Radiation Protection: Sphingolipids.

Dmitri Popov, PhD Radiobiology , MD (Russia).

Advanced Medical Technology and Systems Inc. (Canada)

Radiation Protection.Sphingolipids. – Key words: Sphingolipids, radiation.

– Research Proposal: Radiation Protection: Sphingolipids.

– Dmitri Popov

– Full-text Research Proposal · Feb 2015

– Add resources

– File name: RadiationProtectionSphingolipids.pptxDOI: 10.13140/RG.2.1.4824.4726

Sphingolipids.

– The cell membrane (also known as the plasma membrane or cytoplasmic membrane) is a biological membrane that separates the interior of all cells from the outside environment.

– The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells.

– Jesse Gray; Shana Groeschler; Tony Le; Zara Gonzalez (2002). "Membrane Structure" (SWF). Davidson College. Retrieved 2007-01-11.

– Kimball's Biology pages, Cell Membranes.

Plasma membrane. http://biology.tutorvista.com/animal-and-plant-cells/plasma-membrane.html

Sphingolipid Synthesis.http://physiologyonline.physiology.org/content/15/1/11

Sphingolipids.

– Sphingolipids, or glycosylceramides, are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. These compounds play important roles in signal transmission and cell recognition. Sphingolipidoses, or disorders of sphingolipid metabolism, have particular impact on neural tissue. A sphingolipid with an R group consisting of a hydrogen atom only is a ceramide. Other common R groups include phosphocholine, yielding a sphingomyelin, and various sugar monomers or dimers, yielding cerebrosides and globosides, respectively. Cerebrosides and globosides are collectively known as glycosphingolipids.

Sphingolipids

– Sphingolipids are commonly believed to protect the cell surface against harmful environmental factors by forming a mechanically stable and chemically resistant outer leaflet of the plasma membrane lipid bilayer.

– Certain complex glycosphingolipids were found to be involved in specific functions, such as cell recognition and signaling.

– Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or with proteins.

Sphingolipids.

– Cell recognition depends mainly on the physical properties of the sphingolipids, whereas signaling involves specific interactions of the glycan structures of glycosphingolipids with similar lipids present on neighboring cells or with proteins.

Sphingolipids.

– Recently, simple sphingolipid metabolites, such as ceramide and sphingosine-1-phosphate, have been shown to be important mediators in the signaling cascades involved in apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation.

Sphingolipids.

– Ceramide-based lipids self-aggregate in cell membranes and form separate phases less fluid than the bulk phospholipids. These sphingolipid-based micro-domains, or "lipid rafts" were originally proposed to sort membrane proteins along the cellular pathways of membrane transport.

– At present, most research focuses on the organizing function during signal transduction

Sphingolipids.

– Sphingolipids are synthesized in a pathway that begins in the ER and is completed in the Golgi apparatus, but these lipids are enriched in the plasma membrane and in endosomes, where they perform many of their functions. Transport occurs via vesicles and monomeric transport in the cytosol. Sphingolipids are virtually absent from mitochondria and the ER, but constitute a 20-35 molar fraction of plasma membrane lipids.

Sphingolipids and Radiation.

– The effect of gamma-radiation on aqueous solutions of saturated phospholipids, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), 1-palmitoyl-2-lyso-sn-glycero-3-phosphocholine (lysoPC), and bovine brain sphingomyelin (SM) has been investigated. It is shown that the phospholipids with an OH group in beta-position to the P-O bond (DPPG and lysoPC), or to the amide bond (SM), undergo a free radical fragmentation.

– The damage to phospholipids caused by free radical attack on glycerol and sphingosine backbone.

– Edimecheva IP1, Kisel MA, Shadyro OI, Vlasov AP, Yurkova IL.

– Int J Radiat Biol. 1997 May;71(5):555-60.

Sphingolipids and Radiation.

– Sphingoglycolipids are a family of complex lipids with structures representing

– a large variety of carbohydrate compositions: which are characteristics

– for a mammalian organ and can vary depending on the species of origin.

– The glycolipids located on the surface of the cells may play a important

– functional characteristics of mammalian cells.

The study of sphingoglycolipid composition in various, radiosensitive and

– non-rádiosensitive tissues, might indicate whether damages induced by the

– Ionizing radiation on the plasma membrane matrix are involved in the

– cell death.

Sphingolipids and Radiation.

– “Title of Project : slide 12, slide 14.

– The effect of gamma irradiation on the lipid

– metabolism of radiosensitive tissues.

– Institute • Biochemical Research Laboratory, Department

– of Clinical Therapeutics, School of Medicine,

– Univ. of Athens at the "Alexandra" Hospital,

– Vas. Sophias and K. Lourou Str., Athens, Greece.

– Chief Scientific Investigator: Prof. C. J. Miras”

Sphingolipids and Radiation.

– The results are

– clearly demonstrate that sphingoglycolipids from plasma membranes

– of both thymus and liver are found decreased twelve hours following

– irradiation» . However, the ratio of glucose to galactose which represent

– the glycolipid composition (the higher the ratio the lower content in

– glycolipid with large carbohydrate chain) it does change to a higher

– extent in thymus than in liver. This may indicate that irradiation results

– to an activation of enzymes specific for the catabolism of large glycolipids

– like the aminoglycolipids.

Sphingolipids and Radiation.

– “Effects of 60Co-gamma-ray on liposomal membranes were studied in terms of the correlation between lipid peroxidation and glucose efflux. Malondialdehyde (MDA) formation in glucose-retaining liposomes after gamma-irradiation was highly correlated with the increase in glucose efflux. The MDA formation, however, occurred only during irradiation in contrast to the glucose efflux which continued after irradiation. Both processes showed a dose threshold and a dependence on dose rate. A one-to-one relationship between glucose efflux and MDA formation was observed with radical scavengers. These results are discussed as a series of processes in membrane damage by ionizing radiation.”

Sphingolipids and Apoptosis. Exp Oncol. 2012 Oct;34(3):231-42.Sphingolipids in apoptosis.Tirodkar TS, Voelkel-Johnson C.

– “ The term "apoptosis" was introduced to describe a form of programmed cell death. Key players that mediate apoptosis at the molecular level such as caspases, death receptors, Bcl-2 family members have since been identified and their regulation remains a research focus of many laboratories. In 1993, approximately 20 years after the introduction of apoptosis, the sphingolipid ceramide was first linked to this form of cell death. Sphingolipids are bioactive components of cellular membranes that are involved in numerous physiological functions.

– The inherent complexities of sphingolipid signaling and elaborate on how sphingolipids, primarily ceramide, influence apoptotic events such as death receptor aggregation in the plasma membrane and pore formation at the mitochondria. Possible roles of sphingolipids in other subcellular compartments, such as the nucleus, endoplasmic reticulum and lysosomes are also discussed. Conclude by summarizing the recent developments in sphingolipid based cancer therapy.

Sphingolipids and Apoptosis.

– Ceramide as a mediator of apoptosis.

– “Ceramide is the central molecule in sphingolipid metabolic pathways, and its generation and metabolism are key in understanding advantageous and dysregulated sphingolipid responses to cancer therapy. While many diverse functions have been ascribed to ceramide, for the purposes of this review, ceramide is best characterized to promote apoptosis and cell senescence.”

– Interdiction of Sphingolipid Metabolism to Improve Standard Cancer Therapies

– Published in final edited form as: Adv Cancer Res. 2013 ; 117: 1–36. doi:10.1016/B978-0-12-394274-6.00001-7. Thomas H. Beckham et al.

Sphingolipids and Apoptosis.

– Mammalian cells respond to diverse stressors including radiation, nutrient deprivation, and oxidative stress with ceramide generation, largely through hydrolysis of sphingomyelin and de novo synthesis (Hannun, 1996; Ogretmen & Hannun, 2001).

– Ionizing Radiation Acts on Cellular Membranes to Generate Ceramide and Initiate Apoptosis By Adriana Haimovitz-Friedman, Chu-Cheng Kan,* Desiree Ehleiter, Roger S. Persaud, Maureen McLoughlin, Zvi Fuks, and Richard N. Kolesnick.

– From the Department of Radiation Oncology and the "Laboratory of Signal Transduction, Memorial Sloan-Kettering Cancer Center, New York 10021

– Slide 20.

Sphingolipids, Radiation, Apoptosis.– Recent investigations provided evidence that the sphingomyelin signal transduction pathway mediates

apoptosis for tumor necrosis factor c~ (TNF-o 0 in several hematopoietic and nonhematopoietic ceils. In this pathway, TNF-receptor interaction initiates sphingomyelin hydrolysis to ceramide by a sphingomyelinase. Ceramide acts as a second messenger stimulating a ceramide-activated serine/threonine protein kinase. The present studies show that ionizing radiation, like TNF, induces rapid sphingomyelin hydrolysis to ceramide and apoptosis in bovine aortic endothelial cells. Elevation of ceramide with exogenous ceramide analogues was su~cient for induction of apoptosis. Protein kinase C activation blocked both radiation-induced sphingomyelin hydrolysis and apoptosis, and apoptosis was restored by ceramide analogues added exogenously. Ionizing radiation acted directly on membrane preparations devoid of nuclei, stimulating sphingomyelin hydrolysis enzymatically through a neutral sphingomyelinase. These studies provide the first conclusive evidence that apoptotic signaling can be generated by interaction of ionizing radiation with cellular membranes and suggest an alternative to the hypothesis that direct DNA damage mediates radiation-induced cell kill.

Sphingomyelinase.

– Sphingomyelinase.

– Sphingomyelin phosphodiesterase (also known as neutral sphingomyelinase, sphingomyelinase, or SMase) is a hydrolase enzyme that is involved in sphingolipid metabolism reactions. SMase is a member of the DNase I superfamily of enzymes and is responsible for breaking sphingomyelin (SM) down into phosphocholine and ceramide.

– The activation of SMase has been suggested as a major route for the production of ceramide in response to cellular stresses

Radiation Protection. Sphingomyelinase Inhibition.– Functional inhibitors of acid sphingomyelinase, or FIASMA,[1] is a term which

characterizes a large group of pharmacological compounds inhibiting the enzyme acid sphingomyelinase (ASM, EC 3.1.4.12). This enzyme is mainly located within the lysosome, where it cleaves sphingomyelin to ceramide and sphingosine, the latter of which is then phosphorylated to sphingosine-1-phosphate. These metabolites, and subsequent inhibition of the enzyme, influence the balance between cell death (apoptosis) and cell growth (proliferation).

– Under way.

Literature

– Bartke, N; Hannun, Y. (2009). "Bioactive sphingolipids: metabolism and function". J Lipid Res. 50: S91–6. doi:10.1194/jlr.R800080-JLR200

– Reviewed in Hannun and Obeid. "Principles of bioactive lipid signalling: lessons from sphingolipids". Nature Reviews Molecular Cell Biology. (2008) 9, 139-150.

– Bandhuvulua & Saba. "Sphingosine-1-phosphate lyase in immunity and cancer: silencing the siren". Trends in Molecular Medicine. (2007) 13:210-217.

– Hannun YA, Obeid LM (July 2002). "The Ceramide-centric universe of lipid-mediated cell regulation: stress encounters of the lipid kind". J. Biol. Chem. 277 (29): 25847–50.doi:10.1074/jbc.R200008200. PMID 12011103.

– Jump up^ Spiegel S, Milstien S (July 2002). "Sphingosine 1

Literature.

– Spiegel S, Milstien S (July 2002). "Sphingosine 1-phosphate, a key cell signaling molecule". J. Biol. Chem. 277 (29): 258514. doi:10.1074/jbc.R200007200.PMID 12011102

– Lavieu, G; Scarlatti, F; Sala, G; Carpentier, S; Levade, T; Ghidoni, R; Botti, J; Codogno, P (2006). "Regulation of autophagy by sphingosine kinase 1 and its role in cell survival during nutrient starvation". J Biol Chem. 281 (13): 8518–27. doi:10.1074/jbc.M506182200.

– Venable, M. E.; Lee, J. Y.; Smyth, M. J.; Bielawska, A.; Obeid, L. M. (1995). "Role of ceramide in cellular senescence". J. Biol. Chem. 270: 30701–30708.doi:10.1074/jbc.270.51.30701. PMID 8530509

Literature

– Hetz, C. A.; Hunn, M.; Rojas, P.; Torres, V.; Leyton, L.; Quest, A. F. (2002). "Caspase-dependent initiation of apoptosis and necrosis by the Fas receptor in lymphoid cells: onset of necrosis is associated with delayed ceramide increase". J. Cell Sci. 115: 4671–4683. doi:10.1242/jcs.00153

– Snider, AJ; Orr Gandy, KA; Obeid, LM (2010). "Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation". Biochimie 92 (6): 707–15.doi:10.1016/j.biochi.2010.02.008

Literature.

– Brown DA, London E (June 2000). "Structure and function of sphingolipid- and cholesterol-rich membrane rafts". J. Biol. Chem. 275 (23): 17221–4.doi:10.1074/jbc.R000005200. PMID 10770957.

– Futerman AH (December 2006). "Intracellular trafficking of sphingolipids: relationship to biosynthesis". Biochim. Biophys. Acta 1758 (12): 1885–92.doi:10.1016/j.bbamem.2006.08.004

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