In this work, the specificity of ubiquinol as inhibitor of the neutral sphingomyelinases present at the plasma membrane (Mg(2+)-dependent and -independent) and structural requirements for such inhibition have been studied. Our results have shown that ubiquinol specifically inhibits Mg(2+)-dependent neutral sphingomyelinase activity in isolated liver plasma membranes, but no significant participation of the Mg(2+)-independent enzyme was observed. Both the reduction state of the (hydro)quinone ring and the length of the hydrophobic side chain were important determinants in neutral sphingomyelinase inhibition. Ubiquinols inhibited the nSMase more efficiently than ubiquinones, and hydrophobic homologs with six or nine isoprene units were the most effective inhibitors. Inhibition of nSMase by ubiquinols displayed similarities with inhibition by manumycin and the hydroquinones F11334's, suggesting that these compounds could act as structural analogs of ubiquinol. Beyond its participation in mitochondrial energy metabolism, and as antioxidant, this novel role for ubiquinol as a neutral sphingomyelinase inhibitor should be considered an important factor to regulate lipid signaling at the plasma membrane that could be related to its beneficial effects on cells, tissues, and organisms.
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http://dx.doi.org/10.1016/s0006-291x(02)02222-2 | DOI Listing |
Mol Psychiatry
January 2025
Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen, Germany.
Schizophrenia is a chronic and severe mental disorder. It is currently treated with antipsychotic drugs (APD). However, APD's work only in a limited number of patients and may have cognition impairing side effects.
View Article and Find Full Text PDFMol Biol Rep
January 2025
Kusuma School of Biological Sciences, Indian Institute of Technology Delhi, Hauz Khas, New Delhi, 110016, India.
Background: Exosomes are extracellular vesicles released by cells that mediate intercellular communication and actively participate in cancer progression, metastasis, and regulation of immune response within the tumour microenvironment. Inhibiting exosome release from cancer cells could be employed as a therapeutic against cancer.
Methods And Results: In the present study, we have studied the effects of Acorus calamus in inhibiting exosome secretion via targetting Rab27a and neutral sphingomyelinase 2 (nSMase2) in HER2-positive (MDA-MB-453), hormone receptor-positive (MCF-7) and triple-negative breast cancer (MDA-MB-231) cells.
Am J Cancer Res
December 2024
Department of Biomedical Sciences, Discipline of Pharmacology, Edward Via College of Osteopathic Medicine (VCOM) Monroe, LA 71203, USA.
Prostate cancer (PCa) is the second leading cause of cancer-related deaths among American men. The development of metastatic castration resistant PCa (mCRPC) is the current clinical challenge. Antiandrogens such as Enzalutamide (ENZ) are commonly used for CRPC treatment.
View Article and Find Full Text PDFJ Lipid Res
December 2024
Department of Physiology, University of Kentucky School of Medicine, Lexington, KY. Electronic address:
Bioorg Chem
January 2025
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330 Ankara, Türkiye. Electronic address:
Bacillus cereus sphingomyelinase C (B. cereus SMase), which plays a crucial role in bacterial virulence, has emerged as a new therapeutic target for treating opportunistic infections caused by this pathogen. It also shares catalytic domain similarity with human neutral sphingomyelinase 2 (nSMase2), which is implicated in Alzheimer's disease.
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