted by cellular stress induced by the absence of ACOX1 activity or by LPS treatment

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients

Review of Particulate Matter Levels and Sources in North Africa over the Period 1990–2019

Africa, particularly West and North Africa, has some of the highest levels of average PM pollution, second only to South and East Asia and the Middle East. This study reports the PM2.5 and PM10 concentrations and their emissions sectors in North Africa from 1990 to 2019. The data were collected online from the following platforms: EDGAR (Emissions Database for Global Atmospheric Research), Climate Watch, Our World in Data, and the World Bank. The analysis of data indicated that outdoor air pollution in North Africa is the fourth leading risk factor for death, with 3.4 million deaths in total from 1990 to 2019. Globally, 43% of PM10 emissions in North Africa from 1970 to 2015 were contributed by buildings, 16.6% by other industrial combustion, 13.7% by transport, 11.4% by other sectors, 9.6% by agriculture, 5.3% by power industry, and 0.2% by waste. For PM2.5, the major emitter sector in North Africa, during the same period, was also buildings with 38.2%, followed by transport (21.5%), other industrial combustion (17.3%), other sectors (12.4%), power industry (6%), agriculture (4.5%), and waste (0.2%)

Synthesis, Structural and Optical Characterization of Titanium Dioxide Doped by (Ce, Yb) Dedicated to Photonic Conversion

The synthesis of TiO2 co-doped by (Ce, Yb) rare earth couple has been realized. This couple of rare earth can convert a high-energy photon to two low energy photons to enhance the energy efficiency of silicon solar cells. The undoped, 2% Ce doped- and (2% Ce, 4% Yb) Codoped- Titanium oxide were prepared by the co-precipitation method. The Infrared spectroscopy FTIR-ATR analysis indicates a continuous visible absorption in the 750–400 cm–1 region, confirming the formation of a titanium-oxygen bond. The X-Ray Diffraction characterization showed the dominance of the rutile crystalline phase with the presence of anatase one and the calculated crystallite size is between 7 to 13 nm. The X-Ray Fluorescence confirms the insertion of the dopants while the Inductively Coupled Plasma Mass Spectrometry ICP-MS showed the ratio 2 between Ce and Yb concentration. The thermogravimetric analysis indicated that Ce/Yb doped titanium was thermally stable. The absorption in the UV-visible (200 and 1000 nm) has been improved proportionally with the dopants