The effect of normobaric hypoxia on acute exercise-induced changes in blood sphingoid base-1-phosphates metabolism in cyclists.

Extracellular sphingosine-1-phosphate (S1P) emerged as an important regulator of muscle function. We previously found that plasma S1P concentration is elevated in response to acute exercise and training. Interestingly, hypoxia, which is commonly utilized in training programs, induces a similar effect. Therefore, the aim of the current study was to determine the effect of normobaric hypoxia on exercise-induced changes in blood sphingolipid metabolism. Fifteen male competitive cyclists performed a graded cycling exercise until exhaustion (GE) and a simulated 30 km individual time trial (TT) in either normoxic or hypoxic (FiO2 = 16.5%) conditions. Blood samples were taken before the exercise, following its cessation, and after 30 min of recovery. We found that TT increased dihydrosphingosine-1-phosphate (dhS1P) concentration in plasma (both HDL- and albumin-bound) and blood cells, as well as the rate of dhS1P release from erythrocytes, regardless of oxygen availability. Plasma concentration of S1P was, however, reduced during the recovery phase, and this trend was augmented by hypoxia. On the other hand, GE in normoxia induced a selective increase in HDL-bound S1P. This effect disappeared when the exercise was performed in hypoxia, and it was associated with reduced S1P level in platelets and erythrocytes. We conclude that submaximal exercise elevates total plasma dhS1P concentration via increased availability of dihydrosphingosine resulting in enhanced dhS1P synthesis and release by blood cells. Maximal exercise, on the other hand, induces a selective increase in HDL-bound S1P, which is a consequence of mechanisms not related to blood cells. We also conclude that hypoxia reduces post-exercise plasma S1P concentration.

Grade-dependent changes in sphingolipid metabolism in clear cell renal cell carcinoma.

There is a host of evidence for the role of bioactive sphingolipids in cancer biology, and dysregulated sphingolipid metabolism was observed in many malignant tumors. The aim of the present study was to provide more detailed data on sphingolipid metabolism in different stages of clear cell renal cell carcinoma (ccRCC). Samples of the tumor and noncancerous fragments of the same kidney were collected from patients who underwent a radical nephrectomy. The subjects were stratified according to the degree of malignancy of the tumor (n = 14 for G2, 12 for G3, and 9 for G4). The content of bioactive sphingolipids/glycosphingolipids was measured with an HPLC and HPTLC method, and the mRNA and protein expression of sphingolipid transporters and metabolizing enzymes was evaluated using real-time polymerase chain reaction (PCR) and Western blot, respectively. Compared to healthy kidney tissue, ccRCC was characterized by accumulation of sphingosine, sphingosine-1-phosphate (S1P), ceramide, dihydrosphingosine, and dihydroceramide. However, in the case of the latter two, the accumulation was limited to higher malignancy grades. In addition, compared to the healthy tissue, the content of gangliosides in the tumor was increased at the expense of globosides. We also found profound grade-dependent changes in the mRNA level of S1P-metabolizing enzymes, and spinster homolog 2. In general, their expression was much higher in G2 tumors compared to higher malignancy grades. We conclude that ccRCC is characterized by profound and multilevel alterations in sphingolipid metabolism, which to a large extent are grade-dependent. We hypothesize that dysregulation of sphingolipid metabolism contributes to the progression of ccRCC.

Sphingosine-1-phosphate in acute exercise and training.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid found in all eukaryotic cells. Although it may function as an intracellular second messenger, most of its effects are induced extracellularly via activation of a family of five specific membrane receptors. Sphingosine-1-phosphate is enriched in plasma, where it is transported by high-density lipoprotein and albumin, as well as in erythrocytes and platelets which store and release large amounts of this sphingolipid. Sphingosine-1-phosphate regulates a host of cellular processes such as growth, proliferation, differentiation, migration, and apoptosis suppression. It was also shown to play an important role in skeletal muscle physiology and pathophysiology. In recent years, S1P metabolism in both muscle and blood was found to be modulated by exercise. In this review, we summarize the current knowledge on the effect of acute exercise and training on S1P metabolism, highlighting the role of this sphingolipid in skeletal muscle adaptation to physical effort.

Pharmacological inhibition of sphingosine-1-phosphate lyase partially reverses spatial memory impairment in streptozotocin-diabetic rats.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid with strong neuroprotective properties that is important for normal excitability and synaptic transmission in the hippocampal neurons. Considering the above, the aim of the present study was to determine whether increasing brain S1P level is able to reverse spatial memory impairment in streptozotocin-diabetic rats. The experiment was carried out on diabetic (n = 22) and nondiabetic (n = 10) male Wistar rats. Diabetes was induced by a single injection of streptozotocin. Eleven weeks later, 11 diabetic animals received injections of THI (S1P lyase inhibitor) for seven days. During the last five days of the experiment spatial reference memory acquisition and retention were tested in the Morris water maze task. The animals were then anaesthetized and samples of the hippocampus, prefrontal cortex, striatum, and cerebellum were excised. The content of S1P and related sphingolipids was measured using a HPLC method. Diabetes induced a depletion of ceramide in the hippocampus and cerebellum that was associated with impaired spatial memory and learning. Administration of THI to the diabetic animals prevented ceramide depletion in the hippocampus and cerebellum, and induced an increase in S1P content in all examined brain structures. These effects were associated with an improvement in spatial memory. We conclude that pharmacological inhibition of S1P lyase partially reverses the impairment in spatial memory induced by chronic hyperglycemia, and that this effect may be related to the prevention of ceramide depletion in the hippocampus and cerebellum, the increase in brain S1P level, or both.

Plasma concentration and expression of adipokines in epicardial and subcutaneous adipose tissue are associated with impaired left ventricular filling pattern.

BACKGROUND: Adipokines in serum derive mainly from subcutaneous and visceral adipose tissues. Epicardial adipose tissue (EAT), being a relatively small but unique fat depot, probably does not make an important contribution to systemic concentrations of adipokines. However, proximity of EAT to cardiac muscle and coronary arteries allows cells and proteins to penetrate between tissues. It is hypothesized that overexpression of proinflammatory cytokines in EAT plays an important role in pathophysiology of the heart. The aim of the study was to analyze the relationship between echocardiographic heart parameters and adipokines in plasma, epicardial, and subcutaneous fat in patients with obesity and type 2 diabetes mellitus (T2DM). Additionally, we evaluate proinflammatory properties of EAT by comparing that depot with subcutaneous adipose tissue. METHODS: The study included 55 male individuals diagnosed with coronary artery disease (CAD) who underwent planned coronary artery bypass graft. Plasma concentrations of leptin, adiponectin, resistin, visfatin, apelin, IL-6, and TNF-α, as well as their mRNA and protein expressions in EAT and subcutaneous adipose tissue (SAT) were determined. RESULTS: Obesity and diabetes were associated with increased leptin and decreased adiponectin plasma levels, higher protein expression of leptin and IL-6 in SAT, and higher visfatin protein expression in EAT. Impaired left ventricular (LV) diastolic function was associated with increased plasma concentrations of leptin, resistin, IL-6, and adiponectin, as well as with increased expressions of resistin, apelin, and adiponectin in SAT, and leptin in EAT. CONCLUSIONS: Obesity and T2DM in individuals with CAD have a limited effect on adipokines. Expression of adipokines in EAT and SAT is linked to certain heart parameters, however diastolic dysfunction of the LV is strongly associated with circulating adipokines.

Assessment of the Main Compounds of the Lipolytic System in Treadmill Running Rats: Different Response Patterns between the Right and Left Ventricle.

The aim of the present study was to investigate the time and intensity dependent effects of exercise on the heart components of the lipolytic complex. Wistar rats ran on a treadmill with the speed of 18 m/min for 30 min (M30) or 120 min (M120) or with the speed of 28 m/min for 30 min (F30). The mRNA and protein expressions of the compounds adipose triglyceride lipase (ATGL), comparative gene identification-58 (CGI-58), G0/G1 switch gene 2 (G0S2), hormone sensitive lipase (HSL) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) were examined by real-time PCR and Western blot, respectively. Lipid content of free fatty acids (FFA), diacylglycerols (DG) and triacylglycerols (TG) were estimated by gas liquid chromatography. We observed virtually no changes in the left ventricle lipid contents and only minor fluctuations in its ATGL mRNA levels. This was in contrast with its right counterpart i.e., the content of TG and DG decreased in response to both increased duration and intensity of a run. This occurred in tandem with increased mRNA expression for ATGL, CGI-58 and decreased expression of G0S2. It is concluded that exercise affects behavior of the components of the lipolytic system and the lipid content in the heart ventricles. However, changes observed in the left ventricle did not mirror those in the right one.

Muscle-Saturated Bioactive Lipids Are Increased with Aging and Influenced by High-Intensity Interval Training.

Ceramide and diacylglycerol are linked to insulin resistance in rodents, but in humans the data are inconsistent. Insulin resistance is frequently observed with aging, but the role of ceramide and diacylglycerol is not clarified. Training improves metabolic health and, therefore, we aimed to elucidate the influence of age and high-intensity interval training (HIIT) on ceramide and diacylglycerol content in muscle. Fourteen young (33 ± 1) and 22 older (63 ± 1) overweight to obese subjects performed 6 weeks HIIT three times a week. Maximal oxygen uptake and body composition were measured and muscle biopsies and fasting blood samples were obtained. Muscle ceramide and diacylglycerol were measured by gas-liquid chromatography and proteins in insulin signaling, lipid and glucose metabolism were measured by Western blotting. Content of ceramide and diacylglycerol total, saturated, C16:0 and C18:0 fatty acids and C18:1 ceramide were higher in older compared to young. HIIT reduced saturated and C18:0 ceramides, while the content of the proteins involved in glucose (GLUT4, glycogen synthase, hexokinase II, AKT) and lipid metabolism (adipose triglyceride lipase, fatty acid binding protein) were increased after HIIT. We demonstrate a higher content of saturated ceramide and diacylglycerol fatty acids in the muscle of older subjects compared to young. Moreover, the content of saturated ceramides was reduced and muscle glucose metabolism improved at protein level after HIIT. This study highlights an increased content of saturated ceramides in aging which could be speculated to influence insulin sensitivity.

Arteriovenous Sphingosine-1-Phosphate Differences Across Selected Organs of the Rat.

BACKGROUND/AIMS: Sphingosine-1-phosphate (S1P) is a bioactive lysosphingolipid that is found in high concentration in plasma. The majority of plasma S1P is transported bound to HDL and albumin. Although the major sources of circulating S1P have been identified, it remains obscure what is the contribution of different organs/tissues to S1P homeostasis in plasma. Answering this question was the major aim of the present study. METHODS: The experiment was performed on male Wistar rats from whom blood samples were taken from either: 1) femoral vein, right ventricle of the heart, and abdominal aorta (n=15) or 2) hepatic vein, portal vein, and abdominal aorta (n=11). Plasma was fractionated by sequential flotation ultracentrifugation and sphingolipids were quantified by a HPLC method. RESULTS: Compared to the mixed venous blood sampled from the right ventricle, total plasma and lipoprotein-depleted plasma (LPDP) concentration of S1P in the arterial blood was lower. On the other hand, the level of S1P increased across the leg both in plasma and LPDP. The concentration of S1P, sphingosine, and sphinganine in the plasma, HDL, and LPDP isolated from the blood taken from the hepatic vein was markedly higher compared to both arterial and portal blood. CONCLUSIONS: We conclude that, in contrast to HDL-bound S1P, albumin-associated S1P is very labile in the circulation. It is degraded in the pulmonary, and to a lesser extent, gastrointestinal circulation, and released across the liver and skeletal muscle. We also conclude that liver is an important source of HDL-bound S1P and circulating free sphingoid bases.

Liver X Receptor Agonist TO901317 Prevents Diacylglycerols Accumulation in the Heart of Streptozotocin-Diabetic Rats.

BACKGROUND/AIMS: Liver X receptors (LXRα and LXRß) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in the heart, and enhanced LXR activity in the streptozotocin (STZ) diabetic myocardium was reported recently. The aim of this study was to investigate effect of in vivo LXR activation on myocardial lipid metabolism under conditions of STZ-induced diabetes. METHODS: Wistar rats were randomly divided into three experimental groups: non-diabetic control, treated with STZ, and treated with STZ and LXR agonist - TO901317. Diabetes was induced by a single intraperitonal injection of STZ at a dose of 55 mg/kg. LXR agonist was administrated once daily in the morning by an oral gavage at a dose of 10 mg/kg/d during the last week of the experiment. After anesthesia samples of blood and the left ventricle were taken. RESULTS: TO901317 administration increased expression of both LXR isoforms and its target genes: sterol response element binding protein 1c (SREBP-1c) and acetyl-coenzyme A carboxylase 1 (ACC1) in the heart of streptozotocin-diabetic rats. Treatment with LXR agonist had no effect on plasma lipids and glucose in the diabetic rats. Concomitantly, content of the examined lipid classes in the diabetic heart (nonesterified fatty acids, triacylglycerols, phospholipids, cholesterol esters, ceramide) was unchanged after treatment with TO901317. On the contrary, myocardial level of cholesterol and diacylglycerols (DAG) was decreased after LXR activation in diabetic rats, the change in DAG level was associated with downregulated expression of adipose triglyceride lipase (ATGL). CONCLUSION: Activation of LXRs by TO901317 protects cardiomyocytes against DAG accumulation and thus may reverse disturbances in lipid metabolism observed in streptozotocin-diabetic heart.

Sources, metabolism, and regulation of circulating sphingosine-1-phosphate.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that acts either as an intracellular messenger or as a ligand for its membrane receptors. S1P is a normal constituent of blood, where it is found both in plasma and blood cells. Compared with other cell types, sphingolipid metabolism in erythrocytes and platelets has unique features that allow the erythrocytes and platelets to accumulate S1P. In plasma, S1P is bound mainly to HDLs and albumin. Of note, metabolism and biological activity of S1P is to a large extent affected by the type of its carrier. Plasma S1P is characterized by a short half-life, indicating rapid clearance by degradative enzymes and the presence of high-capacity sources involved in maintaining its high concentration. These sources include blood cells, vascular endothelium, and hepatocytes. However, the extent to which each of these contributes to the plasma pool of S1P is a matter of debate. Circulating S1P plays a significant physiological role. It was found to be the key regulator of lymphocyte trafficking, endothelial barrier function, and vascular tone. The purpose of this review is to summarize the present state of knowledge on the metabolism, transport, and origin of plasma S1P, and to discuss the mechanisms regulating its homeostasis in blood.

LXR agonist T0901317-Induced hyperlipidemia does not lead to lipid accumulation in the rat heart.

BACKGROUND/AIMS: Liver X receptors (LXRα and LXRß) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in human and rodent cardiac tissue, however, its role in this tissue remains unclear. The aim of this study was to investigate effects of in vivo LXR activation on lipid metabolism in the rat myocardium under the conditions of low and high lipid intake. METHODS: The experiments were performed on male Wistar rats fed for 5 weeks on either low fat diet (LFD) or high fat diet (HFD). Next, the animals were randomly divided into two groups receiving either LXR agonist - T0901317 (10mg/kg/d) or vehicle for the last week of the experiment. After anesthesia samples of the left ventricle and blood were taken. RESULTS: It was found that LXRß is the dominant isoform in the rat myocardium and the expression of both LXR isoforms did not change after administration of T0901317. Agonist treatment induced hyperlipidemia in low fat fed rats and this effect was amplified in high fat fed rats. LXR agonist elevated content of myocardial triacylglycerols in animals fed on LFD and content of phospholipids in animals fed on HFD. Levels of the remaining examined lipid classes (nonesterified fatty acids, diacylglycerol, free cholesterol, cholesterol esters, ceramide) was decreased or unchaged after LXR activation. CONCLUSION: We conclude that administration of T0901317 does not lead to severe myocardial lipid accumulation in rats despite of its high plasma availability.

Myocardial lipid profiling during time course of high fat diet and its relationship to the expression of fatty acid transporters.

BACKGROUND/AIMS: It is well documented that increased fatty acids (FA) supply causes lipid accumulation and insulin resistance in skeletal muscles. Whether the same mechanism is present in the heart is still unclear. Therefore, the goal of our study was to determine the content of specific myocardial lipid fractions during feeding rats a high fat diet (HFD) for 5 weeks. Moreover, the relation between changes in myocardial lipid content, whole body insulin resistance and the expression of fatty acid transporters in each week of HFD was established. METHODS: Gas liquid chromatography and high performance liquid chromatography were used to determine the content of lipid fractions in the left ventricle. Expression of selected proteins was estimated by Western blot technique. All measurements were made after each week of HFD. RESULTS: As expected, lipid profile in myocardium was altered by HFD in different weeks of the study with the most intense changes in triacylglycerols, long chain fatty acid-CoA and ceramide. Furthermore, there was a significant elevation of plasmalemmal (the 4th and the 5th week) and mitochondrial expression (from the 3rd to the 5th week) of fatty acid translocase. CONCLUSION: High fat diet affects myocardial lipid profile in each week of its duration and causes alternations in FA metabolism in cardiomyocytes.

Exercise increases sphingoid base-1-phosphate levels in human blood and skeletal muscle in a time- and intensity-dependent manner.

PURPOSE: Sphingosine-1-phosphate (S1P) regulates cardiovascular function and plays an important role in muscle biology. We have previously reported that cycling exercise increased plasma S1P. Here, we investigated the effect of exercise duration and intensity on plasma and skeletal muscle S1P levels. METHODS: In the first experiment, 13 male athletes performed a 60-min exercise at 65 % of VO2max and a graded exercise until exhaustion on a rowing ergometer. Samples of the venous blood were taken, and plasma, erythrocytes and platelets were isolated. In the second experiment, ten male moderately active subjects performed three consecutive periods of one-leg knee extension exercise (at 25, 55 and 85 % of the maximal workload). Muscle biopsies and blood samples from the radial artery and femoral veins were taken. RESULTS: Under basal conditions, S1P was released from the leg, as its concentration was lower in the arterial than in the venous plasma (p < 0.01). Exercise until exhaustion increased plasma S1P and sphinganine-1-phosphate (SA1P) concentration (p < 0.05), whereas moderate-intensity exercise elevated only SA1P (p < 0.001). Although knee extension increased muscle S1P content (p < 0.05), it was not released but taken up across the leg during exercise. However, sphingosine was released from both working and resting leg at the highest workload (p < 0.05). CONCLUSIONS: Plasma S1P concentration is elevated only by high-intensity exercise which results, at least in part, from increased availability of sphingosine released by skeletal muscle. In addition, exercise markedly affects S1P dynamics across the leg. We speculate that S1P may play an important role in adaptation of skeletal muscle to exercise.

Insulin-sensitizing effect of LXR agonist T0901317 in high-fat fed rats is associated with restored muscle GLUT4 expression and insulin-stimulated AS160 phosphorylation.

BACKGROUND/AIM: Liver X receptors (LXRs) are ligand-activated transcription factors that were shown to stimulate hepatic lipogenesis leading to liver steatosis and hypertriglyceridemia. Despite their pro-lipogenic action, LXR activators normalize glycemia and improve insulin sensitivity in rodent models of type 2 diabetes. Antidiabetic action of LXR agonists is thought to result from suppression of hepatic gluconeogenesis. However, it remains unclear whether LXR activation affects muscle insulin sensitivity. In the present study we attempted to answer this question. METHODS: The experiments were performed on male Wistar rats fed for 5 weeks on either standard chow or high fat diet. The latter group was further divided into two subgroups receiving either selective LXR agonist - T0901317 (10mg/kg/d) or vehicle during the last week of the experiment. All animals were then anaesthetized and samples of the soleus as well as red and white sections of the gastrocnemius muscle were excised. RESULTS: As expected, administration of T0901317 to high-fat fed rats augmented diet-induced hyperlipidemia. Nevertheless, it also normalized glucose tolerance and improved insulin-stimulated glucose uptake in isolated soleus muscle. In addition, LXR agonist completely restored glucose transporter 4 expression and insulin-stimulated Akt substrate of 160 kDa phosphorylation in all investigated muscles. Insulin-sensitizing effect of T0901317 was not related to changes in intramuscular level of lipid mediators of insulin resistance, since neither diacylglycerols nor ceramide content was affected by the treatment. CONCLUSION: We conclude that improvement in muscle insulin sensitivity is one of the mechanisms underlying the antidiabetic action of LXR activators.

Ultramarathon run markedly reduces plasma sphingosine-1-phosphate concentration.

We have previously shown that acute exercise increases the level of sphingosine-1-phosphate (S1P) in plasma and ceramide in erythrocytes of untrained subjects. The aim of the current study was to examine the effect of ultramarathon run on the plasma and erythrocyte levels of the following bioactive sphingolipids: S1P, sphinganine-1-phosphate (SA1P), sphingosine, sphinganine, and ceramide. Blood samples were collected from seven male amateur runners participating in a 48-hr ultramarathon race before the run, after 24 and 48 hr of running, and following 24 and 48 hr of recovery. The sphingolipids were quantified by means of HPLC. Sustained running for 48 hr resulted in a progressive decline in plasma S1P to a level significantly lower than at prerace, and then remained stable over the next 48 hr of recovery. In erythrocytes, S1P content was stable until 24 hr of recovery, then rose abruptly to reach peak values after 48 hr of recovery. The plasma level of SA1P decreased progressively during the competition and remained unchanged over the recovery. In erythrocytes, the level of SA1P increased after 24 hr running and normalized thereafter. The level of ceramide, both in plasma and erythrocytes, was not significantly affected by the ultraendurance run. We speculate that reduction in plasma level of S1P during and after the run reduces its biological actions and might be responsible for some negative side-effects of the ultraendurance effort.

Defining the role of DAG, mitochondrial function, and lipid deposition in palmitate-induced proinflammatory signaling and its counter-modulation by palmitoleate.

Chronic exposure of skeletal muscle to saturated fatty acids, such as palmitate (C16:0), enhances proinflammatory IKK-NFκB signaling by a mechanism involving the MAP kinase (Raf-MEK-ERK) pathway. Raf activation can be induced by its dissociation from the Raf-kinase inhibitor protein (RKIP) by diacylglycerol (DAG)-sensitive protein kinase C (PKC). However, whether these molecules mediate the proinflammatory action of palmitate, an important precursor for DAG synthesis, is currently unknown. Here, involvement of DAG-sensitive PKCs, RKIP, and the structurally related monounsaturated fatty acid palmitoleate (C16:1) on proinflammatory signaling are investigated. Palmitate, but not palmitoleate, induced phosphorylation/activation of the MEK-ERK-IKK axis and proinflammatory cytokine (IL-6, CINC-1) expression. Palmitate increased intramyocellular DAG and invoked PKC-dependent RKIP(Ser153) phosphorylation, resulting in RKIP-Raf1 dissociation and MEK-ERK signaling. These responses were mimicked by PMA, a DAG mimetic and PKC activator. However, while pharmacological inhibition of PKC suppressed PMA-induced activation of MEK-ERK-IKK signaling, activation by palmitate was upheld, suggesting that DAG-sensitive PKC and RKIP were dispensable for palmitate's proinflammatory action. Strikingly, the proinflammatory effect of palmitate was potently repressed by palmitoleate. This repression was not due to reduced palmitate uptake but linked to increased neutral lipid storage and enhanced cellular oxidative capacity brought about by palmitoleate's ability to restrain palmitate-induced mitochondrial dysfunction.

Sustained decrease in plasma sphingosine-1-phosphate concentration and its accumulation in blood cells in acute myocardial infarction.

Sphingosine-1-phosphate (S1P) is a cardioprotective sphingolipid present at high concentration in plasma and blood cells. However, effect of the myocardial infarction on S1P metabolism in blood is poorly recognized. Therefore, we aimed to examine the dynamics of changes in concentration of sphingolipids in blood of patients with acute ST-segment elevation myocardial infarction (STEMI). The study was performed on two groups of subjects: healthy controls (n=32) and patients with STEMI (n=32). In the latter group blood was taken upon admission to intensive heart care unit, and then on the second, fifth and thirtieth day, and approximately two years after admission. STEMI patients showed decreased plasma S1P concentration and accumulation of free sphingoid bases and their 1-phosphates in erythrocytes. This effect was already present upon admission, and was maintained for at least thirty days after the infarction. Interestingly, two years post-infarction plasma S1P level recovered only partially, whereas the content of erythrocyte sphingolipids decreased to the values observed in the control subjects. The most likely reason for the observed reduction in plasma S1P level was its decreased release or increased degradation by vascular endothelial cells, as we did not find any evidence for downregulation of S1P synthesis or release by blood cells. We conclude that patients with STEMI are characterized by marked alterations in sphingolipid metabolism in blood which could be a consequence of the infarction itself, the antiplatelet treatment given or both. Our data suggest that cardioprotective action of S1P may be diminished in patients with acute myocardial infarction.

[Epicardial adipose tissue and its role in cardiac physiology and disease]. / Tkanka tluszczowa nasierdziowa. Znaczenie fizjologiczne oraz rola w patofizjologii chorób serca.

Adipose tissue secretes a number of cytokines, referred to as adipokines. Intensive studies conducted over the last two decades showed that adipokines exert broad effects on cardiac metabolism and function. In addition, the available data strongly suggests that these cytokines play an important role in development of cardiovascular diseases. Epicardial adipose tissue (EAT) has special properties that distinguish it from other deposits of visceral fat. Overall, there appears to be a close functional and anatomic relationship between the EAT and the cardiac muscle. They share the same coronary blood supply, and there is no structure separating the adipose tissue from the myocardium or coronary arteries. The role of EAT in osierdziocardiac physiology remains unclear. Its putative functions include buffering coronary arteries against the torsion induced by the arterial pulse wave and cardiac contraction, regulating fatty acid homeostasis in the coronary microcirculation, thermogenesis, and neuroprotection of the cardiac autonomic ganglia and nerves. Obesity (particularly the abdominal phenotype) leads to elevated EAT content, and the available data suggests that high amount of this fat depot is associated with increased risk of ischemic heart disease, cardiac hypertrophy and diastolic dysfunction. The mass of EAT is small compared to other fat deposits in the body. Nevertheless, its close anatomic relationship to the heart suggests that this organ is highly exposed to EAT-derived adipokines which makes this tissue a very promising area of research. In this paper we review the current knowledge on the role of EAT in cardiac physiology and development of heart disease.

Hepcidin and erythroferrone response to 3 weeks of exposure to normobaric hypoxia at rest in trained cyclists.

Purpose: The effectiveness of altitude training on haematological adaptations is largely dependent on iron metabolism. Hepcidin and erythroferrone (ERFE) are key iron-regulating hormones, yet their response to altitude training is poorly understood. The aim of this study was to analyze changes in hepcidin and ERFE under the influence of 3 weeks of the Live High-Train Low (LH-TL) method. Methods: Twenty male trained cyclists completed a 3-week training program under normoxic conditions (NORM) or with passive exposure to normobaric hypoxia (LH-TL; FiO2 = 16.5%, ∼2000 m; 11-12 h/day). Hepcidin, ERFE, hypoxia inducible factor-2 (HIF-2), ferroportin (Fpn), erythropoietin (EPO), serum iron (Fe) and hematological variables were assessed at baseline (S1), then immediately after (S2) and 3 days after (S3) intervention. Results: In the LH-TL group, hepcidin decreased by 13.0% (p < 0.001) in S2 and remained at a reduced level in S3. ERFE decreased by 28.7% (p < 0.05) in S2 and returned to baseline in S3. HIF-2α decreased gradually, being lower by 25.3% (p < 0.05) in S3. Fpn decreased between S1 and S2 by 18.9% (p < 0.01) and remained lower during S3 (p < 0.01). In the NORM group, in turn, hepcidin levels increased gradually, being higher by 73.9% (p < 0.05) in S3 compared to S1. No statistically significant differences in EPO were observed in both groups. Conclusion: Three weeks of LH-TL suppresses resting hepcidin and ERFE levels in endurance athletes. We found no association between hepcidin and ERFE after LH-TL. Probably, ERFE is not the only factor that suppresses hepcidin expression in response to moderate hypoxia, especially in later stages of hepcidin downregulation. With the cessation of hypoxia, favorable conditions for increasing the availability of iron cease.

Evaluation of Oromucosal Natural Gum-Based Emulgels as Novel Strategy for Photodynamic Therapy of Oral Premalignant Lesions.

Photodynamic therapy (PDT) recently has been shown as a promising option in the treatment of premalignant lesions of the soft oral tissues. Effective delivery of photosensitizer is challenging due to poor drug adherence to the oromucosal epithelium. In the present work, emulgels composed of natural polysaccharide gums (tragacanth, xanthan and gellan) were evaluated as novel oromucosal platforms of delta-aminolevulinic acid (ALA) for PDT. Apart from mucoadhesive and textural analysis, the specific steps involved studies on drug penetration behavior and safety profile using a three-dimensional human oral epithelium model (HOE). All designed emulgels presented greater mucoadhesiveness when compared to commercial oromucosal gel. Incorporation of ALA affected textural properties of emulgels, and tragacanth/xanthan formulation with greater hardness and cohesiveness exhibited a protective function against the mechanical tongue stress. Permeability studies revealed that ALA is capable of penetrating across oromucosal epithelium by passive transport and all formulations promoted its absorption rate when compared to a commercial topical product with ALA. Importantly, the combination of tragacanth and xanthan profoundly enhanced photosensitizer retention in the buccal epithelium. Tested samples performed negligible reduction in cell viability and moderately low IL-1ß release, confirming their non-irritancy and compatibility with HOE. Overall, the presented findings indicate that tragacanth/xanthan emulgel holds promise as an oromucosal ALA-carrier for PDT strategy.