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Foran D, Antoniades C, Akoumianakis I. Emerging Roles for Sphingolipids in Cardiometabolic Disease: A Rational Therapeutic Target? Nutrients 2024; 16:3296. [PMID: 39408263 PMCID: PMC11478599 DOI: 10.3390/nu16193296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 09/19/2024] [Accepted: 09/25/2024] [Indexed: 10/20/2024] Open
Abstract
Cardiovascular disease is a leading cause of morbidity and mortality. New research elucidates increasingly complex relationships between cardiac and metabolic health, giving rise to new possible therapeutic targets. Sphingolipids are a heterogeneous class of bioactive lipids with critical roles in normal human physiology. They have also been shown to play both protective and deleterious roles in the pathogenesis of cardiovascular disease. Ceramides are implicated in dysregulating insulin signalling, vascular endothelial function, inflammation, oxidative stress, and lipoprotein aggregation, thereby promoting atherosclerosis and vascular disease. Ceramides also advance myocardial disease by enhancing pathological cardiac remodelling and cardiomyocyte death. Glucosylceramides similarly contribute to insulin resistance and vascular inflammation, thus playing a role in atherogenesis and cardiometabolic dysfunction. Sphingosing-1-phosphate, on the other hand, may ameliorate some of the pathological functions of ceramide by protecting endothelial barrier integrity and promoting cell survival. Sphingosine-1-phosphate is, however, implicated in the development of cardiac fibrosis. This review will explore the roles of sphingolipids in vascular, cardiac, and metabolic pathologies and will evaluate the therapeutic potential in targeting sphingolipids with the aim of prevention and reversal of cardiovascular disease in order to improve long-term cardiovascular outcomes.
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Affiliation(s)
| | | | - Ioannis Akoumianakis
- Cardiovascular Medicine Division, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK; (D.F.); (C.A.)
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Nishio K, Pasquet L, Camara K, DiSapio J, Hsu KS, Kato S, Bloom A, Richardson SK, Welsh JA, Jiang T, Jones JC, Cardell S, Watarai H, Terabe M, Olkhanud PB, Howell AR, Berzofsky JA. Lysosomal processing of sulfatide analogs alters target NKT cell specificity and immune responses in cancer. J Clin Invest 2023; 134:e165281. [PMID: 38127463 PMCID: PMC10866642 DOI: 10.1172/jci165281] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 12/20/2023] [Indexed: 12/23/2023] Open
Abstract
In a structure-function study of sulfatides that typically stimulate type II NKT cells, we made an unexpected discovery. We compared analogs with sphingosine or phytosphingosine chains and 24-carbon acyl chains with 0-1-2 double bonds (C or pC24:0, 24:1, or 24:2). C24:1 and C24:2 sulfatide presented by the CD1d monomer on plastic stimulated type II, not type I, NKT cell hybridomas, as expected. Unexpectedly, when presented by bone marrow-derived DCs (BMDCs), C24:2 reversed specificity to stimulate type I, not type II, NKT cell hybridomas, mimicking the corresponding β-galactosylceramide (βGalCer) without sulfate. C24:2 induced IFN-γ-dependent immunoprotection against CT26 colon cancer lung metastases, skewed the cytokine profile, and activated conventional DC subset 1 cells (cDC1s). This was abrogated by blocking lysosomal processing with bafilomycin A1, or by sulfite blocking of arylsulfatase or deletion of this enyzme that cleaves off sulfate. Thus, C24:2 was unexpectedly processed in BMDCs from a type II to a type I NKT cell-stimulating ligand, promoting tumor immunity. We believe this is the first discovery showing that antigen processing of glycosylceramides alters the specificity for the target cell, reversing the glycolipid's function from stimulating type II NKT cells to stimulating type I NKT cells, thereby introducing protective functional activity in cancer. We also believe our study uncovers a new role for antigen processing that does not involve MHC loading but rather alteration of which type of cell is responding.
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Affiliation(s)
- Kumiko Nishio
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Lise Pasquet
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Kaddy Camara
- Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA
| | - Julia DiSapio
- Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA
| | - Kevin S. Hsu
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Shingo Kato
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Anja Bloom
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | | | - Joshua A. Welsh
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Tianbo Jiang
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Jennifer C. Jones
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Susanna Cardell
- Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden
| | - Hiroshi Watarai
- Department of Immunology and Stem Cell Biology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Masaki Terabe
- Neuro-Oncology Branch, Center for Cancer Research, NCI, NIH, Bethesda, Maryland, USA
| | - Purevdorj B. Olkhanud
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
| | - Amy R. Howell
- Department of Chemistry, University of Connecticut, Storrs, Connecticut, USA
| | - Jay A. Berzofsky
- Vaccine Branch, Center for Cancer Research, National Cancer Institute (NCI), NIH, Bethesda, Maryland, USA
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Xatse MA, Olsen CP. Defining the glucosylceramide population of C. elegans. Front Physiol 2023; 14:1244158. [PMID: 37772059 PMCID: PMC10524606 DOI: 10.3389/fphys.2023.1244158] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 08/22/2023] [Indexed: 09/30/2023] Open
Abstract
Glucosylceramides (GlcCer) are lipids that impact signaling pathways, serve as critical components of cellular membranes, and act as precursors for hundreds of other complex glycolipid species. Abnormal GlcCer metabolism is linked to many diseases, including cancers, diabetes, Gaucher disease, neurological disorders, and skin disorders. A key hurdle to fully understanding the role of GlcCer in disease is the development of methods to accurately detect and quantify these lipid species in a model organism. This will allow for the dissection of the role of this pool in vivo with a focus on all the individual types of GlcCer. In this review, we will discuss the analysis of the GlcCer population specifically in the nematode Caenorhabditis elegans, focusing on the mass spectrometry-based methods available for GlcCer quantification. We will also consider the combination of these approaches with genetic interrogation of GlcCer metabolic genes to define the biological role of these unique lipids. Furthermore, we will explore the implications and obstacles for future research.
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Affiliation(s)
| | - Carissa Perez Olsen
- Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA, United States
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Microtubules as a potential platform for energy transfer in biological systems: a target for implementing individualized, dynamic variability patterns to improve organ function. Mol Cell Biochem 2023; 478:375-392. [PMID: 35829870 DOI: 10.1007/s11010-022-04513-1] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/24/2022] [Indexed: 02/07/2023]
Abstract
Variability characterizes the complexity of biological systems and is essential for their function. Microtubules (MTs) play a role in structural integrity, cell motility, material transport, and force generation during mitosis, and dynamic instability exemplifies the variability in the proper function of MTs. MTs are a platform for energy transfer in cells. The dynamic instability of MTs manifests itself by the coexistence of growth and shortening, or polymerization and depolymerization. It results from a balance between attractive and repulsive forces between tubulin dimers. The paper reviews the current data on MTs and their potential roles as energy-transfer cellular structures and presents how variability can improve the function of biological systems in an individualized manner. The paper presents the option for targeting MTs to trigger dynamic improvement in cell plasticity, regulate energy transfer, and possibly control quantum effects in biological systems. The described system quantifies MT-dependent variability patterns combined with additional personalized signatures to improve organ function in a subject-tailored manner. The platform can regulate the use of MT-targeting drugs to improve the response to chronic therapies. Ongoing trials test the effects of this platform on various disorders.
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Ishay Y, Potruch A, Schwartz A, Berg M, Jamil K, Agus S, Ilan Y. A digital health platform for assisting the diagnosis and monitoring of COVID-19 progression: An adjuvant approach for augmenting the antiviral response and mitigating the immune-mediated target organ damage. Biomed Pharmacother 2021; 143:112228. [PMID: 34649354 PMCID: PMC8455249 DOI: 10.1016/j.biopha.2021.112228] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 09/17/2021] [Accepted: 09/18/2021] [Indexed: 01/08/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19), which is a respiratory illness associated with high mortality, has been classified as a pandemic. The major obstacles for the clinicians to contain the disease are limited information availability, difficulty in disease diagnosis, predicting disease prognosis, and lack of disease monitoring tools. Additionally, the lack of valid therapies has further contributed to the difficulties in containing the pandemic. Recent studies have reported that the dysregulation of the immune system leads to an ineffective antiviral response and promotes pathological immune response, which manifests as ARDS, myocarditis, and hepatitis. In this study, a novel platform has been described for disseminating information to physicians for the diagnosis and monitoring of patients with COVID-19. An adjuvant approach using compounds that can potentiate antiviral immune response and mitigate COVID-19-induced immune-mediated target organ damage has been presented. A prolonged beneficial effect is achieved by implementing algorithm-based individualized variability measures in the treatment regimen.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
| | - Assaf Potruch
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
| | - Asaf Schwartz
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
| | - Marc Berg
- Altus Care powered by Oberon Sciences, Denmark, Israel; Department of Pediatrics, Lucile Packard Children's Hospital, Stanford, USA.
| | - Khurram Jamil
- Altus Care powered by Oberon Sciences, Denmark, Israel.
| | - Samuel Agus
- Altus Care powered by Oberon Sciences, Denmark, Israel.
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
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Ishay Y, Potruch A, Weksler-Zangen S, Shabat Y, Ilan Y. Augmented antiviral T cell immunity by oral administration of IMM-124E in preclinical models and a phase I/IIa clinical trial: A method for the prevention and treatment of COVID-19. Drug Dev Res 2021; 83:615-621. [PMID: 34596893 PMCID: PMC8652907 DOI: 10.1002/ddr.21890] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/17/2021] [Accepted: 09/25/2021] [Indexed: 01/08/2023]
Abstract
Biological adjuvants that target the gut immune system are being developed for modulating the immune system. Hyperimmune bovine colostrum (HBC), produced by harvesting the bovine colostrum of dairy cows immunized to exogenous antigens, has been shown to modulate the immune responses and alleviate immune‐mediated organ damages. The aim of the present study was to determine the ability of HBC to promote antiviral interferonγ (IFNγ) T cell responses. In a preclinical study, mice were orally administered with HBC for 5 days and tested for the number of T cell clones secreting IFNγ in response to viral antigens of the swine flu, New Caledonia influenza, and cytomegalovirus. In a phase I/IIa clinical trial, five healthy volunteers were treated for 5 days with HBC followed by testing the anti‐coronavirus disease (COVID‐19) immunity. In the preclinical study, oral administration of HBC augmented the number of T cell clones secreting IFNγ in response to viral antigens. In the clinical trial, oral administration of HBC to healthy males significantly increased the number of anti‐COVID‐19 spike protein IFNγ positive T cell clones. Oral administration of HBC provides a novel method for augmenting antiviral responses. Its high‐safety profile makes it ideal for all disease stages and for pre‐emptive therapy among medical personnel and other workers who are at a high risk of exposure to infections. The relatively low cost of HBC is expected to minimize care provider burdens, costs, and enable its global application.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Assaf Potruch
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Sarah Weksler-Zangen
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yehudit Shabat
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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Khoury T, Ishay Y, Rotnemer-Golinkin D, Zolotarovya L, Arkadir D, Zimran A, Ilan Y. A synergistic effect of Ambroxol and Beta-Glucosylceramide in alleviating immune-mediated hepatitis: A novel immunomodulatory non-immunosuppressive formulation for treatment of immune-mediated disorders. Biomed Pharmacother 2020; 132:110890. [PMID: 33080465 DOI: 10.1016/j.biopha.2020.110890] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2020] [Revised: 09/30/2020] [Accepted: 10/12/2020] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Ambroxol hydrochloride is being used in respiratory diseases as a broncholytic therapy. Beta-Glucosylceramide (GC) is a naturally occurring glycosphingolipid that exerts an immune protective effect. The aim of the present study was to determine the synergistic immunomodulatory effect between these two compounds. METHODS Immune-mediated hepatitis was induced in the mice by administration of Con A. Mice were treated with either Ambroxol or GC alone or with the combination of both. Mice were followed for their effect on the liver injury, cytokine profile, and the immune system. RESULTS Coadministration of Ambroxol and GC significantly alleviated the liver injury induced by ConA, as demonstrated by the decreased liver enzymes. The combined treatment had a statistically significant synergistic effect on the suppression of intrahepatic CD8+CD25+, an increase in the CD4/CD8 lymphocyte ratio and in the CD8+ intrahepatic lymphocyte trapping, as well as on change of serum in the IL4 levels. The beneficial effect was associated with the promotion of regulatory T lymphocytes subsets, and with a trend for a pro-inflammatory to an anti-inflammatory cytokine shift. CONCLUSIONS Coadministration of Ambroxol with GC exerted a synergistic immunoprotective effect in a model of immune-mediated acute liver damage. Considering the high safety profile of both agents, the combination may become a novel immunomodulatory non-immunosuppressive therapeutic agent. SIGNIFICANCE STATEMENT Coadministration of Ambroxol with glucocerebroside exerted a synergistic immunoprotective effect in a model of immune-mediated acute liver damage.
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Affiliation(s)
- Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - Yuval Ishay
- Gastroenterology and Liver Units, Department of Medicine, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - Devorah Rotnemer-Golinkin
- Gastroenterology and Liver Units, Department of Medicine, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - Lidya Zolotarovya
- Gastroenterology and Liver Units, Department of Medicine, The Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - David Arkadir
- Department of Neurology, Hadassah-Hebrew University Medical Center, Israel
| | - Ari Zimran
- Gaucher Clinic, Shaare Zedek Medical Center (SZMC), The Hebrew University, Hadassah Medical School, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, The Hebrew University, Hadassah Medical School, Jerusalem, Israel.
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Adar T, Shankar Lankalapalli R, Bittman R, Ilan Y. The assembly of glycosphingolipid determines their immunomodulatory effect: A novel method for structure-based design of immunotherapy. Cell Immunol 2020; 355:104157. [PMID: 32659503 DOI: 10.1016/j.cellimm.2020.104157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Revised: 05/27/2020] [Accepted: 07/01/2020] [Indexed: 11/18/2022]
Abstract
Structure-activity relationships provide insight into the binding interactions of beta-glycosphingolipids (GSLs) with both the TCR and the CD1d molecules, as well as the subsequent immunologic response of regulatory NKT cells. AIM To determine the effects of synthetic GSL structures on their immune modulatory functions. METHODS GSLs of various structures were tested in vitro and in an animal model of Concanavalin A (ConA) immune-mediated hepatitis. RESULTS In vitro, using SV40 binding to live monkey CV1 cells, the l-threo stereoisomer of C8-β-LacCer inhibits caveolar internalization, reducing viral binding to the cell surface. In vivo, in the ConA model, LR172, which has a saturated C8 chain, and LR178, which has a trans double bond at C-2 in the C8 chain, suppressed the immune-mediated liver inflammation and reduced IFNγ levels in a dose dependent manner. The beneficial effects of LR172 and of LR178 are associated with suppression of liver apoptosis, increased phosphorylated STAT3 expression in the liver, and an increase in the NKT liver/spleen ratio. SUMMARY The assembly of GSLs determines their immunomodulatory effect and can serve as a method for structure-based design of immunotherapy.
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Affiliation(s)
- Tomer Adar
- Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel
| | - Ravi Shankar Lankalapalli
- Department of Chemistry & Biochemistry, Queens College of the City University of New York, United States; Chemical Sciences and Technology Division, CSIR-National Institute for Interdisciplinary Science and Technology, Thiruvananthapuram 695019, Kerala, India
| | - Robert Bittman
- Department of Chemistry & Biochemistry, Queens College of the City University of New York, United States
| | - Yaron Ilan
- Department of Medicine, Hadassah Hebrew University Medical Center, Jerusalem, Israel.
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El-Haj M, Kanovitch D, Ilan Y. Personalized inherent randomness of the immune system is manifested by an individualized response to immune triggers and immunomodulatory therapies: a novel platform for designing personalized immunotherapies. Immunol Res 2019; 67:337-347. [DOI: 10.1007/s12026-019-09101-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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Comprehensive Proteomic Analysis Reveals Intermediate Stage of Non-Lesional Psoriatic Skin and Points out the Importance of Proteins Outside this Trend. Sci Rep 2019; 9:11382. [PMID: 31388062 PMCID: PMC6684579 DOI: 10.1038/s41598-019-47774-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Accepted: 06/28/2019] [Indexed: 11/15/2022] Open
Abstract
To better understand the pathomechanism of psoriasis, a comparative proteomic analysis was performed with non-lesional and lesional skin from psoriasis patients and skin from healthy individuals. Strikingly, 79.9% of the proteins that were differentially expressed in lesional and healthy skin exhibited expression levels in non-lesional skin that were within twofold of the levels observed in healthy and lesional skin, suggesting that non-lesional skin represents an intermediate stage. Proteins outside this trend were categorized into three groups: I. proteins in non-lesional skin exhibiting expression similar to lesional skin, which might be predisposing factors (i.e., CSE1L, GART, MYO18A and UGDH); II. proteins that were differentially expressed in non-lesional and lesional skin but not in healthy and lesional skin, which might be non-lesional characteristic alteration (i.e., CHCHD6, CHMP5, FLOT2, ITGA7, LEMD2, NOP56, PLVAP and RRAS); and III. proteins with contrasting differential expression in non-lesional and lesional skin compared to healthy skin, which might contribute to maintaining the non-lesional state (i.e., ITGA7, ITGA8, PLVAP, PSAPL1, SMARCA5 and XP32). Finally, proteins differentially expressed in lesions may indicate increased sensitivity to stimuli, peripheral nervous system alterations, furthermore MYBBP1A and PRKDC were identified as potential regulators of key pathomechanisms, including stress and immune response, proliferation and differentiation.
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Ilan-Ber T, Ilan Y. The role of microtubules in the immune system and as potential targets for gut-based immunotherapy. Mol Immunol 2019; 111:73-82. [DOI: 10.1016/j.molimm.2019.04.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Revised: 04/11/2019] [Accepted: 04/23/2019] [Indexed: 12/18/2022]
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Ilan Y. β-Glycosphingolipids as Mediators of Both Inflammation and Immune Tolerance: A Manifestation of Randomness in Biological Systems. Front Immunol 2019; 10:1143. [PMID: 31178868 PMCID: PMC6538797 DOI: 10.3389/fimmu.2019.01143] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Accepted: 05/07/2019] [Indexed: 12/27/2022] Open
Abstract
Plasticity in biological systems is attributed to the combination of multiple parameters which determine function. These include genotypic, phenotypic, and environmental factors. While biological processes can be viewed as ordered and sequential, biological randomness was suggested to underline part of them. The present review looks into the concept of randomness in biological systems by exploring the glycosphingolipids-NKT cells example. NKT cells are a unique subset of regulatory lymphocytes which play a role in both inflammation and tolerance. Glycosphingolipids promote an immune balance by changing different arms of the immune system in opposing environments. Traditional immunology looks at skewing the immune system into different directions by different types of activation of the same cell stimulation of different cells subsets, use of different ligands, or different the effect of different immune environments. While these may explain some of the effects, the lack of consistency and opposing results under similar settings may involve randomness which may also be part of real life effects of immunomodulatory agents. It means that several of the biological processes, cannot be explained by simple linear models, and may involve more complex concepts. The application for these concepts for improving therapies to patients with Gaucher disease are discussed. SUMMARY The use of different ligands that target a variety of cell subsets in different immune environments may underlie differences in the functionality of NKT cells and their variability in response to NKT-based therapies. The novel concept of randomness in biology means that several biological processes cannot be solely explained by simple linear models and may instead involve much more complicated schemes of random disorder. These may have implications on future design of therapeutic regimens for improving the response to current treatments.
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Affiliation(s)
- Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Mizrahi M, Adar T, Lalazar G, Nachman D, El Haj M, Ben Ya’acov A, Lichtenstein Y, Shabat Y, Kanovich D, Zolotarov L, Ilan Y. Glycosphingolipids Prevent APAP and HMG-CoA Reductase Inhibitors-mediated Liver Damage: A Novel Method for "Safer Drug" Formulation that Prevents Drug-induced Liver Injury. J Clin Transl Hepatol 2018; 6:127-134. [PMID: 29951356 PMCID: PMC6018318 DOI: 10.14218/jcth.2017.00071] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2017] [Revised: 12/08/2017] [Accepted: 01/23/2018] [Indexed: 12/20/2022] Open
Abstract
Background and Aims: Acetaminophen (APAP) and HMG-CoA reductase inhibitors are common causes of drug-induced liver injury (DILI). This study aimed to determine the ability to reduce APAP- and statins-mediated liver injury by using formulations that combine glycosphingolipids and vitamin E. Methods: Mice were injected with APAP or with statins and treated before and after with β-glucosylceramide (GC), with or without vitamin E. Mice were followed for changes in liver enzymes, liver histology, hepatic expression of JNK, STAT3 and caspase 3, as well as intrahepatic natural killer T cells (NKT) and the serum cytokine levels by flow cytometry. Results: Administration of GC before or after APAP alleviated the liver damage, as noted by a reduction of the liver enzymes, improvement in the liver histology and decreased hepatic caspase 3 expression. Beneficial effect was associated with a reduction of the intrahepatic NKT, JNK expression in the liver, and increased glutathione in the liver, and decreased TNF-α serum levels. Synergistic effect of co-administration of GC with vitamin E was observed. Similar protective effect of GC on statin-mediated liver damage was documented by a reduction in liver enzymes and improved liver histology, which was mediated by reduction of NKT, increased STAT3 expression in the liver, and reduced the TGF-β and IL17 levels. Conclusions: β-glycosphingolipids exert a hepatoprotective effect on APAP- and statins-mediated liver damage. Vitamin E exerted a synergistic effect to that of GC. The generation of "safer drug" formulations, which include an active molecule combined with a hepatoprotective adjuvant, may provide an answer to the real unmet need of DILI.
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Affiliation(s)
- Meir Mizrahi
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Tomer Adar
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Gadi Lalazar
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Dean Nachman
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Madi El Haj
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Ami Ben Ya’acov
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yoav Lichtenstein
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yehudit Shabat
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Dimitri Kanovich
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Lida Zolotarov
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
- *Correspondence to: Yaron Ilan, Department of Medicine, Hebrew University-Hadassah Medical Center, P.O.B 12000, Jerusalem, IL-91120, Israel. Tel: +972-2-6777816, Fax: +972-2-6431021, E-mail:
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Khoury T, Rotnemer-Golinkin D, Shabat Y, Zolotarovya L, Ilan Y. Oral Co-administration of Soy-derived Extracts with Alcohol or with Sugar-sweetened Beverages Exerts Liver and Sugar Protective Effects. J Clin Transl Hepatol 2017; 5:208-215. [PMID: 28936402 PMCID: PMC5606967 DOI: 10.14218/jcth.2017.00019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2017] [Revised: 04/14/2017] [Accepted: 04/21/2017] [Indexed: 12/04/2022] Open
Abstract
Background and Aims: Both alcoholic drinks and high sugar-containing soft drinks cause major health problems worldwide. Oral administration of OS and M1 soy-derived extracts has been shown to alleviate liver injury in animal models. The aim of the present study was to determine the liver- and sugar-protective effect of OS and M1 soy-derived extracts when added to alcohol and sugar-enriched drinks. Methods: Mice were treated with alcohol or high sugar-containing drinks, with and without administration of a combination of OS and M1 soy extracts. Mice were observed for the effects on liver injury, glucose metabolism, and the immune system. Results: Co-administration of the soy extracts OS and M1 significantly alleviated the liver injury induced by acute alcohol, as evidenced by decreased liver enzymes. These beneficial effects were associated with promotion of subsets of regulatory T lymphocytes and with a trend towards a pro-inflammatory to an anti-inflammatory cytokine shift. Co-administration of OS M1 soy extracts with sugar-sweetened beverages significantly alleviated the increases in serum sugar levels. Conclusions: OS and M1 extracts exert a synergistic hepato- and glucose-protective effect in models of alcohol-induced liver damage and soft drinks-associated increases in serum glucose. These extracts may provide a solution to the two pressing health problems.
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Affiliation(s)
- Tawfik Khoury
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Devorah Rotnemer-Golinkin
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yehudit Shabat
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Lidya Zolotarovya
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Yaron Ilan
- Gastroenterology and Liver Units, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
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Ishay Y, Zimran A, Szer J, Dinur T, Ilan Y, Arkadir D. Combined beta-glucosylceramide and ambroxol hydrochloride in patients with Gaucher related Parkinson disease: From clinical observations to drug development. Blood Cells Mol Dis 2016; 68:117-120. [PMID: 27866808 DOI: 10.1016/j.bcmd.2016.10.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2016] [Accepted: 10/17/2016] [Indexed: 12/17/2022]
Abstract
Both patients with non-neuronopathic Gaucher disease (GD) and heterozygous GBA mutation carrier are at increased risk for Parkinson disease (PD). The risk for PD in these groups does not linearly increase with glucosylceramide (GC) accumulation or with acid β-glucocerebrosidase (GCase) activity. This observation, together with other clinical systemic observations raises the possibility that extra-cellular GC actually has beneficial, anti-inflammatory, properties. Based on this hypothesis, we suggest here that the administration of supplementary oral GC to GBA carriers at risk for PD may slow inflammatory-driven secondary neuronal death. Such a treatment may act synergistically in GBA carriers once given in combination with an agent that prevent the primary pathologic process that leads to cell death. Ambroxol hydrochloride, a pharmacological chaperone, which reduces endoplasmic reticulum (ER) stress induced by accumulation of mutant misfolded GCase could serve as such an agent. The efficacy of this combined therapy, derived from clinical observations, in vivo and in vitro studies, should be evaluated in clinical trials.
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Affiliation(s)
- Yuval Ishay
- Department of Medicine, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel
| | - Ari Zimran
- Gaucher Clinic, Shaare Zedek Medical Center and the Hebrew University, Jerusalem, Israel
| | - Jeffrey Szer
- Department of Clinical Hematology, The Royal Melbourne Hospital, Melbourne, Australia
| | - Tama Dinur
- Gaucher Clinic, Shaare Zedek Medical Center and the Hebrew University, Jerusalem, Israel
| | - Yaron Ilan
- Department of Medicine, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel
| | - David Arkadir
- Department of Neurology, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel.
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Khoury T, Ben Ya'acov A, Shabat Y, Zolotarovya L, Snir R, Ilan Y. Altered distribution of regulatory lymphocytes by oral administration of soy-extracts exerts a hepatoprotective effect alleviating immune mediated liver injury, non-alcoholic steatohepatitis and insulin resistance. World J Gastroenterol 2015; 21:7443-7456. [PMID: 26139990 PMCID: PMC4481439 DOI: 10.3748/wjg.v21.i24.7443] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 02/08/2015] [Accepted: 03/30/2015] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the immune-modulatory and the hepatoprotective effects of oral administration of two soy extracts in immune mediated liver injury and non-alcoholic steatohepatitis (NASH). METHODS Two soy extracts, M1 and OS, were orally administered to mice with concanavalin A (ConA) immune-mediated hepatitis, to high-fat diet (HFD) mice and to methionine and choline reduced diet combined with HFD mice. Animals were followed for disease and immune biomarkers. RESULTS Oral administration of OS and M1 had an additive effect in alleviating ConA hepatitis manifested by a decrease in alanine aminotransferase and aspartate aminotransferase serum levels. Oral administration of the OS and M1 soy derived fractions, ameliorated liver injury in the high fat diet model of NASH, manifested by a decrease in hepatic triglyceride levels, improvement in liver histology, decreased serum cholesterol and triglycerides and improved insulin resistance. In the methionine and choline reduced diet combined with the high fat diet model, we noted a decrease in hepatic triglycerides and improvement in blood glucose levels and liver histology. The effects were associated with reduced serum tumor necrosis factor alpha and alteration of regulatory T cell distribution. CONCLUSION Oral administration of the combination of OS and M1 soy derived extracts exerted an adjuvant effect in the gut-immune system, altering the distribution of regulatory T cells, and alleviating immune mediated liver injury, hyperlipidemia and insulin resistance.
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Shabat Y, Lichtenstein Y, Zolotarov L, Ben Ya'acov A, Ilan Y. Hepatoprotective effect of DT56a is associated with changes in natural killer T cells and regulatory T cells. J Dig Dis 2013; 14:84-92. [PMID: 23134214 DOI: 10.1111/1751-2980.12003] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To determine the metabolic and immunological effects of the oral administration of DT56a, an enzymatic isolate of soybeans. METHODS DT56a was orally administered to mice in three animal models: leptin deficiency, high-fat diet (HFD) supplementation and immune-mediated hepatitis. Liver damage and immunological status were assessed. RESULTS Oral administration of DT56a to leptin-deficient (ob/ob) and HFD mice led to a significant reduction in serum triglyceride (TG) and total cholesterol (TC) levels. DT56a-treated mice in both models exhibited a significant reduction in hepatic levels of TG and marked alleviation of glycemic control as indicated by significant decreases in fasting blood glucose levels and glucose tolerance tests. The levels of liver enzymes were reduced. These metabolic effects were associated with altered distributions of regulatory T (Tregs) and natural killer T (NKT) cells. DT56a suppressed the immune-mediated liver damage induced by concanavalin A indicated by decreased liver enzymes and serum interferon-γ levels and by improved histology and decreased hepatic apoptosis. Oral administration of DT56a also alleviated immune-mediated hepatitis and affected Tregs and NKT cells. CONCLUSIONS Oral administration of DT56a promotes a hepatoprotective effect associated with an alteration in the distribution of Tregs and NKT cells.
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Affiliation(s)
- Yehudit Shabat
- Liver Unit, Hebrew University-Hadassah Medical Center, Jerusalem, Israel
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Gonzalez-Carmona MA, Sandhoff R, Tacke F, Vogt A, Weber S, Canbay AE, Rogler G, Sauerbruch T, Lammert F, Yildiz Y. Beta-glucosidase 2 knockout mice with increased glucosylceramide show impaired liver regeneration. Liver Int 2012; 32:1354-62. [PMID: 22764777 DOI: 10.1111/j.1478-3231.2012.02841.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Accepted: 05/28/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS Glycolipids have been shown to serve specialized functions in cell signalling, proliferation and differentiation processes, which are all important during liver regeneration. We previously generated beta-glucosidase 2 (GBA2) knockout mice that accumulate the glycolipid glucosylceramide in various tissues, including the liver. The present study addressed the role of GBA2-deficiency and subsequent glucosylceramide accumulation in liver regeneration. METHODS Gba2 knockout and wild-type mice were subjected to two-third partial hepatectomy. Mice were sacrificed at different time points, blood was collected, and the remnant liver was removed. Glucosylceramide and ceramide were quantified using mass spectrometry from whole liver and isolated hepatocytes. Serum and hepatocytic supernatant of IL-6, TNF-α and TGF-β levels were measured using ELISA. Cell signalling proteins were analysed using immunoblots. RESULTS Regenerating liver after partial hepatectomy showed a significant increase of hepatic glucosylceramide in GBA2-deficient mice compared to controls. Accumulation of glucosylceramide was associated with a delay in liver regeneration and reduced serum levels of IL-6 and TNF-α. Furthermore, reduced IL-6 led to decreased expression of the phosphorylated form of the signal transducer and activator of transcription 3 (P-STAT3). CONCLUSIONS We conclude that increased glucosylceramide affects cytokine- and growth factor-mediated signalling pathways during liver regeneration. Thus, the repression of IL-6/STAT3 signalling pathway seems to be one of the mechanisms for the delay of liver regeneration in GBA2-deficient mice.
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Beta-Glucosylceramide Administration (i.p.) Activates Natural Killer T cells In Vivo and Prevents Tumor Metastasis in Mice. Lipids 2012; 47:581-91. [DOI: 10.1007/s11745-012-3666-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2011] [Accepted: 03/02/2012] [Indexed: 01/23/2023]
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Merrill AH. Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 2011; 111:6387-422. [PMID: 21942574 PMCID: PMC3191729 DOI: 10.1021/cr2002917] [Citation(s) in RCA: 588] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2011] [Indexed: 12/15/2022]
Affiliation(s)
- Alfred H Merrill
- School of Biology, and the Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Georgia 30332-0230, USA.
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Napolitano A, Benavides A, Pizza C, Piacente S. Qualitative on-line profiling of ceramides and cerebrosides by high performance liquid chromatography coupled with electrospray ionization ion trap tandem mass spectrometry: The case of Dracontium loretense. J Pharm Biomed Anal 2011; 55:23-30. [DOI: 10.1016/j.jpba.2010.12.035] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2010] [Revised: 12/21/2010] [Accepted: 12/23/2010] [Indexed: 10/18/2022]
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Current Opinion in Clinical Nutrition and Metabolic Care. Current world literature. Curr Opin Clin Nutr Metab Care 2010; 13:215-21. [PMID: 20145440 DOI: 10.1097/mco.0b013e32833643b4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Ilan Y. Alpha versus beta: are we on the way to resolve the mystery as to which is the endogenous ligand for natural killer T cells? Clin Exp Immunol 2009; 158:300-7. [PMID: 19793337 DOI: 10.1111/j.1365-2249.2009.04030.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Natural killer T (NKT) lymphocytes are a unique subset of cells that play a role in regulating the immune system. For the past decade, studies have focused upon attempts to define these cells and to determine the ligand(s) that are required for their development and peripheral activation. Many research groups have focused upon determining the mechanisms for activating or inhibiting NKT cells in an attempt to control immune-mediated disorders as well as infectious and malignant conditions by using different ligand structures. Alpha-anomeric glycolipids and phospholipids derived from mammalian, bacterial, protozoan and plant species have been suggested as potential ligands for these lymphocytes. Some of these ligands were structured in forms that can bind to CD1d molecules. The lack of alpha-anomeric glycosphingolipids in mammals and the modest effect of these ligands in human studies, along with recent data from animal models and humans on the NKT-dependent immunomodulatory effect of beta-glycosphingolipids, suggest that the beta-anomeric ligands have the potential to be the endogenous NKT ligand.
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Affiliation(s)
- Y Ilan
- Department of Medicine, Hebrew University - Hadassah Medical Center, Jerusalem, Israel.
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