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Ramírez-Montiel FB, Andrade-Guillen SY, Medina-Nieto AL, Rangel-Serrano Á, Martínez-Álvarez JA, de la Mora J, Vargas-Maya NI, Mendoza-Macías CL, Padilla-Vaca F, Franco B. Theoretical Study of Sphingomyelinases from Entamoeba histolytica and Trichomonas vaginalis Sheds Light on the Evolution of Enzymes Needed for Survival and Colonization. Pathogens 2025; 14:32. [PMID: 39860993 PMCID: PMC11768322 DOI: 10.3390/pathogens14010032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Revised: 12/16/2024] [Accepted: 12/17/2024] [Indexed: 01/27/2025] Open
Abstract
The path to survival for pathogenic organisms is not straightforward. Pathogens require a set of enzymes for tissue damage generation and to obtain nourishment, as well as a toolbox full of alternatives to bypass host defense mechanisms. Our group has shown that the parasitic protist Entamoeba histolytica encodes for 14 sphingomyelinases (SMases); one of them (acid sphingomyelinase 6, aSMase6) is involved in repairing membrane damage and exhibits hemolytic activity. The enzymatic characterization of aSMase6 has been shown to be activated by magnesium ions but not by zinc, as shown for the human aSMase, and is strongly inhibited by cobalt. However, no structural data are available for the aSMase6 enzyme. In this work, bioinformatic analyses showed that the protist aSMases are diverse enzymes, are evolutionarily related to hemolysins derived from bacteria, and showed a similar overall structure as parasitic, free-living protists and mammalian enzymes. AlphaFold3 models predicted the occupancy of cobalt ions in the active site of the aSMase6 enzyme. Cavity blind docking showed that the substrate is pushed outward of the active site when cobalt is bound instead of magnesium ions. Additionally, the structural models of the aSMase6 of E. histolytica showed a loop that is absent from the rest of the aSMases, suggesting that it may be involved in hemolytic activity, as demonstrated experimentally using the recombinant proteins of aSMase4 and aSMase6. Trichomonas vaginalis enzymes show a putative transmembrane domain and seem functionally different from E. histolytica. This work provides insight into the future biochemical analyses that can show mechanistic features of parasitic protists sphingomyelinases, ultimately rendering these enzymes potential therapeutic targets.
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Affiliation(s)
- Fátima Berenice Ramírez-Montiel
- Departamento de Farmacia, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico;
| | - Sairy Yarely Andrade-Guillen
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Ana Laura Medina-Nieto
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Ángeles Rangel-Serrano
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - José A. Martínez-Álvarez
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Javier de la Mora
- Genética Molecular, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City 04510, Mexico
| | - Naurú Idalia Vargas-Maya
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Claudia Leticia Mendoza-Macías
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Felipe Padilla-Vaca
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
| | - Bernardo Franco
- Departamento de Biología, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta s/n, Guanajuato 36050, Mexico; (S.Y.A.-G.); (J.A.M.-Á.); (C.L.M.-M.)
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Schiller M, Wilson GC, Keitsch S, Soddemann M, Wilker B, Edwards MJ, Scherbaum N, Gulbins E. Phosphatidic acid is involved in regulation of autophagy in neurons in vitro and in vivo. Pflugers Arch 2024; 476:1881-1894. [PMID: 39375214 PMCID: PMC11582205 DOI: 10.1007/s00424-024-03026-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2024] [Revised: 09/13/2024] [Accepted: 09/25/2024] [Indexed: 10/09/2024]
Abstract
Major depressive disorder (MDD) is a common and severe psychiatric disease, which does not only lead to variety of neuropsychiatric symptoms, but unfortunately in a relatively large proportion of cases also to suicide. The pathogenesis of MDD still requires definition. We have previously shown that ceramide is increased in the blood plasma of patients with MDD. In mouse models of MDD, which are induced by treatment with corticosterone or application of chronic unpredictable stress, increased blood plasma ceramide also increased and caused an inhibition of phospholipase D in endothelial cells of the hippocampus and reduced phosphatidic acid levels in the hippocampus. Here, we demonstrated that corticosterone treatment of PC12 cells resulted in reduced cellular autophagy, which is corrected by treatment with phosphatidic acid. In vivo, treatment of mice with corticosterone or chronic unpredictable stress also reduced autophagy in hippocampus neurons. Autophagy was normalized upon i.v. injection of phosphatidic acid in these mouse models of MDD. In an attempt to identify targets of phosphatidic acid in neurons, we demonstrated that corticosterone reduced levels of the ganglioside GM1 in PC-12 cells and the hippocampus of mice, which were normalized by treatment of cells or i.v. injection of mice with phosphatidic acid. GM1 application also normalized autophagy in cultured neurons. Phosphatidic acid and GM1 corrected stress-induced alterations in behavior, i.e., mainly anxiety and anhedonia, in experimental MDD in mice. Our data suggest that phosphatidic acid may regulate via GM1 autophagy in neurons.
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Affiliation(s)
- Maximilian Schiller
- LVR-University Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, Faculty of Medicine, University of Duisburg-Essen, 45147, Essen, Germany
| | - Gregory C Wilson
- Department of Surgery, University of Cincinnati College of Medicine, Cincinnati, OH, 45267-0558, USA
| | - Simone Keitsch
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Matthias Soddemann
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Barbara Wilker
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Michael J Edwards
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany
| | - Norbert Scherbaum
- LVR-University Hospital Essen, Department of Psychiatry and Psychotherapy, Faculty of Medicine, Faculty of Medicine, University of Duisburg-Essen, 45147, Essen, Germany
| | - Erich Gulbins
- Department of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122, Essen, Germany.
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Shkurnikov M, Averinskaya D, Stekolshchikova E, Serkina A, Razumovskaya A, Silkina M, Antipenko I, Makarova J, Evtushenko E, Nikulin S, Tonevitsky A. IGFBP6 regulates extracellular vesicles formation via cholesterol abundance in MDA-MB-231 cells. Biochimie 2024; 227:77-85. [PMID: 38942135 DOI: 10.1016/j.biochi.2024.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Revised: 06/06/2024] [Accepted: 06/25/2024] [Indexed: 06/30/2024]
Abstract
Breast cancer recurrence is associated with the growth of disseminated cancer cells that separate from the primary tumor before surgical treatment and hormonal therapy and form a metastatic niche in distant organs. We previously demonstrated that IGFBP6 expression is associated with the risk of early relapse of luminal breast cancer. Knockdown of IGFBP6 in MDA-MB-231 breast cancer cells increased their invasiveness, proliferation, and metastatic potential. In addition, the knockdown of IGFBP6 leads to impaired lipid metabolism. In this study, we demonstrated that the knockdown of the IGFBP6 gene, a highly selective inhibitor of IGF-II, led to a significant decline in the number of secreted extracellular vesicles (EVs) and altered cholesterol metabolism in MDA-MB-231 cells. Knockdown of IGFBP6 led to a decrease in the essential proteins responsible for the biogenesis of cholesterol LDLR and LSS, which reduced the amount by more than 13 times. In addition, the knockdown of IGFBP6 led to a possible change in the profile of adhesion molecules on the surface of EVs. The expression of L1CAM, IGSF3, EpCAM, CD24, and CD44 decreased, and the expression of EGFR increased. We can conclude that the negative prognostic value of low expression of this gene could be associated with increased activity of IGF2 in tumor-associated fibroblasts due to low secretion of IGFBP6 by tumor cells. In addition, changing the profile of adhesion molecules on the surface of tumor EVs may contribute to the more efficient formation of metastatic niches.
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Affiliation(s)
- Maxim Shkurnikov
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia.
| | - Darya Averinskaya
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | - Elena Stekolshchikova
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Anna Serkina
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Alexandra Razumovskaya
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
| | - Maria Silkina
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia
| | - Ivan Antipenko
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | - Julia Makarova
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia
| | | | - Sergey Nikulin
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; P. Hertsen Moscow Oncology Research Institute-Branch of the National Medical Research Radiological Centre of the Ministry of Health of Russian Federation, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - Alexander Tonevitsky
- Faculty of Biology and Biotechnology, HSE University, Moscow, Russia; Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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Weber-Stout M, Nicholson RJ, Dumaguit CDC, Holland WL, Summers SA. Ceramide microdomains: the major influencers of the sphingolipid media platform. Biochem Soc Trans 2024; 52:1765-1776. [PMID: 39082976 PMCID: PMC11845337 DOI: 10.1042/bst20231395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2024]
Abstract
Like 'influencers' who achieve fame and power through social media, ceramides are low abundance members of communication platforms that have a mighty impact on their surroundings. Ceramide microdomains form within sphingolipid-laden lipid rafts that confer detergent resistance to cell membranes and serve as important signaling hubs. In cells exposed to excessive amounts of saturated fatty acids (e.g. in obesity), the abundance of ceramide-rich microdomains within these rafts increases, leading to concomitant alterations in cellular metabolism and survival that contribute to cardiometabolic disease. In this mini-review, we discuss the evidence supporting the formation of these ceramide microdomains and describe the spectrum of harmful ceramide-driven metabolic actions under the context of an evolutionary theory. Moreover, we discuss the proximal 'followers' of these ceramide media stars that account for the diverse intracellular actions that allow them to influence obesity-linked disease.
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Affiliation(s)
- Mariah Weber-Stout
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, U.S.A
| | - Rebekah J Nicholson
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, U.S.A
| | - Carlos Dave C Dumaguit
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, U.S.A
| | - William L Holland
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, U.S.A
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology and the Diabetes and Metabolism Research Center, University of Utah, Salt Lake City, UT 84112, U.S.A
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Liu T, Xie Q, Wang W. Ultrasound-stimulated microbubbles enhances radiosensitivity in cervical cancer. Int J Radiat Biol 2024; 100:1416-1425. [PMID: 39101819 DOI: 10.1080/09553002.2024.2374903] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 03/08/2024] [Accepted: 06/21/2024] [Indexed: 08/06/2024]
Abstract
BACKGROUND Ultrasound-stimulated microbubble (USMB) therapy has proven efficacy of targeting tumor vasculature and enhancing the effect of radiation in tumor xenografts. In this investigation, we studied whether this treatment enhances the sensitivity of cervical cancer to radiation. METHODS Human cervical cancer (ME-180 and SiHa) cells were treated with USMB or exposed to radiation (0, 2, 4, 6 and 8 Gy) or radiation (8 Gy) in combination with USMB. Clone formation assay and CCK-8 assay were used to analyze the proliferation capacity of cells. Apoptosis and DNA double-strand breaks were detected using flow cytometry and immunofluorescence staining of gamma-H2AX (γ-H2AX), respectively. Matrigel tubule formation was performed to evaluate the angiogenesis of human umbilical vein endothelial cells. In xenograft model of SiHa cells, tumor tissue expression of CD31 was detected by immunohistochemistry. RESULTS USMB and radiation synergistically restrained the growth of ME-180 and SiHa cells. USMB promoted radiation-induced apoptosis by enhancing the levels of proapoptotic proteins. Furthermore, USMB enhanced radiation-induced γ-H2AX foci to induce DNA double-strand breaks in cervical cancer cells. USMB in combination with radiation reduced the angiogenic capacity of endothelial cells in vitro. Moreover, USMB strengthened the inhibitory effect of radiation on tumor growth and angiogenesis in xenograft models. CONCLUSION In conclusion, USMB exposure effectively enhanced the destructive effect of radiation on cervical cancer, suggesting that USMB might be a promising sensitizer of radiotherapy to treat cervical cancer.
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Affiliation(s)
- Tianying Liu
- Department of Ultrasonography, Xidian Group Hospital, Xi'an, China
| | - Qing Xie
- Department of Ultrasonography, The Third Hospital of Xi 'an, Affiliated Hospital of Northwest University, Xi'An, China
| | - Wenli Wang
- Department of Ultrasonography, The Third Hospital of Xi 'an, Affiliated Hospital of Northwest University, Xi'An, China
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Nojima H, Shimizu H, Murakami T, Shuto K, Koda K. Critical Roles of the Sphingolipid Metabolic Pathway in Liver Regeneration, Hepatocellular Carcinoma Progression and Therapy. Cancers (Basel) 2024; 16:850. [PMID: 38473211 DOI: 10.3390/cancers16050850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 02/14/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
The sphingolipid metabolic pathway, an important signaling pathway, plays a crucial role in various physiological processes including cell proliferation, survival, apoptosis, and immune regulation. The liver has the unique ability to regenerate using bioactive lipid mediators involving multiple sphingolipids, including ceramide and sphingosine 1-phosphate (S1P). Dysregulation of the balance between sphingomyelin, ceramide, and S1P has been implicated in the regulation of liver regeneration and diseases, including liver fibrosis and hepatocellular carcinoma (HCC). Understanding and modulating this balance may have therapeutic implications for tumor proliferation, progression, and metastasis in HCC. For cancer therapy, several inhibitors and activators of sphingolipid signaling, including ABC294640, SKI-II, and FTY720, have been discussed. Here, we elucidate the critical roles of the sphingolipid pathway in the regulation of liver regeneration, fibrosis, and HCC. Regulation of sphingolipids and their corresponding enzymes may considerably influence new insights into therapies for various liver disorders and diseases.
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Affiliation(s)
- Hiroyuki Nojima
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Hiroaki Shimizu
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Takashi Murakami
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Kiyohiko Shuto
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
| | - Keiji Koda
- Department of Surgery, Teikyo University Chiba Medical Center, 3426-3, Anesaki, Ichihara, Chiba 299-0011, Japan
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Kleuser B, Schumacher F, Gulbins E. New Therapeutic Options in Pulmonal Diseases: Sphingolipids and Modulation of Sphingolipid Metabolism. Handb Exp Pharmacol 2024; 284:289-312. [PMID: 37922034 DOI: 10.1007/164_2023_700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2023]
Abstract
Sphingolipids are crucial molecules in the respiratory airways. As in most other tissues and organs, in the lung sphingolipids play an essential role as structural constituents as they regulate barrier function and fluidity of cell membranes. A lung-specific feature is the occurrence of sphingolipids as minor structural components in the surfactant. However, sphingolipids are also key signaling molecules involved in airway cell signaling and their dynamical formation and metabolism are important for normal lung physiology. Dysregulation of sphingolipid metabolism and signaling is involved in altering lung tissue and initiates inflammatory processes promoting the pathogenesis of pulmonal diseases including cystic fibrosis (CF), chronic obstructive pulmonary disease (COPD), and asthma.In the present review, the important role of specific sphingolipid species in pulmonal diseases will be discussed. Only such an understanding opens up the possibility of developing new therapeutic strategies with the aim of correcting the imbalance in sphingolipid metabolism and signaling. Such delivery strategies have already been studied in animal models of these lung diseases, demonstrating that targeting the sphingolipid profile represents new therapeutic opportunities for lung disorders.
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Affiliation(s)
- Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany.
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, Berlin, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
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Shi M, Tang C, Wu JX, Ji BW, Gong BM, Wu XH, Wang X. Mass Spectrometry Detects Sphingolipid Metabolites for Discovery of New Strategy for Cancer Therapy from the Aspect of Programmed Cell Death. Metabolites 2023; 13:867. [PMID: 37512574 PMCID: PMC10384871 DOI: 10.3390/metabo13070867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Sphingolipids, a type of bioactive lipid, play crucial roles within cells, serving as integral components of membranes and exhibiting strong signaling properties that have potential therapeutic implications in anti-cancer treatments. However, due to the diverse group of lipids and intricate mechanisms, sphingolipids still face challenges in enhancing the efficacy of different therapy approaches. In recent decades, mass spectrometry has made significant advancements in uncovering sphingolipid biomarkers and elucidating their impact on cancer development, progression, and resistance. Primary sphingolipids, such as ceramide and sphingosine-1-phosphate, exhibit contrasting roles in regulating cancer cell death and survival. The evasion of cell death is a characteristic hallmark of cancer cells, leading to treatment failure and a poor prognosis. The escape initiates with long-established apoptosis and extends to other programmed cell death (PCD) forms when patients experience chemotherapy, radiotherapy, and/or immunotherapy. Gradually, supportive evidence has uncovered the fundamental molecular mechanisms underlying various forms of PCD leading to the development of innovative molecular, genetic, and pharmacological tools that specifically target sphingolipid signaling nodes. In this study, we provide a comprehensive overview of the sphingolipid biomarkers revealed through mass spectrometry in recent decades, as well as an in-depth analysis of the six main forms of PCD (apoptosis, autophagy, pyroptosis, necroptosis, ferroptosis, and cuproptosis) in aspects of tumorigenesis, metastasis, and tumor response to treatments. We review the corresponding small-molecule compounds associated with these processes and their potential implications in cancer therapy.
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Affiliation(s)
- Ming Shi
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
- Dongguan Key Laboratory of Medical Bioactive Molecular Developmental and Translational Research, Guangdong Provincial Key Laboratory of Medical Molecular Diagnostics, Guangdong Medical University, Dongguan 523808, China
| | - Chao Tang
- National Clinical Research Center for Child Health, The Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Jia-Xing Wu
- SINO-SWISS Institute of Advanced Technology, School of Microelectronics, Shanghai University, Shanghai 200444, China
| | - Bao-Wei Ji
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai 200032, China
| | - Bao-Ming Gong
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xiao-Hui Wu
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
| | - Xue Wang
- State Key Laboratory of Genetic Engineering and National Center for International Research of Development and Disease, Collaborative Innovation Center of Genetics and Development, Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200438, China
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Ghadami S, Dellinger K. The lipid composition of extracellular vesicles: applications in diagnostics and therapeutic delivery. Front Mol Biosci 2023; 10:1198044. [PMID: 37520326 PMCID: PMC10381967 DOI: 10.3389/fmolb.2023.1198044] [Citation(s) in RCA: 43] [Impact Index Per Article: 21.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 07/03/2023] [Indexed: 08/01/2023] Open
Abstract
Extracellular vesicles (EVs), including exosomes, with nanoscale sizes, biological origins, various functions, and unique lipid and protein compositions have been introduced as versatile tools for diagnostic and therapeutic medical applications. Numerous studies have reported the importance of the lipid composition of EVs and its influence on their mechanism of action. For example, changes in the lipidomic profile of EVs have been shown to influence the progression of various diseases, including ovarian malignancies and prostate cancer. In this review, we endeavored to examine differences in the lipid content of EV membranes derived from different cell types to characterize their capabilities as diagnostic tools and treatments for diseases like cancer and Alzheimer's disease. We additionally discuss designing functionalized vesicles, whether synthetically by hybrid methods or by changing the lipid composition of natural EVs. Lastly, we provide an overview of current and potential biomedical applications and perspectives on the future of this growing field.
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Affiliation(s)
| | - Kristen Dellinger
- Department of Nanoengineering, Joint School of Nanoscience and Nanoengineering, North Carolina A&T State University, Greensboro, NC, United States
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Mishra A, Bharti PS, Rani N, Nikolajeff F, Kumar S. A tale of exosomes and their implication in cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188908. [PMID: 37172650 DOI: 10.1016/j.bbcan.2023.188908] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 05/01/2023] [Accepted: 05/05/2023] [Indexed: 05/15/2023]
Abstract
Cancer is a cause of high deaths worldwide and also a huge burden for the health system. Cancer cells have unique properties such as a high rate of proliferation, self-renewal, metastasis, and treatment resistance, therefore, the development of novel diagnoses of cancers is a tedious task. Exosomes are secreted by virtually all cell types and have the ability to carry a multitude of biomolecules crucial for intercellular communication, hence, contributing a crucial part in the onset and spread of cancer. These exosomal components can be utilized in the development of markers for diagnostic and prognostic purposes for various cancers. This review emphasized primarily the following topics: exosomes structure and functions, isolation and characterization strategies of exosomes, the role of exosomal contents in cancer with a focus in particular on noncoding RNA and protein, exosomes, and the cancer microenvironment interactions, cancer stem cells, and tumor diagnosis and prognosis based on exosomes.
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Affiliation(s)
- Abhay Mishra
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Prahalad Singh Bharti
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Neerja Rani
- Department of Anatomy, All India Institute of Medical Sciences, New Delhi 110029, India
| | - Fredrik Nikolajeff
- Department of Health, Education, and Technology, Lulea University of Technology, 97187, Sweden
| | - Saroj Kumar
- Department of Biophysics, All India Institute of Medical Sciences, New Delhi 110029, India; Department of Health, Education, and Technology, Lulea University of Technology, 97187, Sweden.
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Xiang H, Xu Z, Zhang C, Xiong J. Macrophage-derived exosomes mediate glomerular endothelial cell dysfunction in sepsis-associated acute kidney injury. Cell Biosci 2023; 13:46. [PMID: 36879272 PMCID: PMC9990300 DOI: 10.1186/s13578-023-00990-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Accepted: 02/14/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Sepsis-associated AKI has been shown to be related to sepsis mortality. Macrophage activation and endothelial cell damage are involved in the progression of sepsis-associated AKI, but the specific mechanisms are still unclear. METHODS In vitro experiments, exosomes extracted from lipopolysaccharide (LPS) -stimulated macrophages were co-incubated with rat glomerular endothelial cells (RGECs) and then detected the injury markers of RGECs. Acid sphingomyelinase (ASM) inhibitor amitriptyline were used to investigate the role of ASM. In vivo experiment, exosomes produced by LPS-stimulated macrophages were injected into mice through tail vein to further explore the role of macrophage-derived exosomes. Moreover, ASM knockout mice were used to verify the mechanism. RESULT In vitro, the secretion of macrophage exosomes increased upon the stimulation with LPS. Notably, macrophage-derived exosomes can cause glomerular endothelial cell dysfunction. In vivo, macrophage infiltration and exosome secretion in glomeruli of the LPS-induced AKI group increased. The exosomes produced by LPS-stimulated macrophages were injected into mice, which also led to the injury of renal endothelial cells. In addition, in the LPS-induced AKI mouse model, compared with wild-type mice, the secretion of exosomes in glomeruli of ASM gene knockout mice and the injury of endothelial cells were reduced. CONCLUSION Our study shows that ASM regulates the secretion of macrophage exosomes, leading to endothelial cell injury, which may be a therapeutic target in sepsis-associated AKI.
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Affiliation(s)
- Huiling Xiang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhifeng Xu
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jing Xiong
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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12
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Caterino M, Fedele R, Carnovale V, Castaldo A, Gelzo M, Iacotucci P, Ruoppolo M, Castaldo G. Lipidomic alterations in human saliva from cystic fibrosis patients. Sci Rep 2023; 13:600. [PMID: 36635275 PMCID: PMC9837121 DOI: 10.1038/s41598-022-24429-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 11/15/2022] [Indexed: 01/14/2023] Open
Abstract
Cystic fibrosis is a hereditary metabolic disorder characterized by impaired traffic of chloride ions and water through membranes of the respiratory and gastrointestinal, that causes inadequate hydration of airway surfaces, dehydrated mucous secretions and a high-sodium chloride sweat. Although the classical presentation of the condition is well known, a better characterization of metabolic alterations related is need. In particular, the metabolic composition alterations of biological fluids may be influence by the disease state and could be captured as putative signature to set targeted therapeutic strategies. A targeted comprehensive mass spectrometry-based platform was employed to dissect the lipid content of saliva samples form CF patients, in order to investigate alterations in the lipid metabolic homeostasis related to the pathology, chronic obstructive pulmonary disease, Pseudomonas Aeruginosa infection, pancreatic insufficiency, liver disfunction and diabetes-related complications.
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Affiliation(s)
- Marianna Caterino
- grid.4691.a0000 0001 0790 385XDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy ,grid.511947.f0000 0004 1758 0953CEINGE - Biotecnologie Avanzate F. Salvatore, s.c.ar.l, 80145 Napoli, Italy
| | - Roberta Fedele
- grid.511947.f0000 0004 1758 0953CEINGE - Biotecnologie Avanzate F. Salvatore, s.c.ar.l, 80145 Napoli, Italy
| | - Vincenzo Carnovale
- grid.4691.a0000 0001 0790 385XDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Alice Castaldo
- grid.4691.a0000 0001 0790 385XDepartment of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Monica Gelzo
- grid.4691.a0000 0001 0790 385XDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy ,grid.511947.f0000 0004 1758 0953CEINGE - Biotecnologie Avanzate F. Salvatore, s.c.ar.l, 80145 Napoli, Italy
| | - Paola Iacotucci
- grid.4691.a0000 0001 0790 385XDepartment of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy
| | - Margherita Ruoppolo
- Department of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131, Naples, Italy. .,CEINGE - Biotecnologie Avanzate F. Salvatore, s.c.ar.l, 80145, Napoli, Italy.
| | - Giuseppe Castaldo
- grid.4691.a0000 0001 0790 385XDepartment of Molecular Medicine and Medical Biotechnology, School of Medicine, University of Naples Federico II, 80131 Naples, Italy ,grid.511947.f0000 0004 1758 0953CEINGE - Biotecnologie Avanzate F. Salvatore, s.c.ar.l, 80145 Napoli, Italy
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13
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Gulbins A, Görtz GE, Gulbins E, Eckstein A. Sphingolipids in thyroid eye disease. Front Endocrinol (Lausanne) 2023; 14:1170884. [PMID: 37082124 PMCID: PMC10112667 DOI: 10.3389/fendo.2023.1170884] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 03/22/2023] [Indexed: 04/22/2023] Open
Abstract
Graves' disease (GD) is caused by an autoimmune formation of autoantibodies and autoreactive T-cells against the thyroid stimulating hormone receptor (TSHR). The autoimmune reaction does not only lead to overstimulation of the thyroid gland, but very often also to an immune reaction against antigens within the orbital tissue leading to thyroid eye disease, which is characterized by activation of orbital fibroblasts, orbital generation of adipocytes and myofibroblasts and increased hyaluronan production in the orbit. Thyroid eye disease is the most common extra-thyroidal manifestation of the autoimmune Graves' disease. Several studies indicate an important role of sphingolipids, in particular the acid sphingomyelinase/ceramide system and sphingosine 1-phosphate in thyroid eye disease. Here, we discuss how the biophysical properties of sphingolipids contribute to cell signaling, in particular in the context of thyroid eye disease. We further review the role of the acid sphingomyelinase/ceramide system in autoimmune diseases and its function in T lymphocytes to provide some novel hypotheses for the pathogenesis of thyroid eye disease and potentially allowing the development of novel treatments.
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Affiliation(s)
- Anne Gulbins
- Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Gina-Eva Görtz
- Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Anja Eckstein, ; Erich Gulbins,
| | - Anja Eckstein
- Department of Ophthalmology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
- *Correspondence: Anja Eckstein, ; Erich Gulbins,
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14
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Celauro L, Zattoni M, Legname G. Prion receptors, prion internalization, intra- and inter-cellular transport. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2023; 196:15-41. [PMID: 36813357 DOI: 10.1016/bs.pmbts.2022.06.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Affiliation(s)
- Luigi Celauro
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
| | - Marco Zattoni
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy
| | - Giuseppe Legname
- Laboratory of Prion Biology, Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Trieste, Italy.
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15
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Jin Y, Ma L, Zhang W, Yang W, Feng Q, Wang H. Extracellular signals regulate the biogenesis of extracellular vesicles. Biol Res 2022; 55:35. [PMID: 36435789 PMCID: PMC9701380 DOI: 10.1186/s40659-022-00405-2] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/15/2022] [Indexed: 11/28/2022] Open
Abstract
Extracellular vesicles (EVs) are naturally released membrane vesicles that act as carriers of proteins and RNAs for intercellular communication. With various biomolecules and specific ligands, EV has represented a novel form of information transfer, which possesses extremely outstanding efficiency and specificity compared to the classical signal transduction. In addition, EV has extended the concept of signal transduction to intercellular aspect by working as the collection of extracellular information. Therefore, the functions of EVs have been extensively characterized and EVs exhibit an exciting prospect for clinical applications. However, the biogenesis of EVs and, in particular, the regulation of this process by extracellular signals, which are essential to conduct further studies and support optimal utility, remain unclear. Here, we review the current understanding of the biogenesis of EVs, focus on the regulation of this process by extracellular signals and discuss their therapeutic value.
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Affiliation(s)
- Yong Jin
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China
| | - Lele Ma
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China
| | - Wanying Zhang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China
| | - Wen Yang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China.,National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital/Institute, The Second Military Medical University, Shanghai, 20815, China
| | - Qiyu Feng
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China.
| | - Hongyang Wang
- Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230036, Anhui, People's Republic of China. .,National Center for Liver Cancer, Eastern Hepatobiliary Surgery Hospital/Institute, The Second Military Medical University, Shanghai, 20815, China.
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16
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Han QF, Li WJ, Hu KS, Gao J, Zhai WL, Yang JH, Zhang SJ. Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer. Mol Cancer 2022; 21:207. [PMID: 36320056 PMCID: PMC9623991 DOI: 10.1186/s12943-022-01671-0] [Citation(s) in RCA: 271] [Impact Index Per Article: 90.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/13/2022] [Indexed: 12/14/2022] Open
Abstract
Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.
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Affiliation(s)
- Qing-Fang Han
- grid.412633.10000 0004 1799 0733Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,grid.412633.10000 0004 1799 0733Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Wen-Jia Li
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research Center, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, 510120 China
| | - Kai-Shun Hu
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation Medical Research Center, Sun Yat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, 510120 China
| | - Jie Gao
- grid.412633.10000 0004 1799 0733Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,Henan Diagnosis & Treatment League for Hepatopathy, Zhengzhou, 450052 Henan China
| | - Wen-Long Zhai
- grid.412633.10000 0004 1799 0733Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Jing-Hua Yang
- grid.412633.10000 0004 1799 0733Clinical Systems Biology Key Laboratories of Henan, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Shui-Jun Zhang
- grid.412633.10000 0004 1799 0733Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,grid.412633.10000 0004 1799 0733Henan Research Centre for Organ Transplantation, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China ,Henan Diagnosis & Treatment League for Hepatopathy, Zhengzhou, 450052 Henan China ,Henan Engineering & Research Center for Diagnosis and Treatment of Hepatobiliary and Pancreatic Surgical Diseases, Zhengzhou, 450052 Henan China
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17
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Nakhaee H, Zangiabadian M, Bayati R, Rahmanian M, Ghaffari Jolfayi A, Rakhshanderou S. The effect of antidepressants on the severity of COVID-19 in hospitalized patients: A systematic review and meta-analysis. PLoS One 2022; 17:e0267423. [PMID: 36201406 PMCID: PMC9536564 DOI: 10.1371/journal.pone.0267423] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Accepted: 09/21/2022] [Indexed: 11/20/2022] Open
Abstract
INTRODUCTION Clinical Depression and the subsequent low immunity is a comorbidity that can act as a risk factor for the severity of COVID-19 cases. Antidepressants such as Selective serotonin reuptake inhibitor and Serotonin-norepinephrine reuptake inhibitors are associated with immune-modulatory effects, which dismiss inflammatory responses and reduce lung tissue damage. The current systematic review and meta-analysis aims to evaluate the effect of antidepressant drugs on the prognosis and severity of COVID-19 in hospitalized patients. METHODS A systematic search was carried out in PubMed/Medline, EMBASE, and Scopus up to June 14, 2022. The following keywords were used: "COVID-19", "SARS-CoV-2", "2019-nCoV", "SSRI", "SNRI", "TCA", "MAOI", and "Antidepressant". A fixed or random-effect model assessed the pooled risk ratio (RR) with 95% CI. We considered P < 0.05 as statistically significant for publication bias. Data were analyzed by Comprehensive Meta-Analysis software, Version 2.0 (Biostat, Englewood, NJ). RESULTS Fourteen studies were included in our systematic review. Five of them were experimental with 2350, and nine of them were observational with 290,950 participants. Eight out of fourteen articles revealed the effect of antidepressants on reducing the severity of COVID-19. Selective serotonin reuptake inhibitors drugs, including Fluvoxamine, Escitalopram, Fluoxetine, and Paroxetine, and among the Serotonin-norepinephrine inhibitors medications Venlafaxine, are reasonably associated with reduced risk of intubation or death. Five studies showed no significant effect, and only one high risk of bias article showed the negative effect of antidepressants on the prognosis of Covid-19. The meta-analysis of clinical trials showed that fluvoxamine could significantly decrease the severity outcomes of COVID-19 (RR: 0.763; 95% CI: 0.602-0.966, I2: 0.0). FINDINGS Most evidence supports that the use of antidepressant medications, mainly Fluvoxamine, may decrease the severity and improve the outcome in hospitalized patients with SARS-CoV-2. Some studies showed contradictory findings regarding the effects of antidepressants on the severity of COVID-19. Further clinical trials should be conducted to clarify the effects of antidepressants on the severity of COVID-19.
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Affiliation(s)
- Hosein Nakhaee
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moein Zangiabadian
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Reza Bayati
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Rahmanian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Ghaffari Jolfayi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sakineh Rakhshanderou
- Environmental and Occupational Hazards Control Research Center, School of Public Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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18
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Stress induces major depressive disorder by a neutral sphingomyelinase 2-mediated accumulation of ceramide-enriched exosomes in the blood plasma. J Mol Med (Berl) 2022; 100:1493-1508. [PMID: 36045177 PMCID: PMC9470690 DOI: 10.1007/s00109-022-02250-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/11/2022] [Accepted: 08/17/2022] [Indexed: 10/28/2022]
Abstract
Major depressive disorder (MDD) is a very common, severe disease with a lifetime prevalence of ~ 10%. The pathogenesis of MDD is unknown and, unfortunately, therapy is often insufficient. We have previously reported that ceramide levels are increased in the blood plasma of patients with MDD and in mice with experimental MDD. Here, we demonstrate that ceramide-enriched exosomes in the blood plasma are increased in mice with stress-induced MDD. Genetic studies reveal that neutral sphingomyelinase 2 is required for the formation of ceramide-enriched exosomes in the blood plasma. Accordingly, induced deficiency of neutral sphingomyelinase 2 prevented mice from the development of stress-induced MDD. Intravenous injection of microparticles from mice with MDD or injection of ceramide-loaded exosomes induced MDD-like behavior in untreated mice, which was abrogated by ex vivo pre-incubation of purified exosomes with anti-ceramide antibodies or ceramidase. Mechanistically, injection of exosomes from mice with MDD or injection of ex vivo ceramide-loaded microparticles inhibited phospholipase D (PLD) in endothelial cells in vitro and in the hippocampus in vivo and thereby decreased phosphatidic acid in the hippocampus, which has been previously shown to mediate MDD by plasma ceramide. In summary, our data indicate that ceramide-enriched exosomes are released by neutral sphingomyelinase 2 into the blood plasma upon stress and mediate stress-induced MDD. KEY MESSAGES: Stress induces ceramide-enriched exosomes in the blood plasma. Ceramide-enriched exosomes mediate major depressive disorder (MDD). Deficiency of neutral sphingomyelinase 2 protects from stress-induced MDD. Neutralization or digestion of ceramide in exosomes prevents stress-induced MDD. Ceramide-enriched exosomes inhibit endothelial phospholipase D in the hippocampus.
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19
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Huang Z, Chu M, Chen X, Wang Z, Jiang L, Ma Y, Wang Y. Th2A cells: The pathogenic players in allergic diseases. Front Immunol 2022; 13:916778. [PMID: 36003397 PMCID: PMC9393262 DOI: 10.3389/fimmu.2022.916778] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 07/12/2022] [Indexed: 11/13/2022] Open
Abstract
Proallergic type 2 helper T (Th2A) cells are a subset of memory Th2 cells confined to atopic individuals, and they include all the allergen-specific Th2 cells. Recently, many studies have shown that Th2A cells characterized by CD3+ CD4+ HPGDS+ CRTH2+ CD161high ST2high CD49dhigh CD27low play a crucial role in allergic diseases, such as atopic dermatitis (AD), food allergy (FA), allergic rhinitis (AR), asthma, and eosinophilic esophagitis (EoE). In this review, we summarize the discovery, biomarkers, and biological properties of Th2A cells to gain new insights into the pathogenesis of allergic diseases.
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Affiliation(s)
- Ziyu Huang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
- Department of Clinical Medicine, Mudanjiang Medical University, Mudanjiang, China
| | - Ming Chu
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Xi Chen
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Ziyuan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Lin Jiang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yinchao Ma
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
| | - Yuedan Wang
- Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Beijing, China
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20
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Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial and Natural Cell Membranes. MEMBRANES 2022; 12:membranes12080727. [PMID: 35893445 PMCID: PMC9330320 DOI: 10.3390/membranes12080727] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/19/2022] [Accepted: 07/20/2022] [Indexed: 02/02/2023]
Abstract
Ceramide is the simplest precursor of sphingolipids and is involved in a variety of biological functions ranging from apoptosis to the immune responses. Although ceramide is a minor constituent of plasma membranes, it drastically increases upon cellular stimulation. However, the mechanistic link between ceramide generation and signal transduction remains unknown. To address this issue, the effect of ceramide on phospholipid membranes has been examined in numerous studies. One of the most remarkable findings of these studies is that ceramide induces the coalescence of membrane domains termed lipid rafts. Thus, it has been hypothesised that ceramide exerts its biological activity through the structural alteration of lipid rafts. In the present article, we first discuss the characteristic hydrogen bond functionality of ceramides. Then, we showed the impact of ceramide on the structures of artificial and cell membranes, including the coalescence of the pre-existing lipid raft into a large patch called a signal platform. Moreover, we proposed a possible structure of the signal platform, in which sphingomyelin/cholesterol-rich and sphingomyelin/ceramide-rich domains coexist. This structure is considered to be beneficial because membrane proteins and their inhibitors are separately compartmentalised in those domains. Considering the fact that ceramide/cholesterol content regulates the miscibility of those two domains in model membranes, the association and dissociation of membrane proteins and their inhibitors might be controlled by the contents of ceramide and cholesterol in the signal platform.
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21
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Zhuo C, Zhao F, Tian H, Chen J, Li Q, Yang L, Ping J, Li R, Wang L, Xu Y, Cai Z, Song X. Acid sphingomyelinase/ceramide system in schizophrenia: implications for therapeutic intervention as a potential novel target. Transl Psychiatry 2022; 12:260. [PMID: 35739089 PMCID: PMC9226132 DOI: 10.1038/s41398-022-01999-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 11/09/2022] Open
Abstract
Schizophrenia is a severe mental illness, as the efficacies of current antipsychotic medications are far from satisfactory. An improved understanding of the signaling molecules involved in schizophrenia may provide novel therapeutic targets. Acid sphingomyelinase (ASM) catalyzes cellular membrane sphingomyelin into ceramide, which is further metabolized into sphingosine-1-phophate (S1P). ASM, ceramide, and S1P at the cell surface exert critical roles in the regulation of biophysical processes that include proliferation, apoptosis, and inflammation, and are thereby considered important signaling molecules. Although research on the ASM/ceramide system is still in its infancy, structural and metabolic abnormalities have been demonstrated in schizophrenia. ASM/ceramide system dysfunction is linked to the two important models of schizophrenia, the dopamine (DA) hypothesis through affecting presynaptic DA signaling, and the vulnerability-stress-inflammation model that includes the contribution of stress on the basis of genetic predisposition. In this review, we highlight the current knowledge of ASM/ceramide system dysfunction in schizophrenia gained from human and animal studies, and formulate future directions from the biological landscape for the development of new treatments. Collectively, these discoveries suggest that aberrations in the ASM/ceramide system, especially in ASM activity and levels of ceramide and S1P, may alter cerebral microdomain structure and neuronal metabolism, leading to neurotransmitter (e.g., DA) dysfunction and neuroinflammation. As such, the ASM/ceramide system may offer therapeutic targets for novel medical interventions. Normalization of the aberrant ASM/ceramide system or ceramide reduction by using approved functional inhibitors of ASM, such as fluvoxamine and rosuvastatin, may improve clinical outcomes of patients with schizophrenia. These transformative findings of the ASM/ceramide system in schizophrenia, although intriguing and exciting, may pose scientific questions and challenges that will require further studies for their resolution.
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Affiliation(s)
- Chuanjun Zhuo
- Key Laboratory of Real Time Tracing Brain Circuit, Tianjin Medical Affiliated Tianjin Fourth Center Hospital, Nankai University Affiliated Tianjin Fourth Center Hospital, Tianjin Fourth Hospital, 300140, Tianjin, China. .,The key Laboratory of Psychiatric-Neuroimaging-Genetics and Comorbidity (PNGC_Lab) of Tianjin Anding Hospital, Tianjin Mental Health Center of Tianjin Medical University, 300222, Tianjin, China. .,Brain Micro-imaging Center of Psychiatric Animal Model, Wenzhou Seventh Peoples Hospital, 325000, Wenzhou, China. .,Department of Psychiatry, The Fourth Center Hospital of Tianjin Medical University, 300222, Tianjin, China. .,Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000, Wenzhou, China. .,Department of Psychiatry, The First Hospital of Shanxi Medical University, 03000, Taiyuan, China. .,Department of Psychiatry, First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
| | - Feifei Zhao
- Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000 Wenzhou, China
| | - Hongjun Tian
- grid.265021.20000 0000 9792 1228Department of Psychiatry, The Fourth Center Hospital of Tianjin Medical University, 300222 Tianjin, China
| | - Jiayue Chen
- grid.265021.20000 0000 9792 1228Department of Psychiatry, The Fourth Center Hospital of Tianjin Medical University, 300222 Tianjin, China
| | - Qianchen Li
- grid.265021.20000 0000 9792 1228Department of Psychiatry, The Fourth Center Hospital of Tianjin Medical University, 300222 Tianjin, China
| | - Lei Yang
- grid.265021.20000 0000 9792 1228Department of Psychiatry, The Fourth Center Hospital of Tianjin Medical University, 300222 Tianjin, China
| | - Jing Ping
- Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000 Wenzhou, China
| | - Ranli Li
- Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000 Wenzhou, China
| | - Lina Wang
- Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000 Wenzhou, China
| | - Yong Xu
- grid.452461.00000 0004 1762 8478Department of Psychiatry, The First Hospital of Shanxi Medical University, 03000 Taiyuan, China
| | - Ziyao Cai
- Key Laboratory of the Macro-Brain Neuroimaging Center of Animal Model, Wenzhou Seventh Peoples Hospital, 325000 Wenzhou, China
| | - Xueqin Song
- Department of Psychiatry, First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China.
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22
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Shi J, Wang T, Guo H, Li C, Li L, Jin Y, Chen H, Huang J. High-resolution mass spectrometry assay for quantifying ceramides and dihydroceramides in the cerebrospinal fluid from patients who experienced intracranial infection after craniotomy. J Pharm Biomed Anal 2022; 219:114907. [PMID: 35772235 DOI: 10.1016/j.jpba.2022.114907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 06/13/2022] [Accepted: 06/20/2022] [Indexed: 10/17/2022]
Abstract
Ceramides (CERs) and dihydroceramides (dhCERs) are biologically active lipids involved in cell proliferation, differentiation, and apoptosis, as well as associated with infectious diseases. The concentration of CERs and dhCERs in the cerebrospinal fluid (CSF) could potentially allow the distinction of patients with intracranial infection (ICI) after craniotomy from controls, but the quantification is limited by their ultralow concentrations. Therefore, a novel high performance liquid chromatography-triple-quadrupole/time-of-flight mass spectrometry (HPLC-QTOF-MS) with Sequential Window Acquisition of All Theoretical Fragment Ion Spectra (SWATH) was applied to measure CERs and dhCERs in CSF, since it possesses a higher sensitivity (LLOQ = 0.1 pmol/mL) than the multiple reaction monitoring (MRM) acquisition carried on triple quadrupole (QqQ) MS. This method was validated and applied to CSF samples from patients who experienced postoperative ICI (63 patients) and controls who did not experience it after surgery (62 patients). This assay was linear over the measuring range 0.1-100 pmol/mL for these CER and dhCER species with good accuracy and precision. Elevated CERs and dhCERs were observed in CSF from patients who experienced postoperative ICI. CER 16:0 was found with a clinical sensitivity of 93.65 % and specificity of 87.1 % in distinguishing the 63 patients with ICI from the 62 controls. Therefore, this method could be applied in the detection of CERs and dhCERs in CSF, which were correlated with the presence of ICI.
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Affiliation(s)
- Jiawei Shi
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Tingting Wang
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Haiyang Guo
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Chen Li
- Department of Neurosurgery, The First Hospital of Jilin University, Jilin 130021, China
| | - Li Li
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Yuting Jin
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Haizhen Chen
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China
| | - Jing Huang
- Department of Clinical Laboratory, The First Hospital of Jilin University, Jilin 130021, China; Department of Neurosurgery, The First Hospital of Jilin University, Jilin 130021, China.
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23
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Wang S, Moreau F, Chadee K. Gasdermins in Innate Host Defense Against Entamoeba histolytica and Other Protozoan Parasites. Front Immunol 2022; 13:900553. [PMID: 35795683 PMCID: PMC9251357 DOI: 10.3389/fimmu.2022.900553] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Accepted: 05/23/2022] [Indexed: 11/16/2022] Open
Abstract
Gasdermins (GSDMs) are a group of proteins that are cleaved by inflammatory caspases to induce pore formation in the plasma membrane to cause membrane permeabilization and lytic cell death or pyroptosis. All GSDMs share a conserved structure, containing a cytotoxic N-terminal (NT) pore-forming domain and a C-terminal (CT) repressor domain. Entamoeba histolytica (Eh) in contact with macrophages, triggers outside-in signaling to activate inflammatory caspase-4/1 via the noncanonical and canonical pathway to promote cleavage of gasdermin D (GSDMD). Cleavage of GSDMD removes the auto-inhibition that masks the active pore-forming NT domain in the full-length protein by interactions with GSDM-CT. The cleaved NT-GSDMD monomers then oligomerize to form pores in the plasma membrane to facilitate the release of IL-1β and IL-18 with a measured amount of pyroptosis. Pyroptosis is an effective way to counteract intracellular parasites, which exploit replicative niche to avoid killing. To date, most GSDMs have been verified to perform pore-forming activity and GSDMD-induced pyroptosis is rapidly emerging as a mechanism of anti-microbial host defence. Here, we review our comprehensive and current knowledge on the expression, activation, biological functions, and regulation of GSDMD cleavage with emphases on physiological scenario and related dysfunctions of each GSDM member as executioner of cell death, cytokine secretion and inflammation against Eh and other protozoan parasitic infections.
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Affiliation(s)
| | | | - Kris Chadee
- Department of Microbiology, Immunology and Infectious Diseases, University of Calgary, Calgary, AB, Canada
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24
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Sharma D, Czarnota GJ. Involvement of Ceramide Signalling in Radiation-Induced Tumour Vascular Effects and Vascular-Targeted Therapy. Int J Mol Sci 2022; 23:ijms23126671. [PMID: 35743121 PMCID: PMC9223569 DOI: 10.3390/ijms23126671] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/31/2022] [Accepted: 06/06/2022] [Indexed: 02/04/2023] Open
Abstract
Sphingolipids are well-recognized critical components in several biological processes. Ceramides constitute a class of sphingolipid metabolites that are involved in important signal transduction pathways that play key roles in determining the fate of cells to survive or die. Ceramide accumulated in cells causes apoptosis; however, ceramide metabolized to sphingosine promotes cell survival and angiogenesis. Studies suggest that vascular-targeted therapies increase endothelial cell ceramide resulting in apoptosis that leads to tumour cure. Specifically, ultrasound-stimulated microbubbles (USMB) used as vascular disrupting agents can perturb endothelial cells, eliciting acid sphingomyelinase (ASMase) activation accompanied by ceramide release. This phenomenon results in endothelial cell death and vascular collapse and is synergistic with other antitumour treatments such as radiation. In contrast, blocking the generation of ceramide using multiple approaches, including the conversion of ceramide to sphingosine-1-phosphate (S1P), abrogates this process. The ceramide-based cell survival "rheostat" between these opposing signalling metabolites is essential in the mechanotransductive vascular targeting following USMB treatment. In this review, we aim to summarize the past and latest findings on ceramide-based vascular-targeted strategies, including novel mechanotransductive methodologies.
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Affiliation(s)
- Deepa Sharma
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, ON M4N 3M5, Canada
- Correspondence: ; Tel.: +1-416-480-6100 (ext. 89533)
| | - Gregory J. Czarnota
- Physical Sciences, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada;
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada
- Departments of Medical Biophysics and Radiation Oncology, University of Toronto, Toronto, ON M4N 3M5, Canada
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Varre JV, Holland WL, Summers SA. You aren't IMMUNE to the ceramides that accumulate in cardiometabolic disease. Biochim Biophys Acta Mol Cell Biol Lipids 2022; 1867:159125. [PMID: 35218934 PMCID: PMC9050903 DOI: 10.1016/j.bbalip.2022.159125] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 02/14/2022] [Indexed: 02/06/2023]
Abstract
Obesity leads to persistent increases in immune responses that contribute to cardiometabolic pathologies such as diabetes and cardiovascular disease. Pro-inflammatory macrophages infiltrate the expanding fat mass, which leads to increased production of cytokines such as tumor necrosis factor-alpha. Moreover, saturated fatty acids enhance signaling through the toll-like receptors involved in innate immunity. Herein we discuss the evidence that ceramides-which are intermediates in the biosynthetic pathway that produces sphingolipids-are essential intermediates that link these inflammatory signals to impaired tissue function. We discuss the mechanisms linking these immune insults to ceramide production and review the numerous ceramide actions that alter cellular metabolism, induce oxidative stress, and stimulate apoptosis. Lastly, we evaluate the correlation of ceramides in humans with inflammation-linked cardiometabolic disease and discuss preclinical studies which suggest that ceramide-lowering interventions may be an effective strategy to treat or prevent such maladies.
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Affiliation(s)
- Joseph V Varre
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 94108, United States of America
| | - William L Holland
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 94108, United States of America
| | - Scott A Summers
- Department of Nutrition and Integrative Physiology, University of Utah, Salt Lake City, UT 94108, United States of America.
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26
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Meacci E, Pierucci F, Garcia-Gil M. Skeletal Muscle and COVID-19: The Potential Involvement of Bioactive Sphingolipids. Biomedicines 2022; 10:biomedicines10051068. [PMID: 35625805 PMCID: PMC9138286 DOI: 10.3390/biomedicines10051068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 01/08/2023] Open
Abstract
SARS-CoV-2 virus infection is the cause of the coronavirus disease 2019 (COVID-19), which is still spreading over the world. The manifestation of this disease can range from mild to severe and can be limited in time (weeks) or persist for months in about 30–50% of patients. COVID-19 is considered a multiple organ dysfunction syndrome and the musculoskeletal system manifestations are beginning to be considered of absolute importance in both COVID-19 patients and in patients recovering from the SARS-CoV-2 infection. Musculoskeletal manifestations of COVID-19 and other coronavirus infections include loss of muscle mass, muscle weakness, fatigue or myalgia, and muscle injury. The molecular mechanisms by which SARS-CoV-2 can cause damage to skeletal muscle (SkM) cells are not yet well understood. Sphingolipids (SLs) represent an important class of eukaryotic lipids with structural functions as well as bioactive molecules able to modulate crucial processes, including inflammation and viral infection. In the last two decades, several reports have highlighted the role of SLs in modulating SkM cell differentiation, regeneration, aging, response to insulin, and contraction. This review summarizes the consequences of SARS-CoV-2 infection on SkM and the potential involvement of SLs in the tissue responses to virus infection. In particular, we highlight the role of sphingosine 1-phosphate signaling in order to aid the prediction of novel targets for preventing and/or treating acute and long-term musculoskeletal manifestations of virus infection in COVID-19.
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Affiliation(s)
- Elisabetta Meacci
- Unit of Biochemical Sciences and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50121 Florence, Italy;
- Interuniversity Institute of Myology, University of Florence, 50121 Florence, Italy
- Correspondence: ; Tel.: +39-055-2751231
| | - Federica Pierucci
- Unit of Biochemical Sciences and Molecular Biology, Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, Viale GB Morgagni 50, 50121 Florence, Italy;
| | - Mercedes Garcia-Gil
- Unit of Physiology, Department of Biology, University of Pisa, Via S. Zeno 31, 56127 Pisa, Italy;
- Interdepartmental Research Center “Nutraceuticals and Food for Health”, University of Pisa, 56127 Pisa, Italy
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27
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Lai JJ, Chau ZL, Chen S, Hill JJ, Korpany KV, Liang N, Lin L, Lin Y, Liu JK, Liu Y, Lunde R, Shen W. Exosome Processing and Characterization Approaches for Research and Technology Development. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2103222. [PMID: 35332686 PMCID: PMC9130923 DOI: 10.1002/advs.202103222] [Citation(s) in RCA: 208] [Impact Index Per Article: 69.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 01/28/2022] [Indexed: 05/05/2023]
Abstract
Exosomes are extracellular vesicles that share components of their parent cells and are attractive in biotechnology and biomedical research as potential disease biomarkers as well as therapeutic agents. Crucial to realizing this potential is the ability to manufacture high-quality exosomes; however, unlike biologics such as proteins, exosomes lack standardized Good Manufacturing Practices for their processing and characterization. Furthermore, there is a lack of well-characterized reference exosome materials to aid in selection of methods for exosome isolation, purification, and analysis. This review informs exosome research and technology development by comparing exosome processing and characterization methods and recommending exosome workflows. This review also provides a detailed introduction to exosomes, including their physical and chemical properties, roles in normal biological processes and in disease progression, and summarizes some of the on-going clinical trials.
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Affiliation(s)
- James J. Lai
- Department of BioengineeringUniversity of WashingtonSeattleWA98195USA
| | - Zoe L. Chau
- Department of BioengineeringUniversity of WashingtonSeattleWA98195USA
| | - Sheng‐You Chen
- Department of Mechanical EngineeringUniversity of WashingtonSeattleWA98195USA
| | - John J. Hill
- Department of BioengineeringUniversity of WashingtonSeattleWA98195USA
| | | | - Nai‐Wen Liang
- Department of Materials Science and EngineeringNational Tsing Hua UniversityHsinchu30013Taiwan
| | - Li‐Han Lin
- Department of Mechanical EngineeringNational Taiwan UniversityTaipei City10617Taiwan
| | - Yi‐Hsuan Lin
- Department of Engineering and System ScienceNational Tsing Hua UniversityHsinchu30013Taiwan
| | - Joanne K. Liu
- Department of BioengineeringUniversity of WashingtonSeattleWA98195USA
| | - Yu‐Chung Liu
- Department of Materials Science and EngineeringNational Tsing Hua UniversityHsinchu30013Taiwan
| | - Ruby Lunde
- Department of BioengineeringUniversity of WashingtonSeattleWA98195USA
| | - Wei‐Ting Shen
- Department of Biomedical Engineering and Environmental SciencesNational Tsing Hua UniversityHsinchu30013Taiwan
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28
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Sphingolipid control of cognitive functions in health and disease. Prog Lipid Res 2022; 86:101162. [DOI: 10.1016/j.plipres.2022.101162] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 03/10/2022] [Accepted: 03/12/2022] [Indexed: 12/14/2022]
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Zhao L, Fang J, Tang S, Deng F, Liu X, Shen Y, Liu Y, Kong F, Du Y, Cui L, Shi W, Wang Y, Wang J, Zhang Y, Dong X, Gao Y, Dong L, Zhou H, Sun Q, Dong H, Peng X, Zhang Y, Cao M, Wang Y, Zhi H, Du H, Zhou J, Li T, Shi X. PM2.5 and Serum Metabolome and Insulin Resistance, Potential Mediation by the Gut Microbiome: A Population-Based Panel Study of Older Adults in China. ENVIRONMENTAL HEALTH PERSPECTIVES 2022; 130:27007. [PMID: 35157499 PMCID: PMC8843086 DOI: 10.1289/ehp9688] [Citation(s) in RCA: 81] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 12/19/2021] [Accepted: 01/03/2022] [Indexed: 05/19/2023]
Abstract
BACKGROUND Insulin resistance (IR) affects the development of type 2 diabetes mellitus (T2DM), which is also influenced by accumulated fine particle air pollution [particulate matter (PM) with aerodynamic diameter of <2.5μm (PM2.5)] exposure. Previous experimental and epidemiological studies have proposed several potential mechanisms by which PM2.5 contributes to IR/T2DM, including inflammation imbalance, oxidative stress, and endothelial dysfunction. Recent evidence suggests that the imbalance of the gut microbiota affects the metabolic process and may precede IR. However, the underlying mechanisms of PM2.5, gut microbiota, and metabolic diseases are unclear. OBJECTIVES We investigated the associations between personal exposure to PM2.5 and fasting blood glucose and insulin levels, the IR index, and other related biomarkers. We also explored the potential underlying mechanisms (systemic inflammation and sphingolipid metabolism) between PM2.5 and insulin resistance and the mediating effects between PM2.5 and sphingolipid metabolism. METHODS We recruited 76 healthy seniors to participate in a repeated-measures panel study and conducted clinical examinations every month from September 2018 to January 2019. Linear mixed-effects (LME) models were used to analyze the associations between PM2.5 and health data (e.g., functional factors, the IR index, inflammation and other IR-related biomarkers, metabolites, and gut microbiota). We also performed mediation analyses to evaluate the effects of mediators (gut microbiota) on the associations between exposures (PM2.5) and featured metabolism outcomes. RESULTS Our prospective panel study illustrated that exposure to PM2.5 was associated with an increased risk of higher IR index and functional biomarkers, and our study provided mechanistic evidence suggesting that PM2.5 exposure may contribute to systemic inflammation and altered sphingolipid metabolism. DISCUSSION Our findings demonstrated that PM2.5 was associated with the genera of the gut microbiota, which partially mediated the association between PM2.5 and sphingolipid metabolism. These findings may extend our current understanding of the pathways of PM2.5 and IR. https://doi.org/10.1289/EHP9688.
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Affiliation(s)
- Liang Zhao
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jianlong Fang
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Song Tang
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Fuchang Deng
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaohui Liu
- National Protein Science Technology Center and School of Life Sciences, Tsinghua University, Beijing, China
| | - Yu Shen
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yuanyuan Liu
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Fanling Kong
- Shandong Provincial Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Yanjun Du
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Liangliang Cui
- Jinan Municipal Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Wanying Shi
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yan Wang
- Shandong Provincial Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Jiaonan Wang
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Yingjian Zhang
- Jinan Municipal Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Xiaoyan Dong
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Ying Gao
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Li Dong
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Huichan Zhou
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Qinghua Sun
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Haoran Dong
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiumiao Peng
- Jinan Municipal Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Yi Zhang
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Meng Cao
- Jinan Municipal Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Yanwen Wang
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hong Zhi
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Hang Du
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Jingyang Zhou
- Shandong Provincial Center for Disease Control and Prevention, Jinan, Shandong, China
| | - Tiantian Li
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
| | - Xiaoming Shi
- China CDC Key Laboratory of Environment and Population Health, National Institute of Environmental Health, Chinese Center for Disease Control and Prevention, Beijing, China
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30
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The acid sphingomyelinase/ceramide system in COVID-19. Mol Psychiatry 2022; 27:307-314. [PMID: 34608263 PMCID: PMC8488928 DOI: 10.1038/s41380-021-01309-5] [Citation(s) in RCA: 74] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Revised: 08/10/2021] [Accepted: 09/14/2021] [Indexed: 02/08/2023]
Abstract
Acid sphingomyelinase (ASM) cleaves sphingomyelin into the highly lipophilic ceramide, which forms large gel-like rafts/platforms in the plasma membrane. We showed that SARS-CoV-2 uses these platforms for cell entry. Lowering the amount of ceramide or ceramide blockade due to inhibitors of ASM, genetic downregulation of ASM, anti-ceramide antibodies or degradation by neutral ceramidase protected against infection with SARS-CoV-2. The addition of ceramide restored infection with SARS-CoV-2. Many clinically approved medications functionally inhibit ASM and are called FIASMAs (functional inhibitors of acid sphingomyelinase). The FIASMA fluvoxamine showed beneficial effects on COVID-19 in a randomized prospective study and a prospective open-label real-world study. Retrospective and observational studies showed favorable effects of FIASMA antidepressants including fluoxetine, and the FIASMA hydroxyzine on the course of COVID-19. The ASM/ceramide system provides a framework for a better understanding of the infection of cells by SARS-CoV-2 and the clinical, antiviral, and anti-inflammatory effects of functional inhibitors of ASM. This framework also supports the development of new drugs or the repurposing of "old" drugs against COVID-19.
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31
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Abstract
Ceramides are a class of sphingolipid that is the backbone structure for all sphingolipids, such as glycosphingolipids and phosphosphingolipids. While being a minor constituent of cellular membranes, ceramides are the major lipid component (along with cholesterol, free fatty acid, and other minor components) of the intercellular spaces of stratum corneum that forms the epidermal permeability barrier. These stratum corneum ceramides consist of unique heterogenous molecular species that have only been identified in terrestrial mammals. Alterations of ceramide molecular profiles are characterized in skin diseases associated with compromised permeability barrier functions, such as atopic dermatitis, psoriasis and xerosis. In addition, hereditary abnormalities of some ichthyoses are associated with an epidermal unique ceramide species, omega-O-acylceramide. Ceramides also serve as lipid modulators to regulate cellular functions, including cell cycle arrest, differentiation, and apoptosis, and it has been demonstrated that changes in ceramide metabolism also cause certain diseases. In addition, ceramide metabolites, sphingoid bases, sphingoid base-1-phosphate and ceramide-1-phosphate are also lipid mediators that regulate cellular functions. In this review article, we describe diverse physiological and pathological roles of ceramides and their metabolites in epidermal permeability barrier function, epidermal cell proliferation and differentiation, immunity, and cutaneous diseases. Finally, we summarize the utilization of ceramides as therapy to treat cutaneous disease.
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32
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Kornhuber J, Gulbins E. New Molecular Targets for Antidepressant Drugs. Pharmaceuticals (Basel) 2021; 14:894. [PMID: 34577594 PMCID: PMC8472072 DOI: 10.3390/ph14090894] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 08/25/2021] [Accepted: 08/25/2021] [Indexed: 12/27/2022] Open
Abstract
Major depressive disorder (MDD) is a common and severe mental disorder that is usually recurrent and has a high risk of suicide. This disorder manifests not only with psychological symptoms but also multiple changes throughout the body, including increased risks of obesity, diabetes, and cardiovascular disease. Peripheral markers of oxidative stress and inflammation are elevated. MDD is therefore best described as a multisystem whole-body disease. Pharmacological treatment with antidepressants usually requires several weeks before the desired effects manifest. Previous theories of depression, such as the monoamine or neurogenesis hypotheses, do not explain these characteristics well. In recent years, new mechanisms of action have been discovered for long-standing antidepressants that also shed new light on depression, including the sphingolipid system and the receptor for brain-derived neurotrophic factor (BDNF).
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Affiliation(s)
- Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University of Erlangen-Nuremberg, 91054 Erlangen, Germany
| | - Erich Gulbins
- Department of Molecular Biology, University of Duisburg-Essen, 45117 Essen, Germany;
- Department of Surgery, University of Cincinnati, Cincinnati, OH 45267, USA
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Schneider-Schaulies S, Schumacher F, Wigger D, Schöl M, Waghmare T, Schlegel J, Seibel J, Kleuser B. Sphingolipids: Effectors and Achilles Heals in Viral Infections? Cells 2021; 10:cells10092175. [PMID: 34571822 PMCID: PMC8466362 DOI: 10.3390/cells10092175] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 08/16/2021] [Accepted: 08/20/2021] [Indexed: 12/26/2022] Open
Abstract
As viruses are obligatory intracellular parasites, any step during their life cycle strictly depends on successful interaction with their particular host cells. In particular, their interaction with cellular membranes is of crucial importance for most steps in the viral replication cycle. Such interactions are initiated by uptake of viral particles and subsequent trafficking to intracellular compartments to access their replication compartments which provide a spatially confined environment concentrating viral and cellular components, and subsequently, employ cellular membranes for assembly and exit of viral progeny. The ability of viruses to actively modulate lipid composition such as sphingolipids (SLs) is essential for successful completion of the viral life cycle. In addition to their structural and biophysical properties of cellular membranes, some sphingolipid (SL) species are bioactive and as such, take part in cellular signaling processes involved in regulating viral replication. It is especially due to the progress made in tools to study accumulation and dynamics of SLs, which visualize their compartmentalization and identify interaction partners at a cellular level, as well as the availability of genetic knockout systems, that the role of particular SL species in the viral replication process can be analyzed and, most importantly, be explored as targets for therapeutic intervention.
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Affiliation(s)
- Sibylle Schneider-Schaulies
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Fabian Schumacher
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
| | - Dominik Wigger
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
| | - Marie Schöl
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Trushnal Waghmare
- Institute for Virology and Immunobiology, University of Wuerzburg, 97078 Würzburg, Germany; (S.S.-S.); (M.S.); (T.W.)
| | - Jan Schlegel
- Department for Biotechnology and Biophysics, University of Wuerzburg, 97074 Würzburg, Germany;
| | - Jürgen Seibel
- Department for Organic Chemistry, University of Wuerzburg, 97074 Würzburg, Germany;
| | - Burkhard Kleuser
- Institute of Pharmacy, Pharmacology and Toxicology, Freie Universität Berlin, 14195 Berlin, Germany; (F.S.); (D.W.)
- Correspondence: ; Tel.: +49-30-8386-9823
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Breiden B, Sandhoff K. Acid Sphingomyelinase, a Lysosomal and Secretory Phospholipase C, Is Key for Cellular Phospholipid Catabolism. Int J Mol Sci 2021; 22:9001. [PMID: 34445706 PMCID: PMC8396676 DOI: 10.3390/ijms22169001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/14/2021] [Accepted: 08/16/2021] [Indexed: 02/06/2023] Open
Abstract
Here, we present the main features of human acid sphingomyelinase (ASM), its biosynthesis, processing and intracellular trafficking, its structure, its broad substrate specificity, and the proposed mode of action at the surface of the phospholipid substrate carrying intraendolysosomal luminal vesicles. In addition, we discuss the complex regulation of its phospholipid cleaving activity by membrane lipids and lipid-binding proteins. The majority of the literature implies that ASM hydrolyses solely sphingomyelin to generate ceramide and ignores its ability to degrade further substrates. Indeed, more than twenty different phospholipids are cleaved by ASM in vitro, including some minor but functionally important phospholipids such as the growth factor ceramide-1-phosphate and the unique lysosomal lysolipid bis(monoacylglycero)phosphate. The inherited ASM deficiency, Niemann-Pick disease type A and B, impairs mainly, but not only, cellular sphingomyelin catabolism, causing a progressive sphingomyelin accumulation, which furthermore triggers a secondary accumulation of lipids (cholesterol, glucosylceramide, GM2) by inhibiting their turnover in late endosomes and lysosomes. However, ASM appears to be involved in a variety of major cellular functions with a regulatory significance for an increasing number of metabolic disorders. The biochemical characteristics of ASM, their potential effect on cellular lipid turnover, as well as a potential impact on physiological processes will be discussed.
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Affiliation(s)
| | - Konrad Sandhoff
- Membrane Biology and Lipid Biochemistry Unit, LIMES Institute, University of Bonn, 53121 Bonn, Germany
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Rhein C, Zoicas I, Marx LM, Zeitler S, Hepp T, von Zimmermann C, Mühle C, Richter-Schmidinger T, Lenz B, Erim Y, Reichel M, Gulbins E, Kornhuber J. mRNA Expression of SMPD1 Encoding Acid Sphingomyelinase Decreases upon Antidepressant Treatment. Int J Mol Sci 2021; 22:ijms22115700. [PMID: 34071826 PMCID: PMC8198802 DOI: 10.3390/ijms22115700] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Revised: 05/14/2021] [Accepted: 05/23/2021] [Indexed: 12/24/2022] Open
Abstract
Major depressive disorder (MDD) is a severe psychiatric condition with key symptoms of low mood and lack of motivation, joy, and pleasure. Recently, the acid sphingomyelinase (ASM)/ceramide system has been implicated in the pathogenesis of MDD. ASM is a lysosomal glycoprotein that catalyzes the hydrolysis of sphingomyelin, an abundant component of membranes, into the bioactive sphingolipid ceramide, which impacts signaling pathways. ASM activity is inhibited by several common antidepressant drugs. Human and murine studies have confirmed that increased ASM activity and ceramide levels are correlated with MDD. To define a molecular marker for treatment monitoring, we investigated the mRNA expression of SMPD1, which encodes ASM, in primary cell culture models, a mouse study, and a human study with untreated MDD patients before and after antidepressive treatment. Our cell culture study showed that a common antidepressant inhibited ASM activity at the enzymatic level and also at the transcriptional level. In a genetically modified mouse line with depressive-like behavior, Smpd1 mRNA expression in dorsal hippocampal tissue was significantly decreased after treatment with a common antidepressant. The large human study showed that SMPD1 mRNA expression in untreated MDD patients decreased significantly after antidepressive treatment. This translational study shows that SMPD1 mRNA expression could serve as a molecular marker for treatment and adherence monitoring of MDD.
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Affiliation(s)
- Cosima Rhein
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany; (T.H.); (Y.E.)
- Correspondence: ; Tel.: +49-9131-85-44542
| | - Iulia Zoicas
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Lena M. Marx
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Stefanie Zeitler
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Tobias Hepp
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany; (T.H.); (Y.E.)
- Institute of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany
| | - Claudia von Zimmermann
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Christiane Mühle
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Tanja Richter-Schmidinger
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
- Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, D-68159 Mannheim, Germany
| | - Yesim Erim
- Department of Psychosomatic Medicine and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), D-91054 Erlangen, Germany; (T.H.); (Y.E.)
| | - Martin Reichel
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
| | - Erich Gulbins
- Department of Molecular Biology, University Hospital, University of Duisburg-Essen, D-45147 Essen, Germany;
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Schwabachanlage 6, D-91054 Erlangen, Germany; (I.Z.); (L.M.M.); (S.Z.); (C.v.Z.); (C.M.); (T.R.-S.); (B.L.); (M.R.); (J.K.)
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Carpinteiro A, Gripp B, Hoffmann M, Pöhlmann S, Hoertel N, Edwards MJ, Kamler M, Kornhuber J, Becker KA, Gulbins E. Inhibition of acid sphingomyelinase by ambroxol prevents SARS-CoV-2 entry into epithelial cells. J Biol Chem 2021; 296:100701. [PMID: 33895135 PMCID: PMC8062550 DOI: 10.1016/j.jbc.2021.100701] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 04/15/2021] [Accepted: 04/21/2021] [Indexed: 12/18/2022] Open
Abstract
The acid sphingomyelinase/ceramide system has been shown to be important for cellular infection with at least some viruses, for instance, rhinovirus or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Functional inhibition of the acid sphingomyelinase using tricyclic antidepressants prevented infection of epithelial cells, for instance with SARS-CoV-2. The structure of ambroxol, that is, trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol, a mucolytic drug applied by inhalation, suggests that the drug might inhibit the acid sphingomyelinase and thereby infection with SARS-CoV-2. To test this, we used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. Viral uptake and formation of ceramide localization were determined by fluorescence microscopy, activity of the acid sphingomyelinase by consumption of [14C]sphingomyelin and ceramide was quantified by a kinase method. We found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, events that were all prevented by pretreatment with ambroxol. We also obtained nasal epithelial cells from human volunteers prior to and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo. The addition of purified acid sphingomyelinase or C16 ceramide restored entry of pp-VSV-SARS-CoV-2 spike into ambroxol-treated epithelial cells. We propose that ambroxol might be suitable for clinical studies to prevent coronavirus disease 2019.
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Affiliation(s)
- Alexander Carpinteiro
- Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Barbara Gripp
- Zentrum für Seelische Gesundheit des Kindes- und Jugendalters, Sana-Klinikum Remscheid GmbH, Remscheid, Germany
| | - Markus Hoffmann
- Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University of Göttingen, Göttingen, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center - Leibniz Institute for Primate Research, Göttingen, Germany; Faculty of Biology and Psychology, University of Göttingen, Göttingen, Germany
| | - Nicolas Hoertel
- AP-HP.Centre-Université de Paris, Hôpital Corentin-Celton, Département de Psychiatrie, Issy-les-Moulineaux, and Université de Paris, INSERM, Institut de Psychiatrie et Neurosciences de Paris, UMR_S1266, and Faculté de Santé, UFR de Médecine, Paris, France
| | - Michael J Edwards
- Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA
| | - Markus Kamler
- Department of Thoracic and Cardiovascular Surgery, Division of Thoracic Transplantation, University Hospital Essen, Essen, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Hospital of Erlangen, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen, Germany
| | - Katrin Anne Becker
- Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University of Duisburg-Essen, Essen, Germany; Department of Surgery, Medical School, University of Cincinnati, Cincinnati, Ohio, USA.
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37
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Lizarraga-Valderrama LR, Sheridan GK. Extracellular vesicles and intercellular communication in the central nervous system. FEBS Lett 2021; 595:1391-1410. [PMID: 33728650 DOI: 10.1002/1873-3468.14074] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 12/30/2022]
Abstract
Neurons and glial cells of the central nervous system (CNS) release extracellular vesicles (EVs) to the interstitial fluid of the brain and spinal cord parenchyma. EVs contain proteins, nucleic acids and lipids that can be taken up by, and modulate the behaviour of, neighbouring recipient cells. The functions of EVs have been extensively studied in the context of neurodegenerative diseases. However, mechanisms involved in EV-mediated neuron-glial communication under physiological conditions or healthy ageing remain unclear. A better understanding of the myriad roles of EVs in CNS homeostasis is essential for the development of novel therapeutics to alleviate and reverse neurological disturbances of ageing. Proteomic studies are beginning to reveal cell type-specific EV cargo signatures that may one day allow us to target specific neuronal or glial cell populations in the treatment of debilitating neurological disorders. This review aims to synthesise the current literature regarding EV-mediated cell-cell communication in the brain, predominantly under physiological conditions.
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Affiliation(s)
| | - Graham K Sheridan
- School of Life Sciences, Queens Medical Centre, University of Nottingham, UK
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38
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Kalinichenko LS, Abdel-Hafiz L, Wang AL, Mühle C, Rösel N, Schumacher F, Kleuser B, Smaga I, Frankowska M, Filip M, Schaller G, Richter-Schmidinger T, Lenz B, Gulbins E, Kornhuber J, Oliveira AWC, Barros M, Huston JP, Müller CP. Neutral Sphingomyelinase is an Affective Valence-Dependent Regulator of Learning and Memory. Cereb Cortex 2021; 31:1316-1333. [PMID: 33043975 DOI: 10.1093/cercor/bhaa298] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 09/11/2020] [Accepted: 09/11/2020] [Indexed: 12/16/2022] Open
Abstract
Sphingolipids and enzymes of the sphingolipid rheostat determine synaptic appearance and signaling in the brain, but sphingolipid contribution to normal behavioral plasticity is little understood. Here we asked how the sphingolipid rheostat contributes to learning and memory of various dimensions. We investigated the role of these lipids in the mechanisms of two different types of memory, such as appetitively and aversively motivated memory, which are considered to be mediated by different neural mechanisms. We found an association between superior performance in short- and long-term appetitively motivated learning and regionally enhanced neutral sphingomyelinase (NSM) activity. An opposite interaction was observed in an aversively motivated task. A valence-dissociating role of NSM in learning was confirmed in mice with genetically reduced NSM activity. This role may be mediated by the NSM control of N-methyl-d-aspartate receptor subunit expression. In a translational approach, we confirmed a positive association of serum NSM activity with long-term appetitively motivated memory in nonhuman primates and in healthy humans. Altogether, these data suggest a new sphingolipid mechanism of de-novo learning and memory, which is based on NSM activity.
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Affiliation(s)
- Liubov S Kalinichenko
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - Laila Abdel-Hafiz
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - An-Li Wang
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - Christiane Mühle
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - Nadine Rösel
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - Fabian Schumacher
- Department of Toxicology, Faculty of Mathematics and Natural Science, Institute of Nutritional Science, University of Potsdam, Potsdam 14558, Germany.,Department of Molecular Biology, University of Duisburg-Essen, Essen 45147, Germany
| | - Burkhard Kleuser
- Department of Toxicology, Faculty of Mathematics and Natural Science, Institute of Nutritional Science, University of Potsdam, Potsdam 14558, Germany
| | - Irena Smaga
- Department of Drug Addiction Pharmacology, Polish Academy of Sciences, Maj Institute of Pharmacology, Kraków 31-343, Poland
| | - Malgorzata Frankowska
- Department of Drug Addiction Pharmacology, Polish Academy of Sciences, Maj Institute of Pharmacology, Kraków 31-343, Poland
| | - Malgorzata Filip
- Department of Drug Addiction Pharmacology, Polish Academy of Sciences, Maj Institute of Pharmacology, Kraków 31-343, Poland
| | - Gerd Schaller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - Tanja Richter-Schmidinger
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - Bernd Lenz
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany.,Department of Addictive Behavior and Addiction Medicine, Central Institute of Mental Health (CIMH), Medical Faculty Mannheim, Heidelberg University, Mannheim 68159, Germany
| | - Erich Gulbins
- Department of Molecular Biology, University of Duisburg-Essen, Essen 45147, Germany.,Department of Surgery, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0558, USA
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
| | - André W C Oliveira
- Department of Pharmacy, School of Health Sciences, University of Brasilia, Brasilia, DF 70910-900, Brazil
| | - Marilia Barros
- Department of Pharmacy, School of Health Sciences, University of Brasilia, Brasilia, DF 70910-900, Brazil.,Primate Center, Institute of Biology, University of Brasilia, Brasilia 70910-900, Brazil
| | - Joseph P Huston
- Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf 40225, Germany
| | - Christian P Müller
- Department of Psychiatry and Psychotherapy, University Clinic, Friedrich-Alexander-University of Erlangen-Nuremberg, Erlangen 91054, Germany
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Abstract
Extracellular vesicles (EVs) produced by cancer cells function as a unique form of intercellular communication that can promote cell growth and survival, help shape the tumor microenvironment, and increase invasive and metastatic activity. There are two major classes of EVs, microvesicles (MVs) and exosomes, and they differ in how they are formed. MVs are generated by the outward budding and fission of the plasma membrane. On the other hand, exosomes are derived as multivesicular bodies (MVBs) fuse with the plasma membrane and release their contents. What makes EVs especially interesting is how they mediate their effects. Both MVs and exosomes have been shown to contain a wide-variety of bioactive cargo, including cell surface, cytosolic, and nuclear proteins, as well as RNA transcripts, micro-RNAs (miRNAs), and even fragments of DNA. EVs, and their associated cargo, can be transferred to other cancer cells, as well as to normal cell types, causing the recipient cells to undergo phenotypic changes that promote different aspects of cancer progression. These findings, combined with those demonstrating that the amounts and contents of EVs produced by cancer cells can vary depending on their cell of origin, stage of development, or response to therapies, have raised the exciting possibility that EVs can be used for diagnostic purposes. Moreover, the pharmaceutical community is aggressively pursuing the use of EVs as a potential drug delivery platform. Here, in this chapter, we will highlight what is currently known about how EVs are generated, how they impact cancer progression, and the different ways they are being exploited for clinical applications.
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Affiliation(s)
- Wen-Hsuan Chang
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA
| | - Richard A Cerione
- Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, USA.
- Department of Molecular Medicine, Cornell University, Ithaca, NY, USA.
- Veterinary Medical Center, Cornell University, Ithaca, NY, USA.
| | - Marc A Antonyak
- Department of Molecular Medicine, Cornell University, Ithaca, NY, USA
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40
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Nikolova-Karakashian M. Methods to Characterize Synthesis and Degradation of Sphingomyelin at the Plasma Membrane and Its Impact on Lipid Raft Dynamics. Methods Mol Biol 2021; 2187:113-129. [PMID: 32770504 DOI: 10.1007/978-1-0716-0814-2_7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
This chapter will discuss methods for analyses of the rates of sphingomyelin synthesis and turnover associated with lipid rafts or plasma membrane. These methods involve the use of fluorescently (NBD-C6-ceramide or NBD-C6-Sphingomyelin)) or radioactively labeled substrates ([3H-methyl]-phosphatidylcholine, [3H-acyl]-ceramide, [14C-methyl]-sphingomyelin) to quantify in vitro the activity of the sphingomyelin synthase (SMS) (also known as phosphatidylcholine:ceramide phosphocholine transferase), acid sphingomyelinase (the endosomal/lysosomal (L-SMase) and the secretory (S-SMase) forms) and neutral sphingomyelinase-2 (nSMase-2). These methods allow to quantify changes in the activity of enzymes that affect the SM-to-ceramide ratio on the plasma membrane, and consequently, the lipid rafts biophysical properties, dynamics, and raft-associated receptor clustering and signaling events. Specific attention is paid to challenges caused by the fact that SMS and nSMase-2 are integral/membrane bound proteins and how to avoid the use of detergent that suppress their specific activities.
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Neutral sphingomyelinase mediates the co-morbidity trias of alcohol abuse, major depression and bone defects. Mol Psychiatry 2021; 26:7403-7416. [PMID: 34584229 PMCID: PMC8872992 DOI: 10.1038/s41380-021-01304-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/06/2021] [Accepted: 09/09/2021] [Indexed: 02/07/2023]
Abstract
Mental disorders are highly comorbid and occur together with physical diseases, which are often considered to arise from separate pathogenic pathways. We observed in alcohol-dependent patients increased serum activity of neutral sphingomyelinase. A genetic association analysis in 456,693 volunteers found associations of haplotypes of SMPD3 coding for NSM-2 (NSM) with alcohol consumption, but also with affective state, and bone mineralisation. Functional analysis in mice showed that NSM controls alcohol consumption, affective behaviour, and their interaction by regulating hippocampal volume, cortical connectivity, and monoaminergic responses. Furthermore, NSM controlled bone-brain communication by enhancing osteocalcin signalling, which can independently supress alcohol consumption and reduce depressive behaviour. Altogether, we identified a single gene source for multiple pathways originating in the brain and bone, which interlink disorders of a mental-physical co-morbidity trias of alcohol abuse-depression/anxiety-bone disorder. Targeting NSM and osteocalcin signalling may, thus, provide a new systems approach in the treatment of a mental-physical co-morbidity trias.
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42
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Carpinteiro A, Edwards MJ, Hoffmann M, Kochs G, Gripp B, Weigang S, Adams C, Carpinteiro E, Gulbins A, Keitsch S, Sehl C, Soddemann M, Wilker B, Kamler M, Bertsch T, Lang KS, Patel S, Wilson GC, Walter S, Hengel H, Pöhlmann S, Lang PA, Kornhuber J, Becker KA, Ahmad SA, Fassbender K, Gulbins E. Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of SARS-CoV-2 by Epithelial Cells. Cell Rep Med 2020; 1:100142. [PMID: 33163980 PMCID: PMC7598530 DOI: 10.1016/j.xcrm.2020.100142] [Citation(s) in RCA: 130] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 09/23/2020] [Accepted: 10/22/2020] [Indexed: 12/20/2022]
Abstract
The acid sphingomyelinase/ceramide system plays an important role in bacterial and viral infections. Here, we report that either pharmacological inhibition of acid sphingomyelinase with amitriptyline, imipramine, fluoxetine, sertraline, escitalopram, or maprotiline or genetic downregulation of the enzyme prevents infection of cultured cells or freshy isolated human nasal epithelial cells with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or vesicular stomatitis virus (VSV) pseudoviral particles (pp-VSV) presenting SARS-CoV-2 spike protein (pp-VSV-SARS-CoV-2 spike), a bona fide system mimicking SARS-CoV-2 infection. Infection activates acid sphingomyelinase and triggers a release of ceramide on the cell surface. Neutralization or consumption of surface ceramide reduces infection with pp-VSV-SARS-CoV-2 spike. Treating volunteers with a low dose of amitriptyline prevents infection of freshly isolated nasal epithelial cells with pp-VSV-SARS-CoV-2 spike. The data justify clinical studies investigating whether amitriptyline, a safe drug used clinically for almost 60 years, or other antidepressants that functionally block acid sphingomyelinase prevent SARS-CoV-2 infection.
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Affiliation(s)
- Alexander Carpinteiro
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
- Department of Hematology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Michael J. Edwards
- Department of Surgery, University of Cincinnati Medical School, 231 Albert Sabin Way, ML0558, Cincinnati, OH 45267, USA
| | - Markus Hoffmann
- Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany
- Faculty of Biology and Psychology, University of Göttingen, 37073 Göttingen, Germany
| | - Georg Kochs
- Institute of Virology and Faculty of Medicine, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany
| | - Barbara Gripp
- Zentrum für Seelische Gesundheit des Kindes- und Jugendalters, Sana-Klinikum Remscheid GmbH, Burger Strasse 211, 42859 Remscheid, Germany
| | - Sebastian Weigang
- Institute of Virology and Faculty of Medicine, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany
| | - Constantin Adams
- Department of Paediatrics, University Hospital Tuebingen, 72076 Tuebingen, Germany
| | - Elisa Carpinteiro
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Anne Gulbins
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Simone Keitsch
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Carolin Sehl
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Matthias Soddemann
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Barbara Wilker
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Markus Kamler
- Department of Thoracic and Cardiovascular Surgery, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Thomas Bertsch
- Institute of Clinical Chemistry, Laboratory Medicine and Transfusion Medicine, Paracelsus Medical University, Nuremberg, Germany
| | - Karl S. Lang
- Institute of Immunology, University of Duisburg-Essen, Hufelandstrasse 55, 45147 Essen, Germany
| | - Sameer Patel
- Department of Surgery, University of Cincinnati Medical School, 231 Albert Sabin Way, ML0558, Cincinnati, OH 45267, USA
| | - Gregory C. Wilson
- Department of Surgery, University of Cincinnati Medical School, 231 Albert Sabin Way, ML0558, Cincinnati, OH 45267, USA
| | - Silke Walter
- Department of Neurology, University Hospital of the Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany
| | - Hartmut Hengel
- Institute of Virology and Faculty of Medicine, University of Freiburg, Hermann-Herder-Strasse 11, 79104 Freiburg, Germany
| | - Stefan Pöhlmann
- Infection Biology Unit, German Primate Center – Leibniz Institute for Primate Research, Göttingen, Germany
- Faculty of Biology and Psychology, University of Göttingen, 37073 Göttingen, Germany
| | - Philipp A. Lang
- Department of Molecular Medicine II, Medical Faculty, Heinrich Heine University, Universitaetsstrasse 1, 40225 Düsseldorf, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, Friedrich-Alexander University Erlangen-Nürnberg (FAU), Schwabachanlage 6, 91054 Erlangen, Germany
| | - Katrin Anne Becker
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
| | - Syed A. Ahmad
- Department of Surgery, University of Cincinnati Medical School, 231 Albert Sabin Way, ML0558, Cincinnati, OH 45267, USA
| | - Klaus Fassbender
- Department of Neurology, University Hospital of the Saarland, Kirrberger Strasse, 66421 Homburg/Saar, Germany
| | - Erich Gulbins
- Institute of Molecular Biology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany
- Department of Surgery, University of Cincinnati Medical School, 231 Albert Sabin Way, ML0558, Cincinnati, OH 45267, USA
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Niziolek GM, Hoehn RS, Seitz AP, Jernigan PL, Makley AT, Gulbins E, Edwards MJ, Goodman MD. The Role of Acid Sphingomyelinase Inhibition in Repetitive Mild Traumatic Brain Injury. J Surg Res 2020; 259:296-304. [PMID: 33131764 DOI: 10.1016/j.jss.2020.09.034] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 09/01/2020] [Accepted: 09/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Chronic traumatic encephalopathy is a consequence of repetitive mild traumatic brain injury (rmTBI). These injuries can result in psychiatric disorders that are treated with amitriptyline. Amitriptyline improves neuronal regeneration in major depression via inhibition of acid sphingomyelinase. We hypothesized that acid sphingomyelinase inhibition would preserve neuronal regeneration and decrease depressive symptoms following rmTBI in a murine model. METHODS A murine model of rmTBI was established using a weight-drop method. Mice were subjected to mTBI every other day for 7 d. Mice received amitriptyline injection 2 h prior to each mTBI. After the final mTBI, mice underwent behavioral studies or biochemical analysis. Hippocampi were analyzed for markers of neurogenesis and phosphorylated tau aggregation. RESULTS Mice that underwent rmTBI showed increased hippocampal phosphorylated tau aggregation 1 mo following rmTBI as well as decreased neuronal regeneration by bromodeoxyuridine uptake and doublecortin immunohistochemistry. Mice with either genetic deficiency or pharmacologic inhibition of acid sphingomyelinase demonstrated improved neuronal regeneration and decreased phosphorylated tau aggregation compared to untreated rmTBI mice. Behavioral testing showed rmTBI mice spent significantly more time in the dark and waiting to initiate feeding compared to sham mice. These behaviors were partially prevented by the inhibition of acid sphingomyelinase. CONCLUSIONS We established a murine model of rmTBI that leads to tauopathy, depression, and impaired hippocampal neurogenesis. Inhibition of acid sphingomyelinase prevented the harmful neurologic and behavioral effects of rmTBI. These findings highlight an important opportunity to improve recovery or prevent neuropsychiatric decline in patients at risk for chronic traumatic encephalopathy.
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Affiliation(s)
- Grace M Niziolek
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Richard S Hoehn
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Aaron P Seitz
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Peter L Jernigan
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Amy T Makley
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio
| | - Erich Gulbins
- Department of Surgery, University of Cincinnati, Cincinnati, Ohio; Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany
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McNabb E, Al-Mahrouki A, Law N, McKay S, Tarapacki C, Hussein F, Czarnota GJ. Ultrasound-stimulated microbubble radiation enhancement of tumors: Single-dose and fractionated treatment evaluation. PLoS One 2020; 15:e0239456. [PMID: 32976517 PMCID: PMC7518623 DOI: 10.1371/journal.pone.0239456] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Accepted: 09/07/2020] [Indexed: 12/14/2022] Open
Abstract
The use of ultrasound-stimulated microbubble therapy has successfully been used to target tumor vasculature and enhance the effects of radiation therapy in tumor xenografts in mice. Here, we further investigate this treatment using larger, more clinically relevant tumor models. New Zealand white rabbits bearing prostate tumor (PC3) xenografts received a single treatment of either ultrasound-stimulated microbubbles (USMB), ionizing radiation (XRT; 8Gy), or a combination of both treatments (USMB+XRT). Treatment outcome was evaluated 24 hours after treatment using histopathology, immunolabeling, 3D Doppler ultrasound and photoacoustic imaging. A second cohort of rabbits received multiple treatments over a period of three weeks, where USMB treatments were delivered twice weekly with daily XRT treatments to deliver a fractionated 2Gy dose five days per week. A significant decrease in vascular function, observed through immunolabeling of vascular endothelial cells, was observed in tumors receiving the combined treatment (USMB+XRT) compared to control and single treatment groups. This was associated with an increase in cell death as observed through in situ end labeling (ISEL), a decrease in vascular index measured by Power Doppler imaging, and a decrease in oxygen saturation. In rabbits undergoing the long-term fractionated combined treatment, a significant growth delay was observed after 1 week and a significant reduction in tumor size was observed after 3 weeks with combined therapy. Results demonstrated an enhancement of radiation effect and superior anti-tumor effect of the combination of USMB+XRT compared to the single treatments alone. Tumor growth was maximally inhibited with fractionated radiotherapy combined with the ultrasound-stimulated microbubble-based therapy.
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Affiliation(s)
- Evan McNabb
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Azza Al-Mahrouki
- Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
| | - Niki Law
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
| | - Scott McKay
- Department of Chemistry, University of Manitoba, Winnipeg, Manitoba, Canada
| | | | - Farah Hussein
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
| | - Gregory J. Czarnota
- Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada
- Department of Radiation Oncology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
- Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- * E-mail:
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Neutral ceramidase is a marker for cognitive performance in rats and monkeys. Pharmacol Rep 2020; 73:73-84. [PMID: 32936422 PMCID: PMC7862079 DOI: 10.1007/s43440-020-00159-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 09/02/2020] [Accepted: 09/04/2020] [Indexed: 12/20/2022]
Abstract
Background Ceramides are lipid molecules determining cell integrity and intercellular signaling, and thus, involved in the pathogenesis of several psychiatric and neurodegenerative disorders. However, little is known about the role of particular enzymes of the ceramide metabolism in the mechanisms of normal behavioral plasticity. Here, we studied the contribution of neutral ceramidase (NC), one of the main enzymes mediating ceramide degradation, in the mechanisms of learning and memory in rats and non-human primates. Methods Naïve Wistar rats and black tufted-ear marmosets (Callithrix penicillata) were tested in several tests for short- and long-term memory and then divided into groups with various memory performance. The activities of NC and acid ceramidase (AC) were measured in these animals. Additionally, anxiety and depression-like behavior and brain levels of monoamines were assessed in the rats. Results We observed a predictive role of NC activity in the blood serum for superior performance of long-term object memory tasks in both species. A brain area analysis suggested that high NC activity in the ventral mesencephalon (VM) predicts better short-term memory performance in rats. High NC activity in the VM was also associated with worse long-term object memory, which might be mediated by an enhanced depression-like state and a monoaminergic imbalance. Conclusions Altogether, these data suggest a role for NC in short- and long-term memory of various mammalian species. Serum activity of NC may possess a predictive role in the assessing the performance of certain types of memory. Electronic supplementary material The online version of this article (10.1007/s43440-020-00159-2) contains supplementary material, which is available to authorized users.
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The Emerging Role of Extracellular Vesicles in the Glioma Microenvironment: Biogenesis and Clinical Relevance. Cancers (Basel) 2020; 12:cancers12071964. [PMID: 32707733 PMCID: PMC7409063 DOI: 10.3390/cancers12071964] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/07/2020] [Accepted: 07/16/2020] [Indexed: 02/07/2023] Open
Abstract
Gliomas are a diverse group of brain tumors comprised of malignant cells ('tumor' cells) and non-malignant 'normal' cells, including neural (neurons, glia), inflammatory (microglia, macrophage) and vascular cells. Tumor heterogeneity arises in part because, within the glioma mass, both 'tumor' and 'normal' cells secrete factors that form a unique microenvironment to influence tumor progression. Extracellular vesicles (EVs) are critical mediators of intercellular communication between immediate cellular neighbors and distantly located cells in healthy tissues/organs and in tumors, including gliomas. EVs mediate cell-cell signaling as carriers of nucleic acid, lipid and protein cargo, and their content is unique to cell types and physiological states. EVs secreted by non-malignant neural cells have important physiological roles in the healthy brain, which can be altered or co-opted to promote tumor progression and metastasis, acting in combination with glioma-secreted EVs. The cell-type specificity of EV content means that 'vesiculome' data can potentially be used to trace the cell of origin. EVs may also serve as biomarkers to be exploited for disease diagnosis and to assess therapeutic progress. In this review, we discuss how EVs mediate intercellular communication in glioma, and their potential role as biomarkers and readouts of a therapeutic response.
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47
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Yañez MJ, Marín T, Balboa E, Klein AD, Alvarez AR, Zanlungo S. Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions. Biochim Biophys Acta Mol Basis Dis 2020; 1866:165875. [PMID: 32522631 DOI: 10.1016/j.bbadis.2020.165875] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Revised: 05/06/2020] [Accepted: 06/03/2020] [Indexed: 12/12/2022]
Abstract
Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.
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Affiliation(s)
- M J Yañez
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - T Marín
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - E Balboa
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - A D Klein
- Centro de Genética y Genómica, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago, Chile
| | - A R Alvarez
- Laboratory of Cell Signaling, Department of Cellular and Molecular Biology, Biological Sciences Faculty, Pontificia Universidad Católica de Chile, Santiago, Chile; CARE UC, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - S Zanlungo
- Department of Gastroenterology, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
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Hu W, Liu C, Bi ZY, Zhou Q, Zhang H, Li LL, Zhang J, Zhu W, Song YYY, Zhang F, Yang HM, Bi YY, He QQ, Tan GJ, Sun CC, Li DJ. Comprehensive landscape of extracellular vesicle-derived RNAs in cancer initiation, progression, metastasis and cancer immunology. Mol Cancer 2020; 19:102. [PMID: 32503543 PMCID: PMC7273667 DOI: 10.1186/s12943-020-01199-1] [Citation(s) in RCA: 146] [Impact Index Per Article: 29.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 04/15/2020] [Indexed: 01/18/2023] Open
Abstract
Extracellular vesicles (EVs), a class of heterogeneous membrane vesicles, are generally divided into exosomes and microvesicles on basis of their origination from the endosomal membrane or the plasma membrane, respectively. EV-mediated bidirectional communication among various cell types supports cancer cell growth and metastasis. EVs derived from different cell types and status have been shown to have distinct RNA profiles, comprising messenger RNAs and non-coding RNAs (ncRNAs). Recently, ncRNAs have attracted great interests in the field of EV-RNA research, and growing numbers of ncRNAs ranging from microRNAs to long ncRNAs have been investigated to reveal their specific functions and underlying mechanisms in the tumor microenvironment and premetastatic niches. Emerging evidence has indicated that EV-RNAs are essential functional cargoes in modulating hallmarks of cancers and in reciprocal crosstalk within tumor cells and between tumor and stromal cells over short and long distance, thereby regulating the initiation, development and progression of cancers. In this review, we discuss current findings regarding EV biogenesis, release and interaction with target cells as well as EV-RNA sorting, and highlight biological roles and molecular mechanisms of EV-ncRNAs in cancer biology.
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Affiliation(s)
- Wei Hu
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Cong Liu
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Zhuo-Yue Bi
- Hubei Provincial Key Laboratory for Applied Toxicology (Hubei Provincial Academy for Preventive Medicine), Wuhan, Hubei, 430079, People's Republic of China
| | - Qun Zhou
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Han Zhang
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Lin-Lin Li
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Jian Zhang
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Wei Zhu
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Yang-Yi-Yan Song
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Feng Zhang
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Hui-Min Yang
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Yong-Yi Bi
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Qi-Qiang He
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China
| | - Gong-Jun Tan
- Department of Clinical Laboratory, Zhuhai Hospital, Jinan University, 79 Kangning Road, Zhuhai, Guangdong, 519000, People's Republic of China. .,Department of Biomedical Engineering, University of Houston, Houston, TX, 77204, USA.
| | - Cheng-Cao Sun
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China. .,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
| | - De-Jia Li
- Department of Preventive Medicine, School of Health Science, Wuhan University, No.115 Donghu Road, Wuhan, Hubei, 430071, People's Republic of China. .,Population and Health Research Center, School of Health Sciences, Wuhan University, Wuhan, Hubei, 430071, People's Republic of China.
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Müller CP. Drug instrumentalization. Behav Brain Res 2020; 390:112672. [PMID: 32442549 DOI: 10.1016/j.bbr.2020.112672] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 04/20/2020] [Accepted: 04/21/2020] [Indexed: 12/19/2022]
Abstract
Psychoactive drugs with addiction potential are widely used by people of virtually all cultures in a non-addictive way. In order to understand this behaviour, its population penetrance, and its persistence, drug instrumentalization was suggested as a driving force for this consumption. Drug instrumentalization theory holds that psychoactive drugs are consumed in a very systematic way in order to make other, non-drug-related behaviours more efficient. Here, we review the evolutionary origin of this behaviour and its psychological mechanisms and explore the neurobiological and neuropharmacological mechanisms underlying them. Instrumentalization goals are discussed, for which an environmentally selective and mental state-dependent consumption of psychoactive drugs can be learned and maintained in a non-addictive way. A small percentage of people who regularly instrumentalize psychoactive drugs make a transition to addiction, which often starts with qualitative and quantitative changes in the instrumentalization goals. As such, addiction is proposed to develop from previously established long-term drug instrumentalization. Thus, preventing and treating drug addiction in an individualized medicine approach may essentially require understanding and supporting personal instrumentalization goals.
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Affiliation(s)
- Christian P Müller
- Department of Psychiatry and Psychotherapy, University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany.
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50
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Cottrill KA, Farinha CM, McCarty NA. The bidirectional relationship between CFTR and lipids. Commun Biol 2020; 3:179. [PMID: 32313074 PMCID: PMC7170930 DOI: 10.1038/s42003-020-0909-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Accepted: 03/23/2020] [Indexed: 02/08/2023] Open
Abstract
Cystic Fibrosis (CF) is the most common life-shortening genetic disease among Caucasians, resulting from mutations in the gene encoding the Cystic Fibrosis Transmembrane conductance Regulator (CFTR). While work to understand this protein has resulted in new treatment strategies, it is important to emphasize that CFTR exists within a complex lipid bilayer - a concept largely overlooked when performing structural and functional studies. In this review we discuss cellular lipid imbalances in CF, mechanisms by which lipids affect membrane protein activity, and the specific impact of detergents and lipids on CFTR function.
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Affiliation(s)
- Kirsten A Cottrill
- Molecular and Systems Pharmacology PhD Program, Emory University, Atlanta, GA, USA
| | - Carlos M Farinha
- Biosystems and Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016, Lisboa, Portugal
| | - Nael A McCarty
- Molecular and Systems Pharmacology PhD Program, Emory University, Atlanta, GA, USA.
- Department of Pediatrics and Children's Healthcare of Atlanta, Center for Cystic Fibrosis and Airways Disease Research, Emory University School of Medicine, Atlanta, GA, USA.
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