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1
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Amatruda M, Marechal D, Gacias M, Wentling M, Turpin-Nolan S, Morstein J, Moniruzzaman M, Brüning JC, Haughey NJ, Trauner DH, Casaccia P. Neuroprotective effect of neuron-specific deletion of the C16 ceramide synthetic enzymes in an animal model of multiple sclerosis. Glia 2025; 73:271-290. [PMID: 39489703 DOI: 10.1002/glia.24631] [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: 01/24/2024] [Revised: 09/05/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024]
Abstract
Ceramide C16 is a sphingolipid detected at high levels in several neurodegenerative disorders, including multiple sclerosis (MS). It can be generated de novo or from the hydrolysis of other sphingolipids, such as sphingomyelin or through the recycling of sphingosine, in what is known as the salvage pathway. While the myelin damage occurring in MS suggests the importance of the hydrolytic and salvage pathways, the growing interest on the importance of diet in demyelinating disorders, prompted us to investigate the involvement of de novo ceramide C16 synthesis on disease severity. A diet rich in saturated fats such as palmitic acid, as found in many highly processed foods, provides substrates for the ceramide C16 synthetic enzymes ceramide synthase 6 (CERS6) and 5 (CERS5), which are expressed in the central nervous system. Using the experimental autoimmune encephalomyelitis (EAE) model of inflammatory demyelination, we show here that mice with CamK2a+ neuronal specific deletion of both CerS6 and CerS5 show a milder course of EAE than wild type mice, even when fed a diet enriched in palmitic acid. At a cellular level, neurons lacking both CerS6 and CerS5 are protected from the mitochondrial dysfunction arising from exposure to oxidative stress and palmitic acid in the medium. These data underscore the importance of a healthy diet avoiding processed foods for demyelinating disorders and identifies endogenous neuronal synthesis of ceramide C16 as an important determinant of disease severity.
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Affiliation(s)
- Mario Amatruda
- Neuroscience Initiative, Advanced Science Research Center, CUNY, New York, New York, USA
| | - Damien Marechal
- Neuroscience Initiative, Advanced Science Research Center, CUNY, New York, New York, USA
| | - Mar Gacias
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Maureen Wentling
- Neuroscience Initiative, Advanced Science Research Center, CUNY, New York, New York, USA
| | - Sarah Turpin-Nolan
- Max Planck Institute for Metabolism Research, Cologne, Germany
- Cellular and Molecular Metabolism Laboratory, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Johannes Morstein
- Department of Chemistry, New York University, Silver Center, New York, New York, USA
- Department of Cellular and Molecular Pharmacology, UCSF, San Francisco, California, USA
| | - Mohammed Moniruzzaman
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jens C Brüning
- Max Planck Institute for Metabolism Research, Cologne, Germany
| | - Norman J Haughey
- Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Dirk H Trauner
- Department of Chemistry, New York University, Silver Center, New York, New York, USA
- Chemistry and Translational Therapeutics and Systems Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Patrizia Casaccia
- Neuroscience Initiative, Advanced Science Research Center, CUNY, New York, New York, USA
- Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA
- Program in Biochemistry, The Graduate Center of The City University of New York, New York, New York, USA
- Program in Biology, The Graduate Center of The City University of New York, New York, New York, USA
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2
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Iezhitsa I, Agarwal R, Agarwal P. Unveiling enigmatic essence of Sphingolipids: A promising avenue for glaucoma treatment. Vision Res 2024; 221:108434. [PMID: 38805893 DOI: 10.1016/j.visres.2024.108434] [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: 04/01/2024] [Revised: 05/05/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024]
Abstract
Treatment of glaucoma, the leading cause of irreversible blindness, remains challenging. The apoptotic loss of retinal ganglion cells (RGCs) in glaucoma is the pathological hallmark. Current treatments often remain suboptimal as they aim to halt RGC loss secondary to reduction of intraocular pressure. The pathophysiological targets for exploring direct neuroprotective approaches, therefore are highly relevant. Sphingolipids have emerged as significant target molecules as they are not only the structural components of various cell constituents, but they also serve as signaling molecules that regulate molecular pathways involved in cell survival and death. Investigations have shown that a critical balance among various sphingolipid species, particularly the ceramide and sphingosine-1-phosphate play a role in deciding the fate of the cell. In this review we briefly discuss the metabolic interconversion of sphingolipid species to get an insight into "sphingolipid rheostat", the dynamic balance among metabolites. Further we highlight the role of sphingolipids in the key pathophysiological mechanisms that lead to glaucomatous loss of RGCs. Lastly, we summarize the potential drug candidates that have been investigated for their neuroprotective effects in glaucoma via their effects on sphingolipid axis.
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3
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Jamjoum R, Majumder S, Issleny B, Stiban J. Mysterious sphingolipids: metabolic interrelationships at the center of pathophysiology. Front Physiol 2024; 14:1229108. [PMID: 38235387 PMCID: PMC10791800 DOI: 10.3389/fphys.2023.1229108] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 11/27/2023] [Indexed: 01/19/2024] Open
Abstract
Metabolic pathways are complex and intertwined. Deficiencies in one or more enzymes in a given pathway are directly linked with genetic diseases, most of them having devastating manifestations. The metabolic pathways undertaken by sphingolipids are diverse and elaborate with ceramide species serving as the hubs of sphingolipid intermediary metabolism and function. Sphingolipids are bioactive lipids that serve a multitude of cellular functions. Being pleiotropic in function, deficiency or overproduction of certain sphingolipids is associated with many genetic and chronic diseases. In this up-to-date review article, we strive to gather recent scientific evidence about sphingolipid metabolism, its enzymes, and regulation. We shed light on the importance of sphingolipid metabolism in a variety of genetic diseases and in nervous and immune system ailments. This is a comprehensive review of the state of the field of sphingolipid biochemistry.
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Affiliation(s)
- Rama Jamjoum
- Department of Pharmacy, Birzeit University, West Bank, Palestine
| | - Saurav Majumder
- National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health, Rockville, MD, United States
| | - Batoul Issleny
- Department of Pharmacy, Birzeit University, West Bank, Palestine
| | - Johnny Stiban
- Department of Biology and Biochemistry, Birzeit University, West Bank, Palestine
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4
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Sun C, Chang X, MacIsaac HJ, Wen J, Zhao L, Dai Z, Li J. Phytosphingosine inhibits cell proliferation by damaging DNA in human cell lines. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2023; 256:114840. [PMID: 37001191 DOI: 10.1016/j.ecoenv.2023.114840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/23/2023] [Accepted: 03/24/2023] [Indexed: 06/19/2023]
Abstract
Harmful cyanobacterial blooms have caused numerous biosecurity incidents owing to the production of hazardous secondary metabolites such as microcystin. Additionally, cyanobacteria also release many other components that have not been explored. We identified compounds of a toxic mixture exudated from a dominant, blooming species, Microcystis aeruginosa, and found that phytosphingosine (PHS) was one of the bioactive components. Since PHS exhibited toxicity and is deemed a hazardous substance by the European Chemicals Agency, we hypothesized that PHS is a potentially toxic compound in M. aeruginosa exudates. However, the mechanisms of PHS ecotoxicity remain unclear. We assessed the cytotoxicity of PHS using an in vitro cell model in eight human cell lines and observed that the nasopharyngeal carcinoma cell line CNE2 was the most sensitive. We exposed CNE2 cells to 0-25 µmol/L PHS for 24 hr to explore its toxicity and mechanism. PHS exposure resulted in abnormal nuclear morphology, micronuclei, and DNA damage. Moreover, PHS significantly inhibited cell proliferation and arrested cell cycle at S phase. The results of Western blot suggested that PHS increased the expression of DNA damage-related proteins (ATM, p-P53 and P21) and decreased the expression of S phase-related proteins (CDK2, CyclinA2 and CyclinE1), indicating the toxicological mechanism of PHS on CNE2 cells. These data provide evidence that PHS has genetic toxicity and inhibits cell proliferation by damaging DNA. Our study provides evidence that PHS inhibits cell proliferation by damaging DNA. While additional work is required, we propose that PHS been considered as a potentially toxic component in MaE in addition to other well-characterized secondary compounds.
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Affiliation(s)
- Chunxiao Sun
- School of Ecology and Environmental Science, Yunnan University, Kunming 650091, China; Great Lakes Institute for Environmental Research, University of Windsor, Windsor, ON N9B 3P4, Canada
| | - Xuexiu Chang
- Great Lakes Institute for Environmental Research, University of Windsor, Windsor, ON N9B 3P4, Canada; College of Agronomy and Life Sciences, Kunming University, Kunming 650214, China
| | - Hugh J MacIsaac
- School of Ecology and Environmental Science, Yunnan University, Kunming 650091, China; College of Agronomy and Life Sciences, Kunming University, Kunming 650214, China
| | - Jiayao Wen
- School of Ecology and Environmental Science, Yunnan University, Kunming 650091, China
| | - Lixing Zhao
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Zhi Dai
- Key Laboratory of Medicinal Chemistry for Natural Resource, Ministry of Education, Yunnan Provincial Center for Research & Development of Natural Products, School of Chemical Science and Technology, Yunnan University, Kunming 650091, China
| | - Jiaojiao Li
- School of Ecology and Environmental Science, Yunnan University, Kunming 650091, China.
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5
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Pal P, Atilla-Gokcumen GE, Frasor J. Emerging Roles of Ceramides in Breast Cancer Biology and Therapy. Int J Mol Sci 2022; 23:ijms231911178. [PMID: 36232480 PMCID: PMC9569866 DOI: 10.3390/ijms231911178] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 09/15/2022] [Accepted: 09/20/2022] [Indexed: 11/16/2022] Open
Abstract
One of the classic hallmarks of cancer is the imbalance between elevated cell proliferation and reduced cell death. Ceramide, a bioactive sphingolipid that can regulate this balance, has long been implicated in cancer. While the effects of ceramide on cell death and therapeutic efficacy are well established, emerging evidence indicates that ceramide turnover to downstream sphingolipids, such as sphingomyelin, hexosylceramides, sphingosine-1-phosphate, and ceramide-1-phosphate, is equally important in driving pro-tumorigenic phenotypes, such as proliferation, survival, migration, stemness, and therapy resistance. The complex and dynamic sphingolipid network has been extensively studied in several cancers, including breast cancer, to find key sphingolipidomic alterations that can be exploited to develop new therapeutic strategies to improve patient outcomes. Here, we review how the current literature shapes our understanding of how ceramide synthesis and turnover are altered in breast cancer and how these changes offer potential strategies to improve breast cancer therapy.
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Affiliation(s)
- Purab Pal
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - G. Ekin Atilla-Gokcumen
- Department of Chemistry, University at Buffalo, The State University of New York (SUNY), Buffalo, NY 14260, USA
- Correspondence: (G.E.A.-G.); (J.F.)
| | - Jonna Frasor
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
- Correspondence: (G.E.A.-G.); (J.F.)
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6
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Li J, Xu Y, Sun Z, Cai Y, Wang B, Zhang M, Ban Y, Hou X, Hao Y, Ouyang Q, Wu B, Wang M, Wang W. Differential lipids in pregnant women with subclinical hypothyroidism and their correlation to the pregnancy outcomes. Sci Rep 2021; 11:19689. [PMID: 34608242 PMCID: PMC8490420 DOI: 10.1038/s41598-021-99252-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Accepted: 09/21/2021] [Indexed: 01/07/2023] Open
Abstract
Subclinical hypothyroidism (SCH) has become a prevalent complication in pregnancy. Recent research links SCH to disturbed thyroid lipid profile; however, it is unclear how lipid metabolism disorders contribute to the pathogenesis of SCH during pregnancy. Thus, we used nontargeted lipidomics to identify and compare the lipids and metabolites expressed by pregnant women with SCH and healthy pregnant women. Multivariate analysis revealed 143 lipid molecules differentially expressed between the SCH group and the control group. Based on fold change, 30 differentially expressed lipid metabolites are potential biomarkers. KEGG pathway enrichment analysis showed that the differentially expressed metabolites participate in several pathways, including response to pathogenic Escherichia coli infection, regulation of lipolysis in adipocytes, metabolic pathways, glycerophospholipid metabolism, and fat digestion and absorption pathways. Correlation analyses revealed sphingomyelin (SM) and phosphatidylcholine (PC) positively correlate to tumor necrosis factor-α (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6), while phosphatidylglycerol (PG), and phosphatidylinositol (PI) negatively correlate with them. In addition, PG positively correlates to birth weight. Thus, the lipid profile of pregnant women with SCH is significantly different from that of healthy pregnant women. Lipid molecules associated with the differential lipid metabolism, such as SM, phosphatidylethanolamine (PE), and PI, should be further investigated for their roles in the pathogenesis of SCH in pregnancy, as they might be targets for reducing the incidence of adverse pregnancy outcomes.
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Affiliation(s)
- Jingjing Li
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yajuan Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Zongzong Sun
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanjun Cai
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Biao Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Miao Zhang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yanjie Ban
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Xiaofeng Hou
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yingqi Hao
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qian Ouyang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Bo Wu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Mengqi Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Wentao Wang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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7
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Velazquez FN, Hernandez-Corbacho M, Trayssac M, Stith JL, Bonica J, Jean B, Pulkoski-Gross MJ, Carroll BL, Salama MF, Hannun YA, Snider AJ. Bioactive sphingolipids: Advancements and contributions from the laboratory of Dr. Lina M. Obeid. Cell Signal 2020; 79:109875. [PMID: 33290840 PMCID: PMC8244749 DOI: 10.1016/j.cellsig.2020.109875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 12/01/2020] [Accepted: 12/02/2020] [Indexed: 02/06/2023]
Abstract
Sphingolipids and their synthetic enzymes have emerged as critical mediators in numerous diseases including inflammation, aging, and cancer. One enzyme in particular, sphingosine kinase (SK) and its product sphingosine-1-phosphate (S1P), has been extensively implicated in these processes. SK catalyzes the phosphorylation of sphingosine to S1P and exists as two isoforms, SK1 and SK2. In this review, we will discuss the contributions from the laboratory of Dr. Lina M. Obeid that have defined the roles for several bioactive sphingolipids in signaling and disease with an emphasis on her work defining SK1 in cellular fates and pathobiologies including proliferation, senescence, apoptosis, and inflammation.
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Affiliation(s)
- Fabiola N Velazquez
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Hernandez-Corbacho
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Magali Trayssac
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jeffrey L Stith
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Joseph Bonica
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Bernandie Jean
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Michael J Pulkoski-Gross
- Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Brittany L Carroll
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Department of Pharmacological Sciences, Stony Brook University, Stony Brook, NY 11790, USA
| | - Mohamed F Salama
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Department of Biochemistry, Faculty of Veterinary Medicine, Mansoura University, Mansoura, Egypt
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook University, Stony Brook, NY 11794, USA; Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA
| | - Ashley J Snider
- Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721, USA.
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8
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Huang Y, Zhao X, Zhang ZT, Chen SS, Li SS, Shi Z, Jing J, Huang A, Guo YM, Bai ZF, Zou ZS, Xiao XH, Wang JB, Niu M. Metabolomics Profiling and Diagnosis Biomarkers Searching for Drug-Induced Liver Injury Implicated to Polygonum multiflorum: A Cross-Sectional Cohort Study. Front Med (Lausanne) 2020; 7:592434. [PMID: 33330552 PMCID: PMC7734208 DOI: 10.3389/fmed.2020.592434] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Accepted: 10/30/2020] [Indexed: 12/17/2022] Open
Abstract
Aim: The diagnosis of drug-induced liver injury (DILI) remains a challenge and the cases of Polygonum multiflorum Thunb. (PM) induced DILI (PM-DILI) have received much attention This study aimed to identify a simple and high-efficiency approach to PM-DILI diagnosis via metabolomics analysis. Methods: Plasma metabolites in 13 PM-DILI patients were profiled by liquid chromatography along with high-resolution mass spectrometry. Meanwhile, the metabolic characteristics of the PM-DILI were compared with that of autoimmune hepatitis (AIH), hepatitis B (HBV), and healthy volunteers. Results: Twenty-four metabolites were identified to present significantly different levels in PM-DILI patients compared with HBV and AIH groups. These metabolites were enriched into glucose, amino acids, and sphingolipids metabolisms. Among these essential metabolites, the ratios of P-cresol sulfate vs. phenylalanine and inosine vs. bilirubin were further selected using a stepwise decision tree to construct a classification model in order to differentiate PM-DILI from HBV and AIH. The model was highly effective with sensitivity of 92.3% and specificity of 88.9%. Conclusions: This study presents an integrated view of the metabolic features of PM-DILI induced by herbal medicine, and the four-metabolite decision tree technique imparts a potent tool in clinical diagnosis.
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Affiliation(s)
- Ying Huang
- College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.,China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xu Zhao
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zi-Teng Zhang
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shuai-Shuai Chen
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Shan-Shan Li
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhuo Shi
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jing Jing
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ang Huang
- Center for Non-Infectious Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yu-Ming Guo
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhao-Fang Bai
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zheng-Sheng Zou
- Center for Non-Infectious Liver Disease, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Xiao-He Xiao
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jia-Bo Wang
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Ming Niu
- China Military Institute of Chinese Medicine, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.,Department of Poisoning Treatment, Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
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9
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Mücke VT, Thomas D, Mücke MM, Waidmann O, Zeuzem S, Sarrazin C, Pfeilschifter J, Vermehren J, Finkelmeier F, Grammatikos G. Serum sphingolipids predict de novo hepatocellular carcinoma in hepatitis C cirrhotic patients with sustained virologic response. Liver Int 2019; 39:2174-2183. [PMID: 31207039 DOI: 10.1111/liv.14178] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/28/2019] [Accepted: 06/08/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Curing hepatitis C virus (HCV) infection reduces the risk of hepatocellular carcinoma (HCC) development, yet HCC occurs despite sustained virologic response (SVR) in 2%-8% of cirrhotic patients. Sphingolipids (SLs) have been identified as new biomarkers of chronic liver disease and HCC. The aim of this study was to evaluate serum SLs as diagnostic HCC biomarkers in patients with HCV-associated cirrhosis at SVR12. METHODS From 2014 to 2016, 166 patients with HCV-cirrhosis and SVR were recruited and SL profiles were measured at baseline and 12 weeks after completion of direct-acting antiviral (DAA) therapy. All patients received HCC surveillance in line with current guideline recommendations. Minimum follow-up period comprised 6 months. RESULTS Our study included 130 (78%) patients without history of HCC, 25 (15%) with history of HCC prior DAA therapy and 11 (7%) patients with de novo HCC after FU12. In those with upcoming de novo HCC serum C24DHC (P = 0.006), C24:1DHC (P = 0.048) and C16Cer (P = 0.011) were significantly upregulated at FU12, but not AFP (P = 0.138). Contemporaneous ultrasound did not visualize HCC, at this time. C16Cer stayed sole independent predictor with high diagnostic accuracy of AFP-positive (AUC = 0.741) and -negative (AUC = 0.766) HCC development. Serum SL parameters decreased from baseline to SVR12. CONCLUSIONS C24DHC, C24:1DHC and especially C16Cer were superior to AFP in early detection of AFP-positive and -negative de novo HCC development. We observed significant SL profile changes upon SVR. SLs may play a role in non-invasive HCC surveillance and hepatocarcinogenesis.
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Affiliation(s)
| | - Dominique Thomas
- Pharmazentrum Frankfurt, Institut für Klinische Pharmakologie, Frankfurt am Main, Germany
| | - Marcus M Mücke
- Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | | | - Stefan Zeuzem
- Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Christoph Sarrazin
- Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St. Josefs-Hospital, Wiesbaden, Germany
| | - Josef Pfeilschifter
- Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie, Frankfurt am Main, Germany
| | | | | | - Georgios Grammatikos
- Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.,St. Luke's Hospital Thessaloniki, Panorama, Greece
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10
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Prokaryotic and Mitochondrial Lipids: A Survey of Evolutionary Origins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019. [PMID: 31502197 DOI: 10.1007/978-3-030-21162-2_2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/28/2024]
Abstract
Mitochondria and bacteria share a myriad of properties since it is believed that the powerhouses of the eukaryotic cell have evolved from a prokaryotic origin. Ribosomal RNA sequences, DNA architecture and metabolism are strikingly similar in these two entities. Proteins and nucleic acids have been a hallmark for comparison between mitochondria and prokaryotes. In this chapter, similarities (and differences) between mitochondrial and prokaryotic membranes are addressed with a focus on structure-function relationship of different lipid classes. In order to be suitable for the theme of the book, a special emphasis is reserved to the effects of bioactive sphingolipids, mainly ceramide, on mitochondrial membranes and their roles in initiating programmed cell death.
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11
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Naviaux RK, Naviaux JC, Li K, Wang L, Monk JM, Bright AT, Koslik HJ, Ritchie JB, Golomb BA. Metabolic features of Gulf War illness. PLoS One 2019; 14:e0219531. [PMID: 31348786 PMCID: PMC6660083 DOI: 10.1371/journal.pone.0219531] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 06/27/2019] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND More than 230,000 veterans-about 1/3 of US personnel deployed in the 1990-1991 Persian Gulf War-developed chronic, multi-symptom health problems now called "Gulf War illness" (GWI), for which mechanisms and objective diagnostic signatures continue to be sought. METHODS Targeted, broad-spectrum serum metabolomics was used to gain insights into the biology of GWI. 40 male participants, included 20 veterans who met both Kansas and CDC diagnostic criteria for GWI and 20 nonveteran controls without similar symptoms that were 1:1 matched to GWI cases by age, sex, and ethnicity. Serum samples were collected and archived at -80° C prior to testing. 358 metabolites from 46 biochemical pathways were measured by hydrophilic interaction liquid chromatography and tandem mass spectrometry. RESULTS Veterans with GWI, compared to healthy controls, had abnormalities in 8 of 46 biochemical pathways interrogated. Lipid abnormalities accounted for 78% of the metabolic impact. Fifteen ceramides and sphingomyelins, and four phosphatidylcholine lipids were increased. Five of the 8 pathways were shared with the previously reported metabolic phenotype of males with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, 4 of the 5 shared pathways were regulated in opposite directions; key pathways that were up-regulated in GWI were down-regulated in ME/CFS. The single pathway regulated in the same direction was purines, which were decreased. CONCLUSIONS Our data show that despite heterogeneous exposure histories, a metabolic phenotype of GWI was clearly distinguished from controls. Metabolomic differences between GWI and ME/CFS show that common clinical symptoms like fatigue can have different chemical mechanisms and different diagnostic implications. Larger studies will be needed to validate these findings.
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Affiliation(s)
- Robert K. Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Pediatrics, Division of Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Pathology, Division of Comparative Pathology, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Jane C. Naviaux
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Neurosciences, Division of Pediatric Neurology, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Kefeng Li
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Lin Wang
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Jonathan M. Monk
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - A. Taylor Bright
- The Mitochondrial and Metabolic Disease Center, University of California San Diego School of Medicine, San Diego, California, United States of America
- Department of Medicine, Division of Medical Genetics, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Hayley J. Koslik
- Department of Medicine, Division of General Internal Medicine, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Janis B. Ritchie
- Department of Medicine, Division of General Internal Medicine, University of California San Diego School of Medicine, San Diego, California, United States of America
| | - Beatrice A. Golomb
- Department of Medicine, Division of General Internal Medicine, University of California San Diego School of Medicine, San Diego, California, United States of America
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12
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Restoration of cytosolic calcium inhibits Mycobacterium tuberculosis intracellular growth: Theoretical evidence and experimental observation. J Theor Biol 2019; 472:110-123. [DOI: 10.1016/j.jtbi.2019.04.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 04/14/2019] [Accepted: 04/15/2019] [Indexed: 01/05/2023]
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13
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Verruck S, Balthazar CF, Rocha RS, Silva R, Esmerino EA, Pimentel TC, Freitas MQ, Silva MC, da Cruz AG, Prudencio ES. Dairy foods and positive impact on the consumer's health. ADVANCES IN FOOD AND NUTRITION RESEARCH 2019; 89:95-164. [PMID: 31351531 DOI: 10.1016/bs.afnr.2019.03.002] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The objective of the present chapter was to demonstrate the state of the art in the recent advances in nutritional and functional components of dairy products research. In this chapter, the main mechanisms responsible and essential for a better understanding of nutritional and functional values of the components of milk and dairy products are highlighted. It also includes a discussion about the positive impacts of fermented milk, cheese, butter, ice cream, and dairy desserts components on the consumer's health.
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Affiliation(s)
- Silvani Verruck
- Universidade Federal de Santa Catarina (UFSC), Departamento de Ciência e Tecnologia de Alimentos, Florianópolis, Brazil
| | | | - Ramon Silva Rocha
- Universidade Federal Fluminense (UFF), Faculdade de Veterinária, Niterói, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | - Ramon Silva
- Universidade Federal Fluminense (UFF), Faculdade de Veterinária, Niterói, Brazil; Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | | | | | | | - Marcia Cristina Silva
- Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil
| | - Adriano Gomes da Cruz
- Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro (IFRJ), Departamento de Alimentos, Rio de Janeiro, Brazil.
| | - Elane Schwinden Prudencio
- Universidade Federal de Santa Catarina (UFSC), Departamento de Ciência e Tecnologia de Alimentos, Florianópolis, Brazil
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14
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Boulet C, Doerig CD, Carvalho TG. Manipulating Eryptosis of Human Red Blood Cells: A Novel Antimalarial Strategy? Front Cell Infect Microbiol 2018; 8:419. [PMID: 30560094 PMCID: PMC6284368 DOI: 10.3389/fcimb.2018.00419] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Accepted: 11/14/2018] [Indexed: 12/13/2022] Open
Abstract
Malaria is a major global health burden, affecting over 200 million people worldwide. Resistance against all currently available antimalarial drugs is a growing threat, and represents a major and long-standing obstacle to malaria eradication. Like many intracellular pathogens, Plasmodium parasites manipulate host cell signaling pathways, in particular programmed cell death pathways. Interference with apoptotic pathways by malaria parasites is documented in the mosquito and human liver stages of infection, but little is known about this phenomenon in the erythrocytic stages. Although mature erythrocytes have lost all organelles, they display a form of programmed cell death termed eryptosis. Numerous features of eryptosis resemble those of nucleated cell apoptosis, including surface exposure of phosphatidylserine, cell shrinkage and membrane ruffling. Upon invasion, Plasmodium parasites induce significant stress to the host erythrocyte, while delaying the onset of eryptosis. Many eryptotic inducers appear to have a beneficial effect on the course of malaria infection in murine models, but major gaps remain in our understanding of the underlying molecular mechanisms. All currently available antimalarial drugs have parasite-encoded targets, which facilitates the emergence of resistance through selection of mutations that prevent drug-target binding. Identifying host cell factors that play a key role in parasite survival will provide new perspectives for host-directed anti-malarial chemotherapy. This review focuses on the interrelationship between Plasmodium falciparum and the eryptosis of its host erythrocyte. We summarize the current knowledge in this area, highlight the different schools of thoughts and existing gaps in knowledge, and discuss future perspectives for host-directed therapies in the context of antimalarial drug discovery.
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Affiliation(s)
- Coralie Boulet
- Molecular Parasitology Laboratory, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia
| | - Christian D Doerig
- Infection and Immunity Program, Biomedicine Discovery Institute, Department of Microbiology, Monash University, Clayton, VIC, Australia
| | - Teresa G Carvalho
- Molecular Parasitology Laboratory, Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, VIC, Australia
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15
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Lewis LS, Huffman KM, Smith IJ, Donahue MP, Slentz CA, Houmard JA, Hubal MJ, Hoffman EP, Hauser ER, Siegler IC, Kraus WE. Genetic Variation in Acid Ceramidase Predicts Non-completion of an Exercise Intervention. Front Physiol 2018; 9:781. [PMID: 30008672 PMCID: PMC6034073 DOI: 10.3389/fphys.2018.00781] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Accepted: 06/04/2018] [Indexed: 12/23/2022] Open
Abstract
Genetic variation is associated with a number of lifestyle behaviours; it may be associated with adherence and individual responses to exercise training. We tested single nucleotide polymorphisms (SNPs) in the acid ceramidase gene (ASAH1) for association with subject adherence and physiologic benefit with exercise training in two well-characterised randomised, controlled 8-month exercise interventions: STRRIDE I (n = 239) and STRRIDE II (n = 246). Three ASAH1 non-coding SNPs in a linkage disequilibrium block were associated with non-completion: rs2898458(G/T), rs7508(A/G), and rs3810(A/G) were associated with non-completion in both additive (OR = 1.8, 1.8, 2.0; P < 0.05 all) and dominant (OR = 2.5, 2.6, 3.5; P < 0.05 all) models; with less skeletal muscle ASAH expression (p < 0.01) in a subset (N = 60); and poorer training response in cardiorespiratory fitness (peak VO2 change rs3810 r2 = 0.29, P = 0.04; rs2898458 r2 = 0.29, P = 0.08; rs7508 r2 = 0.28, p = 0.09); and similar in direction and magnitude in both independent exploratory and replication studies. Adherence to exercise may be partly biologically and genetically moderated through metabolic regulatory pathways participating in skeletal muscle adaptation to exercise training.
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Affiliation(s)
- Lauren S Lewis
- Department of Obstetrics and Gynecology, Duke University School of Medicine, Durham, NC, United States
| | - Kim M Huffman
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.,Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Ira J Smith
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Mark P Donahue
- Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
| | - Cris A Slentz
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States
| | - Joseph A Houmard
- Human Performance Laboratory, East Carolina University, Greenville, NC, United States
| | - Monica J Hubal
- Children's Genetic Medical Research Center, Children's National Medical Center, Washington, DC, United States
| | - Eric P Hoffman
- Children's Genetic Medical Research Center, Children's National Medical Center, Washington, DC, United States
| | - Elizabeth R Hauser
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.,Cooperative Studies Program-Epidemiology Center Durham, Veterans Administration Medical Center, Durham, NC, United States
| | - Ilene C Siegler
- Division of Behavioral Medicine, Department of Psychiatry, Duke University School of Medicine, Durham, NC, United States
| | - William E Kraus
- Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, NC, United States.,Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, United States
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16
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α-Mangostin protects against high-glucose induced apoptosis of human umbilical vein endothelial cells. Biosci Rep 2017; 37:BSR20170779. [PMID: 29054969 PMCID: PMC5725610 DOI: 10.1042/bsr20170779] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2017] [Revised: 10/17/2017] [Accepted: 10/18/2017] [Indexed: 11/17/2022] Open
Abstract
Diabetic vascular complications result from high-glucose induced vascular endothelial cell dysfunction. There is an emerging need for novel drugs with vascular endothelial cell protective effects for the treatment of diabetic vascular complications. The present study aimed to investigate the protective effect of α-mangostin against high-glucose induced apoptosis of cultured human umbilical vein endothelial cells (HUVECs). HUVECs were treated with glucose to induce apoptosis. The expression of the apoptosis-related proteins, Bcl-2, Bax, and cleaved caspase-3, were detected by Western blotting. Ceramide concentration and acid sphingomyelinase (ASM) activity were assayed by HPLC. The cell apoptosis rate was detected by flow cytometry after staining with annexin V/propidium iodide (PI). Compared with HUVECs cultured in 5 mM glucose, cells cultured in 30 mM glucose exhibited a higher apoptosis rate, up-regulation of cleaved caspase-3 and Bax (proapoptotic proteins), down-regulation of Bcl-2 (anti-apoptotic protein), increased ceramide concentration, and enhanced ASM activity (all P<0.05). α-Mangostin (15 µM) significantly attenuated the high-glucose induced increase in apoptosis rate (8.64 ± 2.16 compared with 19.6 ± 3.54%), up-regulation of cleaved caspase-3 and Bax, down-regulation of Bcl-2, elevation of ceramide level, and enhancement of ASM activity (all P<0.05). The effects of desipramine were similar to those of α-mangostin. The protective effect of α-mangostin on high-glucose induced apoptotic damage may be mediated by an inhibition of ASM and thus a decreased level of ceramide.
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17
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Rodriguez-Cuenca S, Pellegrinelli V, Campbell M, Oresic M, Vidal-Puig A. Sphingolipids and glycerophospholipids - The "ying and yang" of lipotoxicity in metabolic diseases. Prog Lipid Res 2017; 66:14-29. [PMID: 28104532 DOI: 10.1016/j.plipres.2017.01.002] [Citation(s) in RCA: 108] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2016] [Revised: 11/30/2016] [Accepted: 01/05/2017] [Indexed: 12/14/2022]
Abstract
Sphingolipids in general and ceramides in particular, contribute to pathophysiological mechanisms by modifying signalling and metabolic pathways. Here, we present the available evidence for a bidirectional homeostatic crosstalk between sphingolipids and glycerophospholipids, whose dysregulation contributes to lipotoxicity induced metabolic stress. The initial evidence for this crosstalk originates from simulated models designed to investigate the biophysical properties of sphingolipids in plasma membrane representations. In this review, we reinterpret some of the original findings and conceptualise them as a sort of "ying/yang" interaction model of opposed/complementary forces, which is consistent with the current knowledge of lipid homeostasis and pathophysiology. We also propose that the dysregulation of the balance between sphingolipids and glycerophospholipids results in a lipotoxic insult relevant in the pathophysiology of common metabolic diseases, typically characterised by their increased ceramide/sphingosine pools.
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Affiliation(s)
- S Rodriguez-Cuenca
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK.
| | - V Pellegrinelli
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK
| | - M Campbell
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK
| | - M Oresic
- Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, FI -20520 Turku, Finland
| | - A Vidal-Puig
- Metabolic Research Laboratories, Wellcome Trust MRC Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge. Cambridge, UK; Wellcome Trust Sanger Institute, Hinxton, UK.
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18
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Du H, Zhao H, Lai X, Lin Q, Zhu Z, Chai Y, Lou Z. Metabolic profiles revealed synergistically antidepressant effects of lilies and Rhizoma Anemarrhenae in a rat model of depression. Biomed Chromatogr 2017; 31. [PMID: 28009452 DOI: 10.1002/bmc.3923] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/14/2016] [Accepted: 12/21/2016] [Indexed: 12/12/2022]
Affiliation(s)
- Hongli Du
- School of Pharmacy; Second Military Medical University; Shanghai China
- Department of Pharmacy; Eastern Hepatobiliary Surgery Hospital; Shanghai China
| | - Hongxia Zhao
- School of Pharmacy; Second Military Medical University; Shanghai China
| | - Xueli Lai
- Changhai Hospital; Second Military Medical University; Shanghai China
| | - Qishan Lin
- Proteomics/Mass Spec Facility, Center for Functional Genomics; State University of New York at Albany; New York USA
| | - Zhenyu Zhu
- School of Pharmacy; Second Military Medical University; Shanghai China
| | - Yifeng Chai
- School of Pharmacy; Second Military Medical University; Shanghai China
| | - Ziyang Lou
- School of Pharmacy; Second Military Medical University; Shanghai China
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19
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Kuzmenko DI, Klimentyeva TK. Role of Ceramide in Apoptosis and Development of Insulin Resistance. BIOCHEMISTRY (MOSCOW) 2017; 81:913-27. [PMID: 27682164 DOI: 10.1134/s0006297916090017] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
This review presents data on the functional biochemistry of ceramide, one of the key sphingolipids with properties of a secondary messenger. Molecular mechanisms of the involvement of ceramide in apoptosis in pancreatic β-cells and its role in the formation of insulin resistance in pathogenesis of type 2 diabetes are reviewed. One of the main predispositions for the development of insulin resistance and diabetes is obesity, which is associated with ectopic fat deposition and significant increase in intracellular concentrations of cytotoxic ceramides. A possible approach to the restoration of tissue sensitivity to insulin in type 2 diabetes based on selective reduction of the content of cytotoxic ceramides is discussed.
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Affiliation(s)
- D I Kuzmenko
- Siberian State Medical University, Ministry of Healthcare of the Russian Federation, Tomsk, 634050, Russia.
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20
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Abstract
The sphingolipid family of lipids modulate several cellular processes, including proliferation, cell cycle regulation, inflammatory signaling pathways, and cell death. Several members of the sphingolipid pathway have opposing functions and thus imbalances in sphingolipid metabolism result in deregulated cellular processes, which cause or contribute to diseases and disorders in humans. A key cellular process regulated by sphingolipids is apoptosis, or programmed cell death. Sphingolipids play an important role in both extrinsic and intrinsic apoptotic pathways depending on the stimuli, cell type and cellular response to the stress. During mitochondrial-mediated apoptosis, multiple pathways converge on mitochondria and induce mitochondrial outer membrane permeabilization (MOMP). MOMP results in the release of intermembrane space proteins such as cytochrome c and Apaf1 into the cytosol where they activate the caspases and DNases that execute cell death. The precise molecular components of the pore(s) responsible for MOMP are unknown, but sphingolipids are thought to play a role. Here, we review evidence for a role of sphingolipids in the induction of mitochondrial-mediated apoptosis with a focus on potential underlying molecular mechanisms by which altered sphingolipid metabolism indirectly or directly induce MOMP. Data available on these mechanisms is reviewed, and the focus and limitations of previous and current studies are discussed to present important unanswered questions and potential future directions.
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Affiliation(s)
- Gauri A Patwardhan
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA
| | - Levi J Beverly
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA.,Department of Medicine, University of Louisville, Louisville, KY, 40202, USA.,James Graham Brown Cancer Center, University of Louisville, 505 South Hancock Street, Clinical and Translational Research Building, Room 203, Louisville, KY, 40202, USA
| | - Leah J Siskind
- Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, 40202, USA. .,James Graham Brown Cancer Center, University of Louisville, 505 South Hancock Street, Clinical and Translational Research Building, Room 203, Louisville, KY, 40202, USA.
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21
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Li YL, Lin ML, He SQ, Jin JF. Sphingolipid metabolism affects the anticancer effect of cisplatin. World J Transl Med 2016; 5:37-45. [DOI: 10.5528/wjtm.v5.i1.37] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Revised: 12/09/2015] [Accepted: 01/11/2016] [Indexed: 02/06/2023] Open
Abstract
Cisplatin, a DNA crosslinking agent, is widely used for the treatment of a variety of solid tumors. Numerous studies have demonstrated that sphingolipid metabolism, which acts as a target for cisplatin treatment, is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes. Ceramide (Cer), which is the central molecule of this network, has been established to induce apoptosis. However, another molecule, sphingosine-1-phosphate (S1P), exerts the opposite function, i.e., serves as a regulator of pro-survival. Other sphingolipid molecules, including dihydroceramide, ceramide-1-phosphate, glucosylceramide (GluCer), and sphingosine (Sph), or sphingolipid catalytic enzymes such as Sph kinase (SphK), Cer synthase (CerS), and S1P lyase, have also attracted considerable attention, particularly Cer, GluCer, SphK, CerS, and S1P lyase, which have been implicated in cisplatin resistance. This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin, particularly in relation to induction of apoptosis and drug resistance.
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22
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Sundaram K, Mather AR, Marimuthu S, Shah PP, Snider AJ, Obeid LM, Hannun YA, Beverly LJ, Siskind LJ. Loss of neutral ceramidase protects cells from nutrient- and energy -deprivation-induced cell death. Biochem J 2016; 473:743-55. [PMID: 26747710 PMCID: PMC5513154 DOI: 10.1042/bj20150586] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2015] [Accepted: 01/08/2016] [Indexed: 02/07/2023]
Abstract
Sphingolipids are a family of lipids that regulate the cell cycle, differentiation and cell death. Sphingolipids are known to play a role in the induction of apoptosis, but a role for these lipids in necroptosis is largely unknown. Necroptosis is a programmed form of cell death that, unlike apoptosis, does not require ATP. Necroptosis can be induced under a variety of conditions, including nutrient deprivation and plays a major role in ischaemia/reperfusion injury to organs. Sphingolipids play a role in ischaemia/reperfusion injury in several organs. Thus, we hypothesized that sphingolipids mediate nutrient-deprivation-induced necroptosis. To address this, we utilized mouse embryonic fibroblast (MEFs) treated with 2-deoxyglucose (2DG) and antimycin A (AA) to inhibit glycolysis and mitochondrial electron transport. 2DG/AA treatment of MEFs induced necroptosis as it was receptor- interacting protein (RIP)-1/3 kinase-dependent and caspase-independent. Ceramides, sphingosine (Sph) and sphingosine 1-phosphate (S1P) were increased following 2DG/AA treatment. Cells lacking neutral ceramidase (nCDase(-/-)) were protected from 2DG/AA. Although nCDase(-/-) cells generated ceramides following 2DG/AA treatment, they did not generate Sph or S1P. This protection was stimulus-independent as nCDase(-/-) cells were also protected from endoplasmic reticulum (ER) stressors [tunicamycin (TN) or thapsigargin (TG)]. nCDase(-/-) MEFs had higher autophagic flux and mitophagy than wild-type (WT) MEFs and inhibition of autophagy sensitized them to necroptosis. These data indicate that loss of nCDase protects cells from nutrient- deprivation-induced necroptosis via autophagy, and clearance of damaged mitochondria. Results suggest that nCDase is a mediator of necroptosis and might be a novel therapeutic target for protection from ischaemic injury.
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Affiliation(s)
- Kumaran Sundaram
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, U.S.A
| | - Andrew R Mather
- University of South Carolina Medical School, Columbia, SC 29209, U.S.A
| | - Subathra Marimuthu
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, U.S.A
| | - Parag P Shah
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 40202, U.S.A
| | - Ashley J Snider
- Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 11794, U.S.A. ∥Northport Veterans Affairs Medical Center, Northport, NY 11768, U.S.A
| | - Lina M Obeid
- Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 11794, U.S.A. ∥Northport Veterans Affairs Medical Center, Northport, NY 11768, U.S.A
| | - Yusuf A Hannun
- Department of Medicine, Stony Brook Cancer Center, Stony Brook University, NY 11794, U.S.A
| | - Levi J Beverly
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 40202, U.S.A. Department of Medicine, University of Louisville, KY 40202, U.S.A
| | - Leah J Siskind
- Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, U.S.A. James Graham Brown Cancer Center, University of Louisville, KY 40202, U.S.A.
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23
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Abstract
Studies over the past two decades have identified ceramide as a multifunctional central molecule in the sphingolipid biosynthetic pathway. Given its diverse tumor suppressive activities, molecular understanding of ceramide action will produce fundamental insights into processes that limit tumorigenesis and may identify key molecular targets for therapeutic intervention. Ceramide can be activated by a diverse array of stresses such as heat shock, genotoxic damage, oxidative stress and anticancer drugs. Ceramide triggers a variety of tumor suppressive and anti-proliferative cellular programs such as apoptosis, autophagy, senescence, and necroptosis by activating or repressing key effector molecules. Defects in ceramide generation and metabolism in cancer contribute to tumor cell survival and resistance to chemotherapy. The potent and versatile anticancer activity profile of ceramide has motivated drug development efforts to (re-)activate ceramide in established tumors. This review focuses on our current understanding of the tumor suppressive functions of ceramide and highlights the potential downstream targets of ceramide which are involved in its tumor suppressive action.
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24
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Regulation of ceramide channel formation and disassembly: Insights on the initiation of apoptosis. Saudi J Biol Sci 2015; 22:760-72. [PMID: 26587005 PMCID: PMC4625378 DOI: 10.1016/j.sjbs.2015.03.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Revised: 03/12/2015] [Accepted: 03/15/2015] [Indexed: 01/04/2023] Open
Abstract
Sphingolipid research has surged in the past two decades and has produced a wide variety of evidence supporting the role of this class of molecules in mediating cellular growth, differentiation, senescence, and apoptosis. Ceramides are a subgroup of sphingolipids (SLs) that are directly involved in the process of initiation of apoptosis. We, and others, have recently shown that ceramides are capable of the formation of protein-permeable channels in mitochondrial outer membranes under physiological conditions. These pores are indeed good candidates for the pathway of release of pro-apoptotic proteins from the mitochondrial intermembrane space (IMS) into the cytosol to initiate intrinsic apoptosis. Here, we review recent findings on the regulation of ceramide channel formation and disassembly, highlighting possible implications on the initiation of the intrinsic apoptotic pathway.
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Key Words
- Apoptosis
- Assembly and disassembly
- Bcl-2 family proteins
- Bcl-2, B cell CLL/lymphoma-2
- Cer, ceramide
- CerS, ceramide synthase
- Ceramide channels
- Chain length
- DES, dihydroceramide desaturase
- DHCer, dihydroceramide
- ER, endoplasmic reticulum
- IMS, intermembrane space
- KSR, 3-ketosphinganine reductase
- MOMP, mitochondrial outer membrane permeability
- Mitochondria
- SLs, sphingolipids
- SM, sphingomyelin
- SPT, serine palmitoyl transferase
- So, sphingosine
- Sphingolipids
- de novo synthesis
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Jiménez-Rojo N, Sot J, Viguera AR, Collado MI, Torrecillas A, Gómez-Fernández JC, Goñi FM, Alonso A. Membrane permeabilization induced by sphingosine: effect of negatively charged lipids. Biophys J 2015; 106:2577-84. [PMID: 24940775 DOI: 10.1016/j.bpj.2014.04.038] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 04/14/2014] [Accepted: 04/23/2014] [Indexed: 10/25/2022] Open
Abstract
Sphingosine [(2S, 3R, 4E)-2-amino-4-octadecen-1, 3-diol] is the most common sphingoid long chain base in sphingolipids. It is the precursor of important cell signaling molecules, such as ceramides. In the last decade it has been shown to act itself as a potent metabolic signaling molecule, by activating a number of protein kinases. Moreover, sphingosine has been found to permeabilize phospholipid bilayers, giving rise to vesicle leakage. The present contribution intends to analyze the mechanism by which this bioactive lipid induces vesicle contents release, and the effect of negatively charged bilayers in the release process. Fluorescence lifetime measurements and confocal fluorescence microscopy have been applied to observe the mechanism of sphingosine efflux from large and giant unilamellar vesicles; a graded-release efflux has been detected. Additionally, stopped-flow measurements have shown that the rate of vesicle permeabilization increases with sphingosine concentration. Because at the physiological pH sphingosine has a net positive charge, its interaction with negatively charged phospholipids (e.g., bilayers containing phosphatidic acid together with sphingomyelins, phosphatidylethanolamine, and cholesterol) gives rise to a release of vesicular contents, faster than with electrically neutral bilayers. Furthermore, phosphorous 31-NMR and x-ray data show the capacity of sphingosine to facilitate the formation of nonbilayer (cubic phase) intermediates in negatively charged membranes. The data might explain the pathogenesis of Niemann-Pick type C1 disease.
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Affiliation(s)
- Noemi Jiménez-Rojo
- Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain
| | - Jesús Sot
- Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain
| | - Ana R Viguera
- Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain
| | - M Isabel Collado
- Servicio General de Resonancia Magnética Nuclear, Universidad del País Vasco, Bilbao, Spain
| | - Alejandro Torrecillas
- Sección de Biología Molecular, Servicio de Apoyo a la Investigación, Universidad de Murcia
| | - J C Gómez-Fernández
- Departamento de Bioquímica y Biología Molecular-A, Facultad de Veterinaria, Universidad de Murcia, Regional Campus of International Excellence "Campus Mare Nostrum", Murcia, Spain
| | - Félix M Goñi
- Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain
| | - Alicia Alonso
- Unidad de Biofísica (CSIC, UPV/EHU) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain.
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Wu S, Chen S, Dong X, Tan G, Li W, Lou Z, Zhu Z, Chai Y. Lipidomic profiling reveals significant alterations in lipid biochemistry in hypothyroid rat cerebellum and the therapeutic effects of Sini decoction. JOURNAL OF ETHNOPHARMACOLOGY 2015; 159:262-273. [PMID: 25435288 DOI: 10.1016/j.jep.2014.11.033] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/13/2014] [Revised: 11/10/2014] [Accepted: 11/20/2014] [Indexed: 06/04/2023]
Abstract
Hypothyroidism is known to be closely associated with lipid metabolism. Although our previous serum and urine metabonomics studies have provided some clues about the molecular mechanism of hypothyroidism at the metabolic level, the precise mechanism underlying the pathogenesis of hypothyroidism remains elusive, especially from the aspect of lipid metabolism. In the present study, we applied an ultra high performance liquid chromatography/time-of-flight mass spectrometry (UHPLC/TOF-MS)-based lipidomics method to analyze the global lipid profiles of hypothyroidism in rat cerebellum. Using unsupervised analysis and multivariate statistical analysis, we separated the Sham and hypothyroid groups clearly and screened out 23 potential lipid biomarkers related to hypothyroidism that were primarily involved in sphingolipid metabolism, glycerophospholipid metabolism and β-oxidation of fatty acid. Subsequently, we conducted computational analysis to build and simulate the lipid network of hypothyroidism, knowing that it would be useful to elucidate the pathological mechanism of hypothyroidism. Based on the selected 23 lipid biomarkers, we systematically evaluated the therapeutic effects of Sini decoction (SND) and the positive drug T4. The results showed that both SND and T4 can to some extent convert the pathological status of hypothyroidism through different pathways. Overall, this investigation illustrates that lipidomic profiling approach is powerful in giving a complementary view to the pathophysiology of hypothyroidism and offers a valuable tool for systematic study of the therapeutic effects of SND on hypothyroidism at lipid level.
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Affiliation(s)
- Si Wu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Si Chen
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Xin Dong
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Guangguo Tan
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China; School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China
| | - Wuhong Li
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Ziyang Lou
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China
| | - Zhenyu Zhu
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
| | - Yifeng Chai
- School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
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Stiban J, Perera M. Very long chain ceramides interfere with C16-ceramide-induced channel formation: A plausible mechanism for regulating the initiation of intrinsic apoptosis. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2014; 1848:561-7. [PMID: 25462172 DOI: 10.1016/j.bbamem.2014.11.018] [Citation(s) in RCA: 90] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Revised: 11/13/2014] [Accepted: 11/17/2014] [Indexed: 12/29/2022]
Abstract
Mitochondria mediate both cell survival and death. The intrinsic apoptotic pathway is initiated by the permeabilization of the mitochondrial outer membrane to pro-apoptotic inter-membrane space (IMS) proteins. Many pathways cause the egress of IMS proteins. Of particular interest is the ability of ceramide to self-assemble into dynamic water-filled channels. The formation of ceramide channels is regulated extensively by Bcl-2 family proteins and dihydroceramide. Here, we show that the chain length of biologically active ceramides serves as an important regulatory factor. Ceramides are synthesized by a family of six mammalian ceramide synthases (CerS) each of which produces a subset of ceramides that differ in their fatty acyl chain length. Various ceramides permeabilize mitochondria differentially. Interestingly, the presence of very long chain ceramides reduces the potency of C16-mediated mitochondrial permeabilization indicating that the intercalation of the lipids in the dynamic channel has a destabilizing effect, reminiscent of dihydroceramide inhibition of ceramide channel formation (Stiban et al., 2006). Moreover, mitochondria isolated from cells overexpressing the ceramide synthase responsible for the production of C16-ceramide (CerS5) are permeabilized faster upon the exogenous addition of C16-ceramide whereas they are resistant to permeabilization with added C24-ceramide. On the other hand mitochondria isolated from CerS2-overexpressing cells show the opposite pattern, indicating that the product of CerS2 inhibits C16-channel formation ex vivo and vice versa. This interplay between different ceramide metabolic enzymes and their products adds a new dimension to the complexity of mitochondrial-mediated apoptosis, and emphasizes its role as a key regulatory step that commits cells to life or death.
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Affiliation(s)
- Johnny Stiban
- Department of Biology and Biochemistry, Birzeit University, P.O. Box 14, West Bank 627, Palestine.
| | - Meenu Perera
- Department of Biology, University of Maryland, College Park, MD 20742, USA.
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Zhang H, Jin X, Huang L, Hong Y, Zhang Y, Ouyang Z, Li X, Song F, Li D. Molecular characterization of rice sphingosine-1-phosphate lyase gene OsSPL1 and functional analysis of its role in disease resistance response. PLANT CELL REPORTS 2014; 33:1745-56. [PMID: 25113543 DOI: 10.1007/s00299-014-1653-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 06/14/2014] [Accepted: 06/29/2014] [Indexed: 05/08/2023]
Abstract
Our results indicate that overexpression of OsSPL1 in transgenic tobacco plants attenuated disease resistance and facilitated programmed cell death. Long-chain base phosphates including sphingosine-1-phosphate have been shown to act as signaling mediators in regulating programmed cell death (PCD) and stress responses in mammals. In the present study, we characterized a rice gene OsSPL1, encoding a putative sphingosine-1-phosphate lyase that is involved in metabolism of sphingosine-1-phosphate. Expression of OsSPL1 was down-regulated in rice plants after treatments with salicylic acid, benzothiadiazole and 1-amino cyclopropane-1-carboxylic acid, but was induced by infection with a virulent strain of Magnaporthe oryzae, the causal agent of rice blast disease. Transgenic tobacco lines with overexpression of OsSPL1 were generated and analyzed for the possible role of OsSPL1 in disease resistance response and PCD. The OsSPL1-overexpressing tobacco plants displayed increased susceptibility to infection of Pseudomonas syringae pv. tabaci (Pst), the causal agent of wildfire disease, showing severity of disease symptom and bacterial titers in inoculated leaves, and attenuated pathogen-induced expression of PR genes after infection of Pst as compared to the wild-type and vector-transformed plants. Higher level of cell death, as revealed by dead cell staining, leakage of electrolyte and expression of hypersensitive response indicator genes, was observed in the OsSPL1-overexpressing plants after treatment with fumonisin B1, a fungal toxin that induces PCD in plants. Our results suggest that OsSPL1 has different functions in regulating disease resistance response and PCD in plants.
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Affiliation(s)
- Huijuan Zhang
- State Key Laboratory of Rice Biology, Institute of Biotechnology, College of Agriculture and Biotechnology, Zhejiang University, Hangzhou, Zhejiang, 310058, People's Republic of China
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29
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El-Dahshan A, Al-Gharabli SI, Radetzki S, Al-Tel TH, Kumar P, Rademann J. Flexible, polymer-supported synthesis of sphingosine derivatives provides ceramides with enhanced biological activity. Bioorg Med Chem 2014; 22:5506-12. [DOI: 10.1016/j.bmc.2014.07.024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2014] [Revised: 07/15/2014] [Accepted: 07/16/2014] [Indexed: 11/26/2022]
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Ferreira NS, Goldschmidt-Arzi M, Sabanay H, Storch J, Levade T, Ribeiro MG, Addadi L, Futerman AH. Accumulation of ordered ceramide-cholesterol domains in farber disease fibroblasts. JIMD Rep 2013; 12:71-7. [PMID: 23846911 PMCID: PMC3897794 DOI: 10.1007/8904_2013_246] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 05/19/2013] [Accepted: 05/30/2013] [Indexed: 12/24/2022] Open
Abstract
Farber disease is an inherited metabolic disorder caused by mutations in the acid ceramidase gene, which leads to ceramide accumulation in lysosomes. Farber disease patients display a wide variety of symptoms with most patients eventually displaying signs of nervous system dysfunction. We now present a novel tool that could potentially be used to distinguish between the milder and more severe forms of the disease, namely, an antibody that recognizes a mixed monolayer or bilayer of cholesterol:C16-ceramide, but does not recognize either ceramide or cholesterol by themselves. This antibody has previously been used to detect cholesterol:C16-ceramide domains in a variety of cultured cells. We demonstrate that levels of cholesterol:C16-ceramide domains are significantly elevated in fibroblasts from types 4 and 7 Farber disease patients, and that levels of the domains can be modulated by either reducing ceramide or cholesterol levels. Moreover, these domains are located in membranes of the endomembrane system, and also in two unexpected locations, namely, the mitochondria and the plasma membrane. This study suggests that the ceramide that accumulates in severe forms of Farber disease cells is sequestered to distinct membrane subdomains, which may explain some of the cellular pathology observed in this devastating lysosomal storage disease.
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Affiliation(s)
- Natalia Santos Ferreira
- />National Health Institute Doutor Ricardo Jorge, Genetic Department, Centre for Medical Genetics Jacinto de Magalhães, Porto, Portugal
- />Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Porto, Portugal
- />Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel
| | - Michal Goldschmidt-Arzi
- />Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel
- />Department of Structural Biology, Weizmann Institute of Science, Rehovot, 76100 Israel
| | - Helena Sabanay
- />Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, 76100 Israel
| | - Judith Storch
- />Department of Nutritional Sciences and Rutgers Center for Lipid Research, Rutgers University, Rutgers, NJ 08901 USA
| | - Thierry Levade
- />Equipe Labellisée Ligue Contre le Cancer 2013, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université de Toulouse, Toulouse, France
- />Laboratoire de Biochimie Métabolique, Institut Fédératif de Biologie, CHU Purpan, Toulouse, France
| | - Maria Gil Ribeiro
- />National Health Institute Doutor Ricardo Jorge, Genetic Department, Centre for Medical Genetics Jacinto de Magalhães, Porto, Portugal
- />Faculty of Health Sciences, Fernando Pessoa University, Porto, Portugal
| | - Lia Addadi
- />Department of Structural Biology, Weizmann Institute of Science, Rehovot, 76100 Israel
| | - Anthony H. Futerman
- />Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, 76100 Israel
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Role of ceramide in diabetes mellitus: evidence and mechanisms. Lipids Health Dis 2013; 12:98. [PMID: 23835113 PMCID: PMC3716967 DOI: 10.1186/1476-511x-12-98] [Citation(s) in RCA: 145] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2013] [Accepted: 06/28/2013] [Indexed: 02/06/2023] Open
Abstract
Diabetes mellitus is a metabolic disease with multiple complications that causes serious diseases over the years. The condition leads to severe economic consequences and is reaching pandemic level globally. Much research is being carried out to address this disease and its underlying molecular mechanism. This review focuses on the diverse role and mechanism of ceramide, a prime sphingolipid signaling molecule, in the pathogenesis of type 1 and type 2 diabetes and its complications. Studies using cultured cells, animal models, and human subjects demonstrate that ceramide is a key player in the induction of β-cell apoptosis, insulin resistance, and reduction of insulin gene expression. Ceramide induces β-cell apoptosis by multiple mechanisms namely; activation of extrinsic apoptotic pathway, increasing cytochrome c release, free radical generation, induction of endoplasmic reticulum stress and inhibition of Akt. Ceramide also modulates many of the insulin signaling intermediates such as insulin receptor substrate, Akt, Glut-4, and it causes insulin resistance. Ceramide reduces the synthesis of insulin hormone by attenuation of insulin gene expression. Better understanding of this area will increase our understanding of the contribution of ceramide to the pathogenesis of diabetes, and further help in identifying potential therapeutic targets for the management of diabetes mellitus and its complications.
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Parra V, Moraga F, Kuzmicic J, López-Crisosto C, Troncoso R, Torrealba N, Criollo A, Díaz-Elizondo J, Rothermel BA, Quest AFG, Lavandero S. Calcium and mitochondrial metabolism in ceramide-induced cardiomyocyte death. Biochim Biophys Acta Mol Basis Dis 2013; 1832:1334-44. [PMID: 23602992 DOI: 10.1016/j.bbadis.2013.04.009] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2012] [Revised: 04/04/2013] [Accepted: 04/08/2013] [Indexed: 10/27/2022]
Abstract
Ceramides are important intermediates in the biosynthesis and degradation of sphingolipids that regulate numerous cellular processes, including cell cycle progression, cell growth, differentiation and death. In cardiomyocytes, ceramides induce apoptosis by decreasing mitochondrial membrane potential and promoting cytochrome-c release. Ca(2+) overload is a common feature of all types of cell death. The aim of this study was to determine the effect of ceramides on cytoplasmic Ca(2+) levels, mitochondrial function and cardiomyocyte death. Our data show that C2-ceramide induces apoptosis and necrosis in cultured cardiomyocytes by a mechanism involving increased Ca(2+) influx, mitochondrial network fragmentation and loss of the mitochondrial Ca(2+) buffer capacity. These biochemical events increase cytosolic Ca(2+) levels and trigger cardiomyocyte death via the activation of calpains.
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Affiliation(s)
- Valentina Parra
- Centro de Estudios Moleculares de la Célula, Facultad de Ciencias Químicas y Farmacéuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile
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Funke C, Schneider SA, Berg D, Kell DB. Genetics and iron in the systems biology of Parkinson’s disease and some related disorders. Neurochem Int 2013; 62:637-52. [DOI: 10.1016/j.neuint.2012.11.015] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Revised: 11/19/2012] [Accepted: 11/28/2012] [Indexed: 12/21/2022]
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Abstract
Sphingolipid-metabolizing enzymes are becoming targets for chemotherapeutic development with an increasing interest in the recent years. In this chapter we introduce the sphingolipid family of lipids, and the role of individual species in cell homeostasis. We also discuss their roles in several rare diseases and overall, in cancer transformation. We follow the biosynthesis pathway of the sphingolipid tree, focusing on the enzymes in order to understand how using small molecule inhibitors makes it possible to modulate cancer progression. Finally, we describe the most used and historically significant inhibitors employed in cancer research, their relationships to sphingolipid metabolism, and some promising results found in this field.
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Affiliation(s)
- Daniel Canals
- Department of Medicine, University of Stony Brook, Stony Brook, New York 11794
| | - Yusuf A. Hannun
- Health Science Center, Stony Brook University, 100 Nicolls Road, L-4, 178, Stony Brook, NY 11794, USA
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Mencarelli C, Martinez–Martinez P. Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 2013; 70:181-203. [PMID: 22729185 PMCID: PMC3535405 DOI: 10.1007/s00018-012-1038-x] [Citation(s) in RCA: 190] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 05/16/2012] [Accepted: 05/21/2012] [Indexed: 12/14/2022]
Abstract
Ceramide, the precursor of all complex sphingolipids, is a potent signaling molecule that mediates key events of cellular pathophysiology. In the nervous system, the sphingolipid metabolism has an important impact. Neurons are polarized cells and their normal functions, such as neuronal connectivity and synaptic transmission, rely on selective trafficking of molecules across plasma membrane. Sphingolipids are abundant on neural cellular membranes and represent potent regulators of brain homeostasis. Ceramide intracellular levels are fine-tuned and alteration of the sphingolipid-ceramide profile contributes to the development of age-related, neurological and neuroinflammatory diseases. The purpose of this review is to guide the reader towards a better understanding of the sphingolipid-ceramide pathway system. First, ceramide biology is presented including structure, physical properties and metabolism. Second, we describe the function of ceramide as a lipid second messenger in cell physiology. Finally, we highlight the relevance of sphingolipids and ceramide in the progression of different neurodegenerative diseases.
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Affiliation(s)
- Chiara Mencarelli
- Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
| | - Pilar Martinez–Martinez
- Department of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, PO Box 616, 6200 MD Maastricht, The Netherlands
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Abstract
Chemotherapy is frequently used to treat primary or metastatic cancers, but intrinsic or acquired drug resistance limits its efficiency. Sphingolipids are important regulators of various cellular processes including proliferation, apoptosis, differentiation, angiogenesis, stress, and inflammatory responses which are linked to various aspects of cancer, like tumor growth, neoangiogenesis, and response to chemotherapy. Ceramide, the central molecule of sphingolipid metabolism, generally mediates antiproliferative and proapoptotic functions, whereas sphingosine-1-phosphate and other derivatives have opposing effects. Among the variety of enzymes that control ceramide generation, acid or neutral sphingomyelinases and ceramide synthases are important targets to allow killing of cancer cells by chemotherapeutic drugs. On the contrary, glucosylceramide synthase, ceramidase, and sphingosine kinase are other targets driving cancer cell resistance to chemotherapy. This chapter focuses on ceramide-based mechanisms leading to cancer therapy sensitization or resistance which could have some impacts on the development of novel cancer therapeutic strategies.
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Schneider SA, Dusek P, Hardy J, Westenberger A, Jankovic J, Bhatia KP. Genetics and Pathophysiology of Neurodegeneration with Brain Iron Accumulation (NBIA). Curr Neuropharmacol 2013; 11:59-79. [PMID: 23814539 PMCID: PMC3580793 DOI: 10.2174/157015913804999469] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2012] [Revised: 06/06/2012] [Accepted: 07/03/2012] [Indexed: 01/19/2023] Open
Abstract
Our understanding of the syndromes of Neurodegeneration with Brain Iron Accumulation (NBIA) continues to grow considerably. In addition to the core syndromes of pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), several other genetic causes have been identified (including FA2H, C19orf12, ATP13A2, CP and FTL). In parallel, the clinical and pathological spectrum has broadened and new age-dependent presentations are being described. There is also growing recognition of overlap between the different NBIA disorders and other diseases including spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis which makes a diagnosis solely based on clinical findings challenging. Autopsy examination of genetically-confirmed cases demonstrates Lewy bodies, neurofibrillary tangles, and other hallmarks of apparently distinct neurodegenerative disorders such as Parkinson's disease (PD) and Alzheimer's disease. Until we disentangle the various NBIA genes and their related pathways and move towards pathogenesis-targeted therapies, the treatment remains symptomatic. Our aim here is to provide an overview of historical developments of research into iron metabolism and its relevance in neurodegenerative disorders. We then focus on clinical features and investigational findings in NBIA and summarize therapeutic results reviewing reports of iron chelation therapy and deep brain stimulation. We also discuss genetic and molecular underpinnings of the NBIA syndromes.
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Affiliation(s)
- Susanne A Schneider
- Department of Neurology; University of Kiel, 24105 Kiel, Germany
- Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK
| | - Petr Dusek
- Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital, Prague, Czech Republic
| | - John Hardy
- Department of Molecular Neuroscience, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, England
| | - Ana Westenberger
- Schilling Section of Clinical and Molecular Neurogenetics at the Department of Neurology, University of Lübeck, Lübeck, Germany
| | - Joseph Jankovic
- Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
| | - Kailash P Bhatia
- Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, UCL, Queen Square, London WC1N 3BG, UK
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Watters RJ, Fox TE, Tan SF, Shanmugavelandy S, Choby JE, Broeg K, Liao J, Kester M, Cabot MC, Loughran TP, Liu X. Targeting glucosylceramide synthase synergizes with C6-ceramide nanoliposomes to induce apoptosis in natural killer cell leukemia. Leuk Lymphoma 2012. [PMID: 23181473 DOI: 10.3109/10428194.2012.752485] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Abstract Natural killer (NK) cell leukemia is characterized by clonal expansion of CD3 - NK cells and comprises both chronic and aggressive forms. Currently no effective treatment exists, thus providing a need for identification of novel therapeutics. Lipidomic studies revealed a dysregulated sphingolipid metabolism as evidenced by decreased levels of overall ceramide species and increased levels of cerebrosides in leukemic NK cells, concomitant with increased glucosylceramide synthase (GCS) expression. GCS, a key enzyme of this pathway, neutralizes pro-apoptotic ceramide by transfer of a uridine diphosphate (UDP)-glucose. Thus, we treated both rat and human leukemic NK cells in combination with: (1) exogenous C6-ceramide nanoliposomes in order to target mitochondria and increase physiological pro-apoptotic levels of long chain ceramide, and (2) 1-phenyl-2-palmitoylamino-3-morpholino-1-propanol (PPMP), an inhibitor of GCS. Co-administration of C6-ceramide nanoliposomes and PPMP elicited an increase in endogenous long-chain ceramide species, which led to cellular apoptosis in a synergistic manner via the mitochondrial intrinsic cell death pathway in leukemic NK cells.
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Affiliation(s)
- Rebecca J Watters
- Penn State Hershey Cancer Institute, Pennsylvania State College of Medicine, Hershey, PA 17033-0850, USA
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Zhang H, Li L, Yu Y, Mo J, Sun L, Liu B, Li D, Song F. Cloning and characterization of two rice long-chain base kinase genes and their function in disease resistance and cell death. Mol Biol Rep 2012; 40:117-27. [PMID: 23054004 DOI: 10.1007/s11033-012-2040-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2012] [Accepted: 10/02/2012] [Indexed: 10/27/2022]
Abstract
Sphingolipid metabolites such as long-chain base 1-phosphates (LCBPs) have been shown to play an important role in plants; however, little is known about their function in plant disease resistance and programmed cell death (PCD). In the present study, we cloned and identified two rice long-chain base kinase (LCBK) genes (OsLCBK1 and OsLCBK2), which are involved in biosynthesis of LCBPs, and performed functional analysis in transgenic tobacco. Expression of OsLCBK1 and OsLCBK2 was induced in rice seedlings after treatments with defense signaling molecules and after infection by Magnaporthe grisea, the causal agent of blast disease. Transgenic tobacco plants overexpressing OsLCBK1 were generated and disease resistance assays indicate that the OsLCBK1-overexpressing plants showed enhanced disease resistance against Pseudmonas syringae pv. tabacci, the causal agent of wildfire disease, and tobacco mosaic virus. Expression levels of some defense-related genes were constitutively up-regulated and further induced after pathogen infection in the OsLCBK1-overexpressing plants. Treatment with fungal toxin fumonisin B1, an effective inducer of PCD in plants, resulted in reduced level of cell death in the OsLCBK1-overexpressing plants, as indicated by cell death staining, leakage of electrolyte and expression of hypersensitive response indicator genes. These data suggest that rice LCBKs, probably through regulation of endogenous LCBP level, play important roles in disease resistance response and PCD in plants.
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Affiliation(s)
- Huijuan Zhang
- State Key Laboratory for Rice Biology, Institute of Biotechnology, Zhejiang University, Hangzhou 310058, Zhejiang, People's Republic of China
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Iron - too much of a good thing. Can J Neurol Sci 2012; 39:263-4. [PMID: 22547502 DOI: 10.1017/s0317167100013354] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
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Abstract
Sphingosine-1-phosphate (S1P) was first described as a signaling molecule over 20 years ago. Since then, great strides have been made to reveal its vital roles in vastly different cellular and disease processes. Initially, S1P was considered nothing more than the terminal point of sphingolipid metabolism; however, over the past two decades, a large number of reports have helped unveil its full potential as an important regulatory, bioactive sphingolipid metabolite. S1P has a plethora of physiological functions, due in part to its many sites of actions and its different pools, which are both intra- and extracellular. S1P plays pivotal roles in many physiological processes, including the regulation of cell growth, migration, autophagy, angiogenesis, and survival, and thus, not surprisingly, S1P has been linked to cancer. In this review, we will summarize the vast body of knowledge, highlighting the connection between S1P and cancer. We will also suggest new avenues for future research.
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Saito M, Chakraborty G, Shah R, Mao RF, Kumar A, Yang DS, Dobrenis K, Saito M. Elevation of GM2 ganglioside during ethanol-induced apoptotic neurodegeneration in the developing mouse brain. J Neurochem 2012; 121:649-61. [PMID: 22372857 DOI: 10.1111/j.1471-4159.2012.07710.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
GM2 ganglioside in the brain increased during ethanol-induced acute apoptotic neurodegeneration in 7-day-old mice. A small but a significant increase observed 2 h after ethanol exposure was followed by a marked increase around 24 h. Subcellular fractionation of the brain 24 h after ethanol treatment indicated that GM2 increased in synaptic and non-synaptic mitochondrial fractions as well as in a lysosome-enriched fraction characteristic to the ethanol-exposed brain. Immunohistochemical staining of GM2 in the ethanol-treated brain showed strong punctate staining mainly in activated microglia, in which it partially overlapped with staining for LAMP1, a late endosomal/lysosomal marker. Also, there was weaker neuronal staining, which partially co-localized with complex IV, a mitochondrial marker, and was augmented in cleaved caspase 3-positive neurons. In contrast, the control brain showed only faint and diffuse GM2 staining in neurons. Incubation of isolated brain mitochondria with GM2 in vitro induced cytochrome c release in a manner similar to that of GD3 ganglioside. Because ethanol is known to trigger mitochondria-mediated apoptosis with cytochrome c release and caspase 3 activation in the 7-day-old mouse brain, the GM2 elevation in mitochondria may be relevant to neuroapoptosis. Subsequently, activated microglia accumulated GM2, indicating a close relationship between GM2 and ethanol-induced neurodegeneration.
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Affiliation(s)
- Mitsuo Saito
- Division of Analytical Psychopharmacology, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, USA
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Ferreira LF, Moylan JS, Stasko S, Smith JD, Campbell KS, Reid MB. Sphingomyelinase depresses force and calcium sensitivity of the contractile apparatus in mouse diaphragm muscle fibers. J Appl Physiol (1985) 2012; 112:1538-45. [PMID: 22362402 DOI: 10.1152/japplphysiol.01269.2011] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Diseases that result in muscle weakness, e.g., heart failure, are characterized by elevated sphingomyelinase (SMase) activity. In intact muscle, SMase increases oxidants that contribute to diminished muscle force. However, the source of oxidants, specific processes of muscle contraction that are dysfunctional, and biochemical changes underlying the weakness elicited by SMase remain unknown. We tested three hypotheses: 1) SMase-induced depression of muscle force is mediated by mitochondrial reactive oxygen species (ROS), 2) SMase depresses force and calcium sensitivity of the contractile apparatus, and 3) SMase promotes oxidation and phosphorylation of myofibrillar proteins. Our experiments included intact muscle bundles, permeabilized single fibers, and isolated myofibrillar proteins. The mitochondrial-targeted antioxidant d-Arg-2',6'-dimethyl-Tyr-Lys-Phe-NH(2), decreased cytosolic oxidants and protected intact muscle bundles from weakness stimulated by SMase. SMase depressed maximal calcium-activated force by 20% in permeabilized single fibers (in kN/m(2): control 117 ± 6; SMase 93 ± 8; P < 0.05). Calcium sensitivity of permeabilized single fibers decreased from 5.98 ± 0.03 (control) to 5.91 ± 0.02 (SMase; P < 0.05). Myofibrillar protein nitrotyrosines, carbonyls, and phosphorylation were unaltered by SMase. Our study shows that the fall in specific force of intact muscle elicited by SMase is mediated by mitochondrial ROS and can be attributed largely to dysfunction of the contractile apparatus.
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Affiliation(s)
- Leonardo F Ferreira
- Department of Physiology and Center for Muscle Biology, University of Kentucky, Lexington, Kentucky 40536-0298, USA
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Watters RJ, Kester M, Tran MA, Loughran TP, Liu X. Development and use of ceramide nanoliposomes in cancer. Methods Enzymol 2012; 508:89-108. [PMID: 22449922 DOI: 10.1016/b978-0-12-391860-4.00005-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Integration of C₆-ceramide into stealth pegylated nanoliposomes has led to the development of a promising preclinical therapeutic alone and in combination with other agents for treatment of cancer. Ceramide itself has been implicated as a bioactive lipid second messenger mediating cell senescence, cell cycle arrest, and apoptosis. Recent lipidomic analyses have demonstrated that specific ceramide species are differentially metabolized in individual cancers. Therapeutics that increase ceramide levels in cancer tissues have shown increased cell death and tumor inhibition. However, the use of ceramide itself as therapeutic has been problematic due to its inherent hydrophobicity and insolubility, therefore limiting the application for intravenous administration. Pegylated nanoliposomes eliminate this issue and are able to enhance the intracellular delivery of ceramide to cancer cells.
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Affiliation(s)
- Rebecca J Watters
- Penn State Hershey Cancer Institute, Pennsylvania State College of Medicine, Hershey, Pennsylvania, USA
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Schneider SA, Hardy J, Bhatia KP. Syndromes of neurodegeneration with brain iron accumulation (NBIA): An update on clinical presentations, histological and genetic underpinnings, and treatment considerations. Mov Disord 2011; 27:42-53. [DOI: 10.1002/mds.23971] [Citation(s) in RCA: 133] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2011] [Revised: 08/09/2011] [Accepted: 08/15/2011] [Indexed: 11/07/2022] Open
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Novgorodov SA, Wu BX, Gudz TI, Bielawski J, Ovchinnikova TV, Hannun YA, Obeid LM. Novel pathway of ceramide production in mitochondria: thioesterase and neutral ceramidase produce ceramide from sphingosine and acyl-CoA. J Biol Chem 2011; 286:25352-62. [PMID: 21613224 DOI: 10.1074/jbc.m110.214866] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Reports suggest that excessive ceramide accumulation in mitochondria is required to initiate the intrinsic apoptotic pathway and subsequent cell death, but how ceramide accumulates is unclear. Here we report that liver mitochondria exhibit ceramide formation from sphingosine and palmitoyl-CoA and from sphingosine and palmitate. Importantly, this activity was markedly decreased in liver from neutral ceramidase (NCDase)-deficient mice. Moreover, the levels of ceramide were dissimilar in liver mitochondria of WT and NCDase KO mice. These results suggest that NCDase is a key participant of ceramide formation in liver mitochondria. We also report that highly purified liver mitochondria have ceramidase, reverse ceramidase, and thioesterase activities. Increased accessibility of palmitoyl-CoA to the mitochondrial matrix with the pore-forming peptide zervamicin IIB resulted in 2-fold increases in palmitoyl-CoA hydrolysis by thioesterase. This increased hydrolysis was accompanied by an increase in ceramide formation, demonstrating that both outer membrane and matrix localized thioesterases can regulate ceramide formation. Also, ceramide formation might occur both in the outer mitochondrial membrane and in the mitochondrial matrix, suggesting the existence of distinct ceramide pools. Taken together, these results suggest that the reverse activity of NCDase contributes to sphingolipid homeostasis in this organelle in vivo.
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Affiliation(s)
- Sergei A Novgorodov
- Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina 29401, USA
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Jeong JC, Shin WY, Kim TH, Kwon CH, Kim JH, Kim YK, Kim KH. Silibinin induces apoptosis via calpain-dependent AIF nuclear translocation in U87MG human glioma cell death. J Exp Clin Cancer Res 2011; 30:44. [PMID: 21501525 PMCID: PMC3108340 DOI: 10.1186/1756-9966-30-44] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Accepted: 04/19/2011] [Indexed: 11/25/2022] Open
Abstract
Background Silibinin, a natural polyphenolic flavonoid, has been reported to induce cell death in various cancer cell types. However, the molecular mechanism is not clearly defined. Our previous study showed that silibinin induces glioma cell death and its effect was effectively prevented by calpain inhibitor. The present study was therefore undertaken to examine the role of calpain in the silibinin-induced glioma cell death. Methods U87MG cells were grown on well tissue culture plates and cell viability was measured by MTT assay. ROS generation and △ψm were estimated using the fluorescence dyes. PKC activation and Bax expression were measured by Western blot analysis. AIF nuclear translocation was determined by Western blot and immunocytochemistry. Results Silibinin induced activation of calpain, which was blocked by EGTA and the calpain inhibitor Z-Leu-Leu-CHO. Silibinin caused ROS generation and its effect was inhibited by calpain inhibitor, the general PKC inhibitor GF 109203X, the specific PKCδ inhibitor rottlerin, and catalase. Silibinin-induce cell death was blocked by calpain inhibitor and PKC inhibitors. Silibinin-induced PKCδ activation and disruption of △ψm were prevented by the calpain inhibitor. Silibinin induced AIF nuclear translocation and its effect was prevented by calpain inhibitor. Transfection of vector expressing microRNA of AIF prevented the silibinin-induced cell death. Conclusions Silibinin induces apoptotic cell death through a calpain-dependent mechanism involving PKC, ROS, and AIF nuclear translocation in U87MG human glioma cells.
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Affiliation(s)
- Ji C Jeong
- Department of Oriental Medicine, Dongguk University, Kyung Ju, 780-714, Korea
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Adipose tissue and ceramide biosynthesis in the pathogenesis of obesity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 721:67-86. [PMID: 21910083 DOI: 10.1007/978-1-4614-0650-1_5] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Although obesity is a complex metabolic disorder often associated with insulin resistance, hyperinsulinemia and Type 2 diabetes, as well as with accelerated atherosclerosis, the molecular changes in obesity that promote these disorders are not completely understood. Several mechanisms have been proposed to explain how increased adipose tissue mass affects whole body insulin resistance and cardiovascular risk. One theory is that increased adipose derived inflammatory cytokines induces a chronic inflammatory state that not only increases cardiovascular risk, but also antagonizes insulin signaling and mitochondrial function and thereby impair glucose hemostasis. Another suggests that lipid accumulation in nonadipose tissues not suited for fat storage leads to the buildup of bioactive lipids that inhibit insulin signaling and metabolism. Recent evidence demonstrates that sphingolipid metabolism is dysregulated in obesity and specific sphingolipids may provide a common pathway that link excess nutrients and inflammation to increased metabolic and cardiovascular risk. This chapter will focus primarily on the expression and regulation of adipose and plasma ceramide biosynthesis in obesity and, its potential contribution to the pathogenesis of obesity and the metabolic syndrome.
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Monette JS, Gómez LA, Moreau RF, Dunn KC, Butler JA, Finlay LA, Michels AJ, Shay KP, Smith EJ, Hagen TM. (R)-α-Lipoic acid treatment restores ceramide balance in aging rat cardiac mitochondria. Pharmacol Res 2011; 63:23-9. [PMID: 20934512 PMCID: PMC3268156 DOI: 10.1016/j.phrs.2010.09.007] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2010] [Revised: 09/29/2010] [Accepted: 09/29/2010] [Indexed: 01/11/2023]
Abstract
Inflammation results in heightened mitochondrial ceramide levels, which cause electron transport chain dysfunction, elevates reactive oxygen species, and increases apoptosis. As mitochondria in aged hearts also display many of these characteristics, we hypothesized that mitochondrial decay stems partly from an age-related ceramidosis that heretofore has not been recognized for the heart. Intact mitochondria or their purified inner membranes (IMM) were isolated from young (4-6 mo) and old (26-28 mo) rats and analyzed for ceramides by LC-MS/MS. Results showed that ceramide levels increased by 32% with age and three ceramide isoforms, found primarily in the IMM (e.g. C(16)-, C(18)-, and C(24:1)-ceramide), caused this increase. The ceramidosis may stem from enhanced hydrolysis of sphingomyelin, as neutral sphingomyelinase (nSMase) activity doubled with age but with no attendant change in ceramidase activity. Because (R)-α-lipoic acid (LA) improves many parameters of cardiac mitochondrial decay in aging and lowers ceramide levels in vascular endothelial cells, we hypothesized that LA may limit cardiac ceramidosis and thereby improve mitochondrial function. Feeding LA [0.2%, w/w] to old rats for two weeks prior to mitochondrial isolation reversed the age-associated decline in glutathione levels and concomitantly improved Complex IV activity. This improvement was associated with lower nSMase activity and a remediation in mitochondrial ceramide levels. In summary, LA treatment lowers ceramide levels to that seen in young rat heart mitochondria and restores Complex IV activity which otherwise declines with age.
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Affiliation(s)
- Jeffrey S. Monette
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
| | - Luis A. Gómez
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
| | - Régis F. Moreau
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
| | - Kevin C. Dunn
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
| | - Judy A. Butler
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
| | - Liam A. Finlay
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
| | | | - Kate Petersen Shay
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
| | - Eric J. Smith
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
| | - Tory M. Hagen
- Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA
- Department of Biochemistry and Biophysics, Oregon State University, Corvallis, OR 97331, USA
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Kalo D, Roth Z. Involvement of the sphingolipid ceramide in heat-shock-induced apoptosis of bovine oocytes. Reprod Fertil Dev 2011; 23:876-88. [DOI: 10.1071/rd10330] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2010] [Accepted: 03/30/2011] [Indexed: 01/29/2023] Open
Abstract
Programmed cell death via the sphingomyelin pathway has been suggested to underlie heat-shock disturbance of oocyte developmental competence. A series of experiments were performed to characterise the role of the sphingolipid ceramide in heat-shock-induced apoptosis, and to determine whether ceramide formation can be regulated. Bovine cumulus–oocyte complexes (COCs) were aspirated from ovaries collected in the cold season (November–April), in vitro-matured, fertilised and cultured for 8 days. Exposure of COCs to heat shock (41°C) during maturation reduced cleavage rate and blastocyst formation relative to the control group (38.5°C). Annexin-V binding (V-FITC assay), which is associated with the early apoptotic event of membrane phosphatidylserine turnover, was higher in oocytes exposed to short-term versus long-term heat shock, suggesting that heat-shock-induced apoptosis involves membrane alterations. Similar to heat exposure, oocyte maturation with C2-ceramide had a dose-dependent deleterious effect on the first cleavages and subsequent embryonic development in association with increased annexin-V binding. Blocking endogenous ceramide generation with fumonisin B1, a specific inhibitor of dihydroceramide synthase (i.e. de novo formation), moderated, to some extent, the effects of heat shock on oocyte developmental competence, suggesting that ceramide plays an important role in heat-shock-induced apoptosis.
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