The Potential Role of Major Argan Oil Compounds as Nrf2 Regulators and Their Antioxidant Effects.

In recent years, research on the discovery of natural compounds with potent antioxidant properties has resulted in growing interest in these compounds due to their potential therapeutic applications in oxidative-stress-related diseases. Argan oil, derived from the kernels of a native tree from Morocco, Argania spinosa, is renowned for its rich composition of bioactive compounds, prominently tocopherols, polyphenols, and fatty acids. Interestingly, a large body of data has shown that several components of argan oil activate the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, playing a crucial role in the cellular defense against oxidative stress. Activation of this Nrf2 pathway by argan oil components leads to the increased expression of downstream target proteins like NAD(P)H quinone oxidoreductase (NQO1), superoxide dismutase (SOD), heme oxygenase 1 (HO-1), and catalase (CAT). Such Nrf2 activation accounts for several health benefits related to antioxidant defense, anti-inflammatory effects, cardiovascular health, and neuroprotection in organisms. Furthermore, the synergistic action of the bioactive compounds in argan oil enhances the Nrf2 pathway. Accordingly, the modulation of the Kelch-like ECH associated protein 1 (Keap1)/Nrf2 signaling pathway by these components highlights the potential of argan oil in protecting cells from oxidative stress and underlines its relevance in dietetic prevention and therapeutic applications. This review aims to provide an overview of how major compounds in argan oil activate the Nrf2 pathway, updating our knowledge on their mechanisms of action and associated health benefits.

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 ß-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 ß-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 ß-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.

Protective Effect of Nopal Cactus (Opuntia ficus-indica) Seed Oil against Short-Term Lipopolysaccharides-Induced Inflammation and Peroxisomal Functions Dysregulation in Mouse Brain and Liver.

Exposure to endotoxins (lipopolysaccharides, LPS) may lead to a potent inflammatory cytokine response and a severe impairment of metabolism, causing tissue injury. The protective effect provided by cactus seed oil (CSO), from Opuntia ficus-indica, was evaluated against LPS-induced inflammation, dysregulation of peroxisomal antioxidant, and ß-oxidation activities in the brain and the liver. In both tissues, a short-term LPS exposure increased the proinflammatory interleukine-1ß (Il-1ß), inducible Nitroxide synthase (iNos), and Interleukine-6 (Il-6). In the brain, CSO action reduced only LPS-induced iNos expression, while in the liver, CSO attenuated mainly the hepatic Il-1ß and Il-6. Regarding the peroxisomal antioxidative functions, CSO treatment (as Olive oil (OO) or Colza oil (CO) treatment) induced the hepatic peroxisomal Cat gene. Paradoxically, we showed that CSO, as well as OO or CO, treatment can timely induce catalase activity or prevent its induction by LPS, respectively, in both brain and liver tissues. On the other hand, CSO (as CO) pretreatment prevented the LPS-associated Acox1 gene and activity decreases in the liver. Collectively, CSO showed efficient neuroprotective and hepato-protective effects against LPS, by maintaining the brain peroxisomal antioxidant enzyme activities of catalase and glutathione peroxidase, and by restoring hepatic peroxisomal antioxidant and ß-oxidative capacities.

Protective effects of milk thistle (Sylibum marianum) seed oil and α-tocopherol against 7ß-hydroxycholesterol-induced peroxisomal alterations in murine C2C12 myoblasts: Nutritional insights associated with the concept of pexotherapy.

Peroxisomes play an important role in regulating cell metabolism and RedOx homeostasis. Peroxisomal dysfunctions favor oxidative stress and cell death. The ability of 7ß-hydroxycholesterol (7ß-OHC; 50 µM, 24 h), known to be increased in patients with age-related diseases such as sarcopenia, to trigger oxidative stress, mitochondrial and peroxisomal dysfunction was studied in murine C2C12 myoblasts. The capacity of milk thistle seed oil (MTSO, 100 µg/mL) as well as α-tocopherol (400 µM; reference cytoprotective agent) to counteract the toxic effects of 7ß-OHC, mainly at the peroxisomal level were evaluated. The impacts of 7ß-OHC, in the presence or absence of MTSO or α-tocopherol, were studied with complementary methods: measurement of cell density and viability, quantification of reactive oxygen species (ROS) production and transmembrane mitochondrial potential (ΔΨm), evaluation of peroxisomal mass as well as topographic, morphologic and functional peroxisomal changes. Our results indicate that 7ß-OHC induces a loss of cell viability and a decrease of cell adhesion associated with ROS overproduction, alterations of mitochondrial ultrastructure, a drop of ΔΨm, and several peroxisomal modifications. In the presence of 7ß-OHC, comparatively to untreated cells, important quantitative and qualitative peroxisomal modifications were also identified: a) a reduced number of peroxisomes with abnormal sizes and shapes, mainly localized in cytoplasmic vacuoles, were observed; b) the peroxisomal mass was decreased as indicated by lower protein and mRNA levels of the peroxisomal ABCD3 transporter; c) lower mRNA level of Pex5 involved in peroxisomal biogenesis as well as higher mRNA levels of Pex13 and Pex14, involved in peroxisomal biogenesis and/or pexophagy, was found; d) lower levels of ACOX1 and MFP2 enzymes, implicated in peroxisomal ß-oxidation, were detected; e) higher levels of very-long-chain fatty acids, which are substrates of peroxisomal ß-oxidation, were found. These different cytotoxic effects were strongly attenuated by MTSO, in the same range of order as with α-tocopherol. These findings underline the interest of MTSO and α-tocopherol in the prevention of peroxisomal damages (pexotherapy).

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 ß-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal ß-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 ß-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 ß-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.