Graphical abstract 7-Ketocholesterol (or 7-oxocholesterol) is an oxysterol essentially formed by ... more Graphical abstract 7-Ketocholesterol (or 7-oxocholesterol) is an oxysterol essentially formed by cholesterol autoxidation. It is often found at enhanced levels in the body fluids and/or target tissues of patients with age-related diseases (cardiovascular, neuronal, and ocular diseases) as well as in subjects concerned with civilization diseases (type 2 diabetes, bowel diseases, and metabolic syndrome). The involvement of increased 7-ketocholesterol levels in the pathophysiology of these diseases is widely suspected. Indeed, 7-ketocholesterol at elevated concentrations is a powerful inducer of oxidative stress, inflammation, and cellular degeneration which are common features of all these diseases. It is important to better know the origin of 7-ketocholesterol (diet, incidence of environmental factors, and endogenous formation (autoxidation and enzymatic synthesis)) and its inactivation mechanisms which include esterification, sulfation, oxidation, and reduction. This knowledge will ...
Malignant brain tumors are among the most devastating types of cancer. Glioblastoma is the most c... more Malignant brain tumors are among the most devastating types of cancer. Glioblastoma is the most common and serious form of brain cancer. Most glioblastomas are surgically unresectable and are typically diagnosed at an advanced stage. The high level of resistance to chemotherapy, radiotherapy and immunotherapy makes glioblastoma one of the most difficult cancers to treat. In brain tumors, the challenges of targeted therapy also include the blood-brain barrier, which often contributes to treatment failure. Therefore, developments of new treatment strategies are required. Metabolic treatments could be an alternative to conventional therapies. Metabolic approaches aim at suppressing glioblastoma tumorigenicity leading to glioblastoma cell death. Since cholesterol metabolism is deregulated in these tumors, this is a promising potential target for therapy. As glioblastoma cells draw on cholesterol from the central nervous system to survive,
Direct translation of findings achieved in experimental cell or animal models to humans is always... more Direct translation of findings achieved in experimental cell or animal models to humans is always a quite difficult if not impossible task. As regards the role of 27hydroxycholesterol and related metabolism in human cancer development we deemed of interest to focus only on the epidemiological and ex vivo human studies so far available in literature. There are some studies in humans that support an adverse effect of 27OHC in breast cancer, based upon the oxysterol's recognized ability to bind to and modulate esterogen receptors. The detrimental role of this side chain oxysterol would be evident in cancer progression, mainly in post-menopausal women and in an advanced stage of the disease. Other human studies, however, would rather correlate 27OHC intratumoral levels with a better prognosis. The analyses on human prostate cancer specimens performed to date are all against a detrimental contribution of 27OHC, rather suggesting interesting antiprostate cancer effects exerted by this oxysterol. Finally, an increased 27OHC synthesis would favor cancer progression in colon, brain and thyroid tissues, as found for breast cancer.
The Journal of Steroid Biochemistry and Molecular Biology, 2021
7-ketocholesterol, which is one of the earliest cholesterol oxidization products identified, is e... more 7-ketocholesterol, which is one of the earliest cholesterol oxidization products identified, is essentially formed by the auto-oxidation of cholesterol. In the body, 7-ketocholesterol is both provided by food and produced endogenously. This pro-oxidant and pro-inflammatory molecule, which can activate apoptosis and autophagy at high concentrations, is an abundant component of oxidized Low Density Lipoproteins. 7-Ketocholesterol appears to significantly contribute to the development of age-related diseases (cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease), chronic inflammatory bowel diseases and to certain cancers. Recent studies have also shown that 7-ketocholesterol has anti-viral activities, including on SARS-CoV-2, which are, however, lower than those of oxysterols resulting from the oxidation of cholesterol on the side chain. Furthermore, 7-ketocholesterol is increased in the serum of moderately and severely affected COVID-19 patients. In the case of COVID-19, it can be assumed that the antiviral activity of 7-ketocholesterol could be counterbalanced by its toxic effects, including pro-oxidant, pro-inflammatory and pro-coagulant activities that might promote the induction of cell death in alveolar cells. It is therefore suggested that this oxysterol might be involved in the pathophysiology of COVID-19 by contributing to the acute respiratory distress syndrome and promoting a deleterious, even fatal outcome. Thus, 7-ketocholesterol could possibly constitute a lipid biomarker of COVID-19 outcome and counteracting its toxic effects with adjuvant therapies might have beneficial effects in COVID-19 patients.
Age-related diseases for which there are no effective treatments include cardiovascular diseases;... more 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-ketocholesterol and 7β-hydroxycholesterol cause a specific form of cytotoxic activity defined as oxiapoptophagy, including oxidative stress and induction of death by apoptosis associated with autophagic criteria. Oxiaptophagy is associated with organelle dysfunction and in particular with mitochondrial and peroxisomal alterations involved in the induction of cell death and in the rupture of redox balance. As the criteria characterizing 7-ketocholesterol- and 7β-hydroxycholesterol-induced cytotoxicity are often simultaneously observed in major age-related diseases (cardiovascular diseases, age-related macular degeneration, Alzheimer's disease) the involvement of these oxysterols in the pathophysiology of the latter seems increasingly likely. It is therefore important to better understand the signalling pathways associated with the toxicity of 7-ketocholesterol and 7β-hydroxycholesterol in order to identify pharmacological targets, nutrients and synthetic molecules attenuating or inhibiting the cytotoxic activities of these oxysterols. Numerous natural cytoprotective compounds have been identified: vitamins, fatty acids, polyphenols, terpenes, vegetal pigments, antioxidants, mixtures of compounds (oils, plant extracts) and bacterial enzymes. However, few synthetic molecules are able to prevent 7-ketocholesterol- and/or 7β-hydroxycholesterol-induced cytotoxicity: dimethyl fumarate, monomethyl fumarate, the tyrosine kinase inhibitor AG126, memantine, simvastatine, Trolox, dimethylsufoxide, mangafodipir and mitochondrial permeability transition pore (MPTP) inhibitors. The effectiveness of these compounds, several of which are already in use in humans, makes it possible to consider using them for the treatment of certain age-related diseases associated with increased plasma and/or tissue levels of 7-ketocholesterol and/or 7β-hydroxycholesterol.
The Journal of Steroid Biochemistry and Molecular Biology, 2019
Oxysterols are involved in many biological processes including the regulation of cholesterol ho... more Oxysterols are involved in many biological processes including the regulation of cholesterol homeostasis The location of oxysterol metabolising enzymes may play an important role in the oxysterol concentration in cellular micro-environments. Oxysterols in biological fluids can use as markers to analyse endogenous flaws in cholesterol/oxysterol homeostasis. List of Abbreviations 20-OHC 20-hydroxycholesterol 22-OHC 22-hydroxycholesterol 24-OHC 24-hydroxycholesterol 25-OHC 25-hydroxycholesterol 26-OHC 26-hydroxycholesterol 27-OHC 27-hydroxycholesterol 5, 6-epox 5, 6-epoxy cholesterols 5α, 6α-epox 5α, 6α-epoxy cholesterol 5β, 6β-epox 5β, 6β-epoxy cholesterol 7-KC 7-ketocholesterol 7-K,25-OHC 7-keto-27-hydroxycholesterol 7α-OHC 7α-hydroxycholesterol 7α,25-OHC 7α, 25-dihydroxycholesterol 7α,27-OHC 7α, 27-hydroxycholesterol 7β-OHC 7β-hydroxycholesterol ABCA1 ATP-binding cassette transporter A1 ABCG1 ATP-binding cassette transporter G1 ACAT Acyl-CoA:cholesterol acyl transferase AD Alzheimer´s disease APP Amyloid precursor protein BBB Blood-brain barrier CH25H Cholesterol 25-hydroxylase ChEH Cholesterol-5, 6-epoxide hydrolase CNBP Cellular nucleic acid binding protein CYP46A1 Cholesterol 24-hydroxylase CYP46A1 Cytochrome P450 46A1 CYP7A1 Sterol 7α-hydroxylase CYP27 Sterol 27-hydroxylase CYP8B1 Cholesterol 12α-hydroxylase DDA Dendrogenin A LXR Liver X receptor MS Multiple Sclerosis NAFLD Non-alcoholic fatty liver disease OSBP Oxysterol binding protein PD Parkinson´s Disease POPC 1-palmitoyl-2-oleoyl-phosphatidylcholine SCAP SREBP cleavage activation protein SMO Smoothed receptor SREBP Sterol regulatory element binding protein StAR Steroidogenic acute regulatory protein THCA Trihydroxycholestanoic acid TSPO Mitochondrial translocator protein ROS Reactive oxygen species VLCFA Very long chain fatty acids WMH White Matter Hyperintensities
Peroxisomal dyfunctions (topographical, morphological, functionnal) OXIAPOPTOPHAGY No apoptosis /... more Peroxisomal dyfunctions (topographical, morphological, functionnal) OXIAPOPTOPHAGY No apoptosis / Slight autophagy Attenuation of 7KC-induced side effects by α-tocopherol Oxidative stress O 2 •and H 2 O 2 overproduction mitochondrial dyfunctions (loss of ΔΨm) Mitochondrial topographical changes
The Journal of Steroid Biochemistry and Molecular Biology, 2019
Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with s... more Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7-hydroxycholesterol on glioma cells
Critical Reviews in Food Science and Nutrition, 2018
Cholesterol oxidation products, also named oxysterols, can be formed either by cholesterol auto-o... more 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 metabolized, except in hepatic cells, its
Graphical abstract 7-Ketocholesterol (or 7-oxocholesterol) is an oxysterol essentially formed by ... more Graphical abstract 7-Ketocholesterol (or 7-oxocholesterol) is an oxysterol essentially formed by cholesterol autoxidation. It is often found at enhanced levels in the body fluids and/or target tissues of patients with age-related diseases (cardiovascular, neuronal, and ocular diseases) as well as in subjects concerned with civilization diseases (type 2 diabetes, bowel diseases, and metabolic syndrome). The involvement of increased 7-ketocholesterol levels in the pathophysiology of these diseases is widely suspected. Indeed, 7-ketocholesterol at elevated concentrations is a powerful inducer of oxidative stress, inflammation, and cellular degeneration which are common features of all these diseases. It is important to better know the origin of 7-ketocholesterol (diet, incidence of environmental factors, and endogenous formation (autoxidation and enzymatic synthesis)) and its inactivation mechanisms which include esterification, sulfation, oxidation, and reduction. This knowledge will ...
Malignant brain tumors are among the most devastating types of cancer. Glioblastoma is the most c... more Malignant brain tumors are among the most devastating types of cancer. Glioblastoma is the most common and serious form of brain cancer. Most glioblastomas are surgically unresectable and are typically diagnosed at an advanced stage. The high level of resistance to chemotherapy, radiotherapy and immunotherapy makes glioblastoma one of the most difficult cancers to treat. In brain tumors, the challenges of targeted therapy also include the blood-brain barrier, which often contributes to treatment failure. Therefore, developments of new treatment strategies are required. Metabolic treatments could be an alternative to conventional therapies. Metabolic approaches aim at suppressing glioblastoma tumorigenicity leading to glioblastoma cell death. Since cholesterol metabolism is deregulated in these tumors, this is a promising potential target for therapy. As glioblastoma cells draw on cholesterol from the central nervous system to survive,
Direct translation of findings achieved in experimental cell or animal models to humans is always... more Direct translation of findings achieved in experimental cell or animal models to humans is always a quite difficult if not impossible task. As regards the role of 27hydroxycholesterol and related metabolism in human cancer development we deemed of interest to focus only on the epidemiological and ex vivo human studies so far available in literature. There are some studies in humans that support an adverse effect of 27OHC in breast cancer, based upon the oxysterol's recognized ability to bind to and modulate esterogen receptors. The detrimental role of this side chain oxysterol would be evident in cancer progression, mainly in post-menopausal women and in an advanced stage of the disease. Other human studies, however, would rather correlate 27OHC intratumoral levels with a better prognosis. The analyses on human prostate cancer specimens performed to date are all against a detrimental contribution of 27OHC, rather suggesting interesting antiprostate cancer effects exerted by this oxysterol. Finally, an increased 27OHC synthesis would favor cancer progression in colon, brain and thyroid tissues, as found for breast cancer.
The Journal of Steroid Biochemistry and Molecular Biology, 2021
7-ketocholesterol, which is one of the earliest cholesterol oxidization products identified, is e... more 7-ketocholesterol, which is one of the earliest cholesterol oxidization products identified, is essentially formed by the auto-oxidation of cholesterol. In the body, 7-ketocholesterol is both provided by food and produced endogenously. This pro-oxidant and pro-inflammatory molecule, which can activate apoptosis and autophagy at high concentrations, is an abundant component of oxidized Low Density Lipoproteins. 7-Ketocholesterol appears to significantly contribute to the development of age-related diseases (cardiovascular diseases, age-related macular degeneration, and Alzheimer's disease), chronic inflammatory bowel diseases and to certain cancers. Recent studies have also shown that 7-ketocholesterol has anti-viral activities, including on SARS-CoV-2, which are, however, lower than those of oxysterols resulting from the oxidation of cholesterol on the side chain. Furthermore, 7-ketocholesterol is increased in the serum of moderately and severely affected COVID-19 patients. In the case of COVID-19, it can be assumed that the antiviral activity of 7-ketocholesterol could be counterbalanced by its toxic effects, including pro-oxidant, pro-inflammatory and pro-coagulant activities that might promote the induction of cell death in alveolar cells. It is therefore suggested that this oxysterol might be involved in the pathophysiology of COVID-19 by contributing to the acute respiratory distress syndrome and promoting a deleterious, even fatal outcome. Thus, 7-ketocholesterol could possibly constitute a lipid biomarker of COVID-19 outcome and counteracting its toxic effects with adjuvant therapies might have beneficial effects in COVID-19 patients.
Age-related diseases for which there are no effective treatments include cardiovascular diseases;... more 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-ketocholesterol and 7β-hydroxycholesterol cause a specific form of cytotoxic activity defined as oxiapoptophagy, including oxidative stress and induction of death by apoptosis associated with autophagic criteria. Oxiaptophagy is associated with organelle dysfunction and in particular with mitochondrial and peroxisomal alterations involved in the induction of cell death and in the rupture of redox balance. As the criteria characterizing 7-ketocholesterol- and 7β-hydroxycholesterol-induced cytotoxicity are often simultaneously observed in major age-related diseases (cardiovascular diseases, age-related macular degeneration, Alzheimer's disease) the involvement of these oxysterols in the pathophysiology of the latter seems increasingly likely. It is therefore important to better understand the signalling pathways associated with the toxicity of 7-ketocholesterol and 7β-hydroxycholesterol in order to identify pharmacological targets, nutrients and synthetic molecules attenuating or inhibiting the cytotoxic activities of these oxysterols. Numerous natural cytoprotective compounds have been identified: vitamins, fatty acids, polyphenols, terpenes, vegetal pigments, antioxidants, mixtures of compounds (oils, plant extracts) and bacterial enzymes. However, few synthetic molecules are able to prevent 7-ketocholesterol- and/or 7β-hydroxycholesterol-induced cytotoxicity: dimethyl fumarate, monomethyl fumarate, the tyrosine kinase inhibitor AG126, memantine, simvastatine, Trolox, dimethylsufoxide, mangafodipir and mitochondrial permeability transition pore (MPTP) inhibitors. The effectiveness of these compounds, several of which are already in use in humans, makes it possible to consider using them for the treatment of certain age-related diseases associated with increased plasma and/or tissue levels of 7-ketocholesterol and/or 7β-hydroxycholesterol.
The Journal of Steroid Biochemistry and Molecular Biology, 2019
Oxysterols are involved in many biological processes including the regulation of cholesterol ho... more Oxysterols are involved in many biological processes including the regulation of cholesterol homeostasis The location of oxysterol metabolising enzymes may play an important role in the oxysterol concentration in cellular micro-environments. Oxysterols in biological fluids can use as markers to analyse endogenous flaws in cholesterol/oxysterol homeostasis. List of Abbreviations 20-OHC 20-hydroxycholesterol 22-OHC 22-hydroxycholesterol 24-OHC 24-hydroxycholesterol 25-OHC 25-hydroxycholesterol 26-OHC 26-hydroxycholesterol 27-OHC 27-hydroxycholesterol 5, 6-epox 5, 6-epoxy cholesterols 5α, 6α-epox 5α, 6α-epoxy cholesterol 5β, 6β-epox 5β, 6β-epoxy cholesterol 7-KC 7-ketocholesterol 7-K,25-OHC 7-keto-27-hydroxycholesterol 7α-OHC 7α-hydroxycholesterol 7α,25-OHC 7α, 25-dihydroxycholesterol 7α,27-OHC 7α, 27-hydroxycholesterol 7β-OHC 7β-hydroxycholesterol ABCA1 ATP-binding cassette transporter A1 ABCG1 ATP-binding cassette transporter G1 ACAT Acyl-CoA:cholesterol acyl transferase AD Alzheimer´s disease APP Amyloid precursor protein BBB Blood-brain barrier CH25H Cholesterol 25-hydroxylase ChEH Cholesterol-5, 6-epoxide hydrolase CNBP Cellular nucleic acid binding protein CYP46A1 Cholesterol 24-hydroxylase CYP46A1 Cytochrome P450 46A1 CYP7A1 Sterol 7α-hydroxylase CYP27 Sterol 27-hydroxylase CYP8B1 Cholesterol 12α-hydroxylase DDA Dendrogenin A LXR Liver X receptor MS Multiple Sclerosis NAFLD Non-alcoholic fatty liver disease OSBP Oxysterol binding protein PD Parkinson´s Disease POPC 1-palmitoyl-2-oleoyl-phosphatidylcholine SCAP SREBP cleavage activation protein SMO Smoothed receptor SREBP Sterol regulatory element binding protein StAR Steroidogenic acute regulatory protein THCA Trihydroxycholestanoic acid TSPO Mitochondrial translocator protein ROS Reactive oxygen species VLCFA Very long chain fatty acids WMH White Matter Hyperintensities
Peroxisomal dyfunctions (topographical, morphological, functionnal) OXIAPOPTOPHAGY No apoptosis /... more Peroxisomal dyfunctions (topographical, morphological, functionnal) OXIAPOPTOPHAGY No apoptosis / Slight autophagy Attenuation of 7KC-induced side effects by α-tocopherol Oxidative stress O 2 •and H 2 O 2 overproduction mitochondrial dyfunctions (loss of ΔΨm) Mitochondrial topographical changes
The Journal of Steroid Biochemistry and Molecular Biology, 2019
Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with s... more Induction of a non-apoptotic mode of cell death associated with autophagic characteristics with steroidal maleic anhydrides and 7-hydroxycholesterol on glioma cells
Critical Reviews in Food Science and Nutrition, 2018
Cholesterol oxidation products, also named oxysterols, can be formed either by cholesterol auto-o... more 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 metabolized, except in hepatic cells, its
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