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  1. Article: Translocator protein in the rise and fall of central nervous system neurons.

    Cheung, Garett / Lin, Yiqi Christina / Papadopoulos, Vassilios

    Frontiers in cellular neuroscience

    2023  Volume 17, Page(s) 1210205

    Abstract: Translocator protein (TSPO), a 18 kDa protein found in the outer mitochondrial membrane, has historically been associated with the transport of cholesterol in highly steroidogenic tissues though it is found in all cells throughout the mammalian body. ... ...

    Abstract Translocator protein (TSPO), a 18 kDa protein found in the outer mitochondrial membrane, has historically been associated with the transport of cholesterol in highly steroidogenic tissues though it is found in all cells throughout the mammalian body. TSPO has also been associated with molecular transport, oxidative stress, apoptosis, and energy metabolism. TSPO levels are typically low in the central nervous system (CNS), but a significant upregulation is observed in activated microglia during neuroinflammation. However, there are also a few specific regions that have been reported to have higher TSPO levels than the rest of the brain under normal conditions. These include the dentate gyrus of the hippocampus, the olfactory bulb, the subventricular zone, the choroid plexus, and the cerebellum. These areas are also all associated with adult neurogenesis, yet there is no explanation of TSPO's function in these cells. Current studies have investigated the role of TSPO in microglia during neuron degeneration, but TSPO's role in the rest of the neuron lifecycle remains to be elucidated. This review aims to discuss the known functions of TSPO and its potential role in the lifecycle of neurons within the CNS.
    Language English
    Publishing date 2023-06-21
    Publishing country Switzerland
    Document type Journal Article ; Review
    ZDB-ID 2452963-1
    ISSN 1662-5102
    ISSN 1662-5102
    DOI 10.3389/fncel.2023.1210205
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Neurosteroidogenic enzymes: CYP11A1 in the central nervous system.

    Lin, Yiqi Christina / Papadopoulos, Vassilios

    Frontiers in neuroendocrinology

    2021  Volume 62, Page(s) 100925

    Abstract: Neurosteroids, steroid hormones synthesized locally in the nervous system, have important neuromodulatory and neuroprotective effects in the central nervous system. Progress in neurosteroid research has led to the successful translation of ... ...

    Abstract Neurosteroids, steroid hormones synthesized locally in the nervous system, have important neuromodulatory and neuroprotective effects in the central nervous system. Progress in neurosteroid research has led to the successful translation of allopregnanolone into an approved therapy for postpartum depression. However, there is insufficient evidence to support the assumption that steroidogenesis is exactly the same between the nervous system and the periphery. This review focuses on CYP11A1, the only enzyme currently known to catalyze the first reaction in steroidogenesis to produce pregnenolone, the precursor to all other steroids. Although CYP11A1 mRNA has been found in brain of many mammals, the presence of CYP11A1 protein has been difficult to detect, particularly in humans. Here, we highlight the discrepancies in the current evidence for CYP11A1 in the central nervous system and propose new directions for understanding neurosteroidogenesis, which will be crucial for developing neurosteroid-based therapies for the future.
    MeSH term(s) Animals ; Brain ; Central Nervous System ; Cholesterol Side-Chain Cleavage Enzyme ; Female ; Humans ; Pregnanolone ; Pregnenolone
    Chemical Substances Pregnenolone (73R90F7MQ8) ; Pregnanolone (BXO86P3XXW) ; Cholesterol Side-Chain Cleavage Enzyme (EC 1.14.15.6)
    Language English
    Publishing date 2021-05-18
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 390985-2
    ISSN 1095-6808 ; 0532-7466 ; 0091-3022
    ISSN (online) 1095-6808
    ISSN 0532-7466 ; 0091-3022
    DOI 10.1016/j.yfrne.2021.100925
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 3423: Show issues Location:
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    Jg. 1995 - 2021: Lesesall (2.OG)
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    Zs.MO 443: Show issues

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  3. Article ; Online: Mitochondrial cytochrome P450 1B1 is involved in pregnenolone synthesis in human brain cells.

    Lin, Yiqi Christina / Cheung, Garett / Zhang, Zeyu / Papadopoulos, Vassilios

    The Journal of biological chemistry

    2023  Volume 299, Issue 8, Page(s) 105035

    Abstract: Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in ... ...

    Abstract Neurosteroids, which are steroids synthesized by the nervous system, can exert neuromodulatory and neuroprotective effects via genomic and nongenomic pathways. The neurosteroid and major steroid precursor pregnenolone has therapeutical potential in various diseases, such as psychiatric and pain disorders, and may play important roles in myelination, neuroinflammation, neurotransmission, and neuroplasticity. Although pregnenolone is synthesized by CYP11A1 in peripheral steroidogenic organs, our recent study showed that pregnenolone must be synthesized by another mitochondrial cytochrome P450 (CYP450) enzyme other than CYP11A1 in human glial cells. Therefore, we sought to identify the CYP450 responsible for pregnenolone production in the human brain. Upon screening for CYP450s expressed in the human brain that have mitochondrial localization, we identified three enzyme candidates: CYP27A1, CYP1A1, and CYP1B1. We found that inhibition of CYP27A1 through inhibitors and siRNA knockdown did not negatively affect pregnenolone synthesis in human glial cells. Meanwhile, treatment of human glial cells with CYP1A1/CYP1B1 inhibitors significantly reduced pregnenolone production in the presence of 22(R)-hydroxycholesterol. We performed siRNA knockdown of CYP1A1 or CYP1B1 in human glial cells and found that only CYP1B1 knockdown significantly decreased pregnenolone production. Furthermore, overexpression of mitochondria-targeted CYP1B1 significantly increased pregnenolone production under basal conditions and in the presence of hydroxycholesterols and low-density lipoprotein. Inhibition of CYP1A1 and/or CYP1B1 via inhibitors or siRNA knockdown did not significantly reduce pregnenolone synthesis in human adrenal cortical cells, implying that CYP1B1 is not a major pregnenolone-producing enzyme in the periphery. These data suggest that mitochondrial CYP1B1 is involved in pregnenolone synthesis in human glial cells.
    MeSH term(s) Humans ; Brain/metabolism ; Cholesterol Side-Chain Cleavage Enzyme/genetics ; Cytochrome P-450 CYP1A1/metabolism ; Cytochrome P-450 CYP1B1/metabolism ; Hydroxycholesterols/metabolism ; Mitochondria/metabolism ; Neuroglia/metabolism ; Pregnenolone/biosynthesis ; RNA, Small Interfering/metabolism ; Steroids/metabolism
    Chemical Substances Cholesterol Side-Chain Cleavage Enzyme (EC 1.14.15.6) ; Cytochrome P-450 CYP1A1 (EC 1.14.14.1) ; Cytochrome P-450 CYP1B1 (EC 1.14.14.1) ; Hydroxycholesterols ; Pregnenolone (73R90F7MQ8) ; RNA, Small Interfering ; Steroids ; CYP1B1 protein, human (EC 1.14.14.1)
    Language English
    Publishing date 2023-07-11
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.105035
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uc I Zs.108: Show issues Location:
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  4. Article ; Online: The neurosteroid pregnenolone is synthesized by a mitochondrial P450 enzyme other than CYP11A1 in human glial cells.

    Lin, Yiqi Christina / Cheung, Garett / Porter, Edith / Papadopoulos, Vassilios

    The Journal of biological chemistry

    2022  Volume 298, Issue 7, Page(s) 102110

    Abstract: Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol is converted to the major steroid precursor pregnenolone by the CYP11A1 enzyme. ... ...

    Abstract Neurosteroids, modulators of neuronal and glial cell functions, are synthesized in the nervous system from cholesterol. In peripheral steroidogenic tissues, cholesterol is converted to the major steroid precursor pregnenolone by the CYP11A1 enzyme. Although pregnenolone is one of the most abundant neurosteroids in the brain, expression of CYP11A1 is difficult to detect. We found that human glial cells produced pregnenolone, detectable by mass spectrometry and ELISA, despite the absence of observable immunoreactive CYP11A1 protein. Unlike testicular and adrenal cortical cells, pregnenolone production in glial cells was not inhibited by CYP11A1 inhibitors DL-aminoglutethimide and ketoconazole. Furthermore, addition of hydroxycholesterols increased pregnenolone synthesis, suggesting desmolase activity that was not blocked by DL-aminoglutethimide or ketoconazole. We explored three different possibilities for an alternative pathway for glial cell pregnenolone synthesis: (1) regulation by reactive oxygen species, (2) metabolism via a different CYP11A1 isoform, and (3) metabolism via another CYP450 enzyme. First, we found oxidants and antioxidants had no significant effects on pregnenolone synthesis, suggesting it is not regulated by reactive oxygen species. Second, overexpression of CYP11A1 isoform b did not alter synthesis, indicating use of another CYP11A1 isoform is unlikely. Finally, we show nitric oxide and iron chelators deferoxamine and deferiprone significantly inhibited pregnenolone production, indicating involvement of another CYP450 enzyme. Ultimately, knockdown of endoplasmic reticulum cofactor NADPH-cytochrome P450 reductase had no effect, while knockdown of mitochondrial CYP450 cofactor ferredoxin reductase inhibited pregnenolone production. These data suggest that pregnenolone is synthesized by a mitochondrial cytochrome P450 enzyme other than CYP11A1 in human glial cells.
    MeSH term(s) Aminoglutethimide ; Cholesterol/metabolism ; Cholesterol Side-Chain Cleavage Enzyme/genetics ; Humans ; Ketoconazole/pharmacology ; Neuroglia/metabolism ; Neurosteroids ; Pregnenolone/biosynthesis ; Pregnenolone/metabolism ; Reactive Oxygen Species
    Chemical Substances Neurosteroids ; Reactive Oxygen Species ; Aminoglutethimide (0O54ZQ14I9) ; Pregnenolone (73R90F7MQ8) ; Cholesterol (97C5T2UQ7J) ; Cholesterol Side-Chain Cleavage Enzyme (EC 1.14.15.6) ; Ketoconazole (R9400W927I)
    Language English
    Publishing date 2022-06-07
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2022.102110
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.108: Show issues Location:
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