The Role of Sphingosine-1-Phosphate in Neurodegenerative Diseases

Russian Journal of Bioorganic Chemistry - Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid metabolite with antiapoptotic action. As a signal molecule, S1P regulates the survival...     

Role of tumor necrosis factor alpha and sphingomyelin cycle activation in the induction of apoptosis by ischemia/reperfusion of the liver

The signal transduction pathways triggering apoptotic mechanisms after ischemia/reperfusion may involve TNF- secretion, ceramide generation, and initiation of lipid peroxidation. In the present study involvement of the TNF-, sphingomyelin cycle, and lipid peroxidation in the initiation of apoptosis induced in liver cells by ischemia and reperfusion was investigated. Wistar rats were subjected to total liver ischemia (for 15, 30 min, and 1 h) followed by subsequent reperfusion. Ischemia caused sharp decrease of neutral sphingomyelinase activity. Activity of acidic sphingomyelinase initially decreased (during 15-30 min ischemia) but then increased (after 1 h of ischemic injury). Reperfusion of the ischemic lobe of the liver caused increase in neutral sphingomyelinase activity and decrease in acidic sphingomyelinase activity. A small amount of TNF- detected by immunoblotting analysis was accumulated in the ischemic area of liver rapidly and the content of this cytokine dramatically increased after the reperfusion. TNF- is known to induce free radical production. We found that the accumulation of TNF and increase of sphingomyelinase activity during the development of ischemic/reperfusion injury coincided with increase in content of lipid peroxidation products (conjugated dienes) and DNA degradation detected by gel electrophoresis. Recently it was shown that superoxide radicals are used as signaling molecules within the sphingomyelin pathway. This suggests the existence of cross-talk between the oxidation system and the sphingomyelin cycle in cells, which may have important implications for the initial phase and subsequent development of post-ischemic injury.     

Changes in Sphingomyelinase Activity,Tumor Necrosis Factor α Level,and Lipid Peroxidation Intensity in the Course of Development of Cholestatic Liver Injury

Changes in sphingomyelinase activity, tumor necrosis factor α expression, and level of lipid peroxidation products in the course of development of cholestatic liver injury have been studied. The same type phase shifts in the analyzed parameters were observed, which included a marked decrease at the early stages of cholestasis (days 3–6) and a pronounced increase at the later stages (days 12–16), i.e., under the conditions of developed pathology. There was a significant positive linear correlation between tumor necrosis factor α expression, sphingomyelinase activity, and lipid peroxidation intensity in cholestatic injury. We propose that detected changes may reflect the balance between the effects of the two major bile components—bilirubin, which is accumulated in the liver at the early stages of cholestasis, and bile acids, whose influence dominates at the later stages of pathologic process. Our results indicate that tumor necrosis factor α overexpression, sphingomyelin cycle activation, and lipid peroxidation intensification may cause apoptosis of hepatocytes at the late stages of cholestasis.     

The relation between sphingomyelinase activity, lipid peroxide oxidation and NO-releasing in mice liver and brain

We used animal models to study connection between oxidating system and sphingomyelin signaling cascade, because this models are more close related to people disease. Activation of n-sphingomyelinase (n-SMase) in mice liver and brain is coincided in time with increased level of peroxide products (conjugated dienes) after injection of tumor necrosis factor alpha (TNF-alpha). We found that ceramide can induce peroxide oxidation and lead to accumulation of TNF-alpha in animal organs. Nitric oxide (NO) donors (S-nitrosoglutathione and dinitrosyl iron complex) reversibly inhibited activity of n-SMase and decreased level of lipid peroxidation products. This data proposed that both SMase and messengers of oxidative systems could be targets for NO-derived oxidants.     

Interaction of the nitric oxide signaling system with the Sphingomyelin cycle and Peroxidation on transmission of toxic signal of tumor necrosis factor-α in ischemia-reperfusion

This review discusses the functional role of nitric oxide in ischemia-reperfusion injury and mechanisms of signal transduction of apoptosis, which accompanies ischemic damage to organs and tissues. On induction of apoptosis an interaction is observed of the nitric oxide signaling system with the sphingomyelin cycle, which is a source of a proapoptotic agent ceramide. Evidence is presented of an interaction of the sphingomyelin cycle enzymes and ceramide with nitric oxide and enzymes synthesizing nitric oxide. The role of a proinflammatory cytokine TNF-α in apoptosis and ischemia-reperfusion and mechanisms of its cytotoxic action, which involve nitric oxide, the sphingomyelin cycle, and lipid peroxidation are discussed. A comprehensive study of these signaling systems provides insight into the molecular mechanism of apoptosis during ischemia and allows us to consider new approaches for treatment of diseases associated with the activation of apoptosis.     

Formation of chromoneme-like fibrils induced in infusorian somatic nuclei by magnesium ions

A study was made of the effect of Mg2+ on higher-order chromatin structure in marconuclei (Ma) of infusoria Paramecium aurelia and Bursaria truncatella. In infusorian Ma, inactive chromatin is commonly packed in chromatin bodies sized 60-200 nm. When isolated chromatin or Ma were treated with Mg2+ (about 3 mM), chromatin bodies arranged into fibrils 100-300 nm in diameter, which resembled higher eukaryotic chromonemes. The formation dynamics of chromoneme-like fibrils was described. The results testified to the similarity of chromatin bodies to chromomeres of higher eukaryotes. Structurally intact central chromomere cores proved to be essential for the formation of chromoneme-like fibrils. Chromatin organization in infusoria was shown to follow the discrete-level model (nucleosomes-nucleomeres-chromomeres-chromonemes) assumed for higher eukaryotes.     

Relationship of tumor necrosis factor α expression with activation of sphingomyelinase and lipid peroxidation after removal of cholestatic factor

The goal of this work was to study the expression of tumor necrosis factor α (TNFα), sphingomyelin cycle activation, and lipid peroxidation (LPO) processes after the removal of a cholestatic factor in the liver subjected to different durations of cholestasis. Restored bile flow after a 9-day hepatic cholestasis normalized sphingomyelinase (SMase) activity and levels of TNFα and LPO products. The removal of a cholestatic factor after a 12-day cholestasis did not normalize the studied parameters: SMase activity and the levels of TNFα and LPO products remained much higher compared to control. A significant positive correlation between TNFα expression, SMase activity, and LPO rate has been revealed. The obtained data indicate that hepatocyte apoptosis after bile outflow restoration in late cholestasis can be due to the activation of the sphingomyelin cycle, LPO, and TNFα expression. The synergistic interaction can sharply increase the proapoptotic capacity of each of these factors since TNFα activates SMase and LPO, SMase activity depends on the LPO rate, while ceramide, an SMase-produced secondary messenger of apoptosis, can induce oxidative stress.     

Formation of Chromoneme-like Fibrils Induced in Infusorian Somatic Nuclei by Magnesium Ions

A study was made of the effect of Mg²⁺ on higher-order chromatin structure in macronuclei (Ma) of infusoria Paramecium aurelia and Bursaria truncatella. In infusorian Ma, inactive chromatin is commonly packed in chromatin bodies sized 60–200 nm. When isolated chromatin or Ma were treated with Mg²⁺ (about 3 mM), chromatin bodies arranged into fibrils 100–300 nm in diameter, which resembled higher eukaryotic chromonemes. The dynamics of chromoneme-like fibril formation was described. The results testified to the similarity of chromatin bodies to chromomeres of higher eukaryotes. Structurally intact central chromomere cores proved to be essential for the formation of chromoneme-like fibrils. Chromatin organization in infusoria was shown to follow the discrete-level model (nucleosomes–nucleomeres–chromomeres–chromonemes) assumed for higher eukaryotes.