Myocardial infarction differentially alters sphingolipid levels in plasma, erythrocytes and platelets of the rat

Three bioactive sphingolipids, namely sphingosine-1-phosphate (S1P), ceramide (CER) and sphingosine (SPH) were shown to be involved in ischemia/reperfusion injury of the heart. S1P is a powerful cardioprotectant, CER activates apoptosis and SPH in a low dose is cardioprotective whereas in a high dose is cardiotoxic. The aim of the present study was to examine effects of experimental myocardial infarction on the level of selected sphingolipids in plasma, erythrocytes and platelets in the rat. Myocardial infarction was produced in male Wistar rats by ligation of the left coronary artery. Blood was taken from the abdominal aorta at 1, 6 and 24 h after the ligation. Plasma, erythrocytes and platelets were isolated and S1P, dihydrosphingosine-1-phosphate (DHS1P), SPH, dihydrosphingosine (DHS) and CER were quantified by means of an Agilent 6460 triple quadrupole mass spectrometer using positive ion electrospray ionization source with multiple reaction monitoring. The infarction reduced the plasma level of S1P, DHS1P, SPH and DHS but increased the level of total CER. In erythrocytes, there was a sharp elevation in the level of SPH and DHS early after the infarction and a reduction after 24 h whereas the level of S1P, DHS1P and total CER gradually increased. In platelets, the level of each of the examined compounds profoundly decreased 1 and 6 h after the infarction and partially normalized in 24 h. The results obtained clearly show that experimental heart infarction in rats produces deep changes in metabolism of sphingolipids in the plasma, platelets and erythrocytes

CHANGE IN BLOOD GELSOLIN CONCENTRATION IN RESPONSE TO PHYSICAL EXERCISE

Plasma gelsolin (pGSN) produced by muscle is an abundant protein of extracellular fluids capable of severing actin filaments and eliminating actin from the circulation. Additionally, pGSN modulates the cellular effects of some bioactive lipids. In this study we test the hypothesis that hormonal and metabolic adaptations to exercise are associated with changes in gelsolin concentration in blood. Plasma samples were collected from twenty healthy males recruited from untrained (UT, n=10) and endurance trained (ET, n=10) groups that performed 30-60 minutes of exercise on a cycloergometer at a workload corresponding to 700of VO2max. Gelsolin concentration was determined by quantitative Western blot analysis with an anti-human gelsolin antibody. The gelsolin concentration in UT and ET subjects before starting exercise ranged from 104 to 330 and 163 to 337 µg•ml-1 respectively. After 30 minutes of exercise we observed a significant decrease of plasma gelsolin in the UT group (p<0.05) while the gelsolin concentration in the ET group rose on average from 244 to 271 µg•ml-1. However, this increase did not reach statistical significance. Endurance training might increase the ability of muscle tissue to express plasma gelsolin as part of an adaptive mechanism

Rola i potencjał terapeutyczny sfingolipidowego szlaku sygnalizacyjnego w nowotworach hematologicznych

One of the key obstacles in the progress of cancer treatment is the lack of balance between theuncontrolled proliferation and cell apoptosis. It is now known that sphingolipids are essentialmolecules regulating the processes of growth, differentiation and death of living cells. Dependingon their chemical nature, sphingolipids may have a stimulatory (S1P, sphingosine-1-phosphate)or inhibitory (ceramide) effect on cellular proliferation. A number of different studies have shownthat the generation of ceramide in response to cytotoxic therapy is an important element leadingto cell death. Cancer cells use different methods limiting the production of ceramides that leads totheir removal. The effect of oncogenic S1P results from its stimulating effect on DNA synthesisand chemotactic mobility of the vascular endothelial cells and angiogenesis. The use of monoclonalanti-S1P antibodies is potentially a valuable therapeutic option for inhibiting angiogenesisdetermining the growth of tumors. It was additionally demonstrated that S1P beyond the directand indirect by stimulating the release of vascular endothelial growth factor and basic fibroblastgrowth factor angiogenic action has an effect on tumor growth and its metastatic potential. Amongthe sphingolipids, ceramide was identified first as inducing differentiation and the death of humanHL-60 promyelocytic leukemia cells. Progress in understanding the role of sphingolipids wasregarded until recently as the only structural component of cell membranes allowing the use in thetreatment of complex properties of this group of signaling molecules. Thus, it has become importantto clarify the role of sphingolipids in the regulation of the balance between proliferation signals//survival rate and death of cells in order to develop new therapies for neoplastic diseases of myeloidand lymphoid origin.Brak skutecznych metod pozwalających na osiągnięcie równowagi między niekontrolowaną proliferacją i apoptozą komórek w procesie nowotworowym stanowi jedną z kluczowych barier postępu w leczeniu. Obecnie wiadomo, że istotnymi cząsteczkami regulującymi procesy wzrostu, różnicowania, życia oraz śmierci komórek są sfingolipidy. Zależnie od natury chemicznej sfingolipidy mogą pobudzać (S1P, sfingozyno-1-fosforan) lub hamować (ceramid) proliferację. W wielu różnych badaniach wykazano, że generacja ceramidu w odpowiedzi na terapię cytotoksyczną jest ważnym elementem prowadzącym do śmierci komórki. Komórki nowotworowe stosują różne sposoby ograniczające wytwarzanie ceramidu i prowadzące do jego usuwania. Działanie onkogenne S1P wynika z jego działania stymulującego syntezę DNA i ruchliwość chemotaktyczną komórek śródbłonka naczyniowego, jak również stymulacji rozwoju naczyń krwionośnych. Dlatego zastosowanie przeciwciał monoklonalnych anty-S1P jest potencjalnie wartościową opcją terapeutyczną w hamowaniu rozwoju naczyń krwionośnych warunkujących wzrost guzów nowotworowych. Dodatkowo udowodniono, że S1P poza bezpośrednim oraz pośrednim — przez stymulację uwalniania czynnika wzrostu śródbłonka naczyniowego i podstawowy czynnik wzrostu fibroblastów — działaniem angiogennym, wpływa na wzrost i potencjał przerzutowy nowotworów. Spośród sfingolipidów ceramid wskazano jako pierwszy indukujący różnicowanie i śmierć w komórkach ludzkiej białaczki promielocytowej HL-60. Postęp w zrozumieniu roli sfingolipidów, uważanych do niedawna za jedynie składową strukturalną błon komórkowych, umożliwia wykorzystanie w terapii złożonych właściwości tej grupy cząsteczek sygnalizacyjnych. Istotne więc stało się wyjaśnienie roli sfingolipidów w regulacji równowagi między sygnałami proliferacji/przeżywalności komórek i ich śmierci w celu opracowania nowych terapii

Preliminary evaluation of the antiglycoxidant activity of verapamil using various in vitro and in silico biochemical/biophysical methods

Introduction: Glycoxidative stress is essential for linking glucose disturbances and cardiovascular diseases. Unfortunately, contemporary antidiabetic drugs do not have an antiglycative effect but only lower blood glucose levels. Therefore, there is an intense search for substances that could inhibit protein glycation and prevent diabetic complications. A potential antioxidant activity has been demonstrated with verapamil, a phenylalkylamine derivative belonging to selective calcium channel blockers. Verapamil has a well-established position in cardiology due to its wide range of indications and good safety profile. Nevertheless, the antidiabetic activity of verapamil is still unclear. We are the first to comprehensively evaluate the verapamil’s effect on protein glycoxidation using various in vitro and in silico models.Methods: Bovine serum albumin (BSA) was used to assess the rate of glycoxidation inhibition by verapamil. As glycating factors, sugars (glucose, fructose, and ribose) and aldehyde (glyoxal) were used. Chloramine T was used as an oxidizing agent. Aminoguanidine (protein glycation inhibitor) and Trolox (antioxidant) were used as control substances. The biomarkers of oxidation (total thiols, protein carbonyls, advanced oxidation protein products), glycation (Amadori products, β-amyloid, advanced glycation end products [AGEs]), and glycoxidation (tryptophan, kynurenine, N-formylkynurenine, dityrosine) were evaluated using colorimetric and fluorimetric methods. The mechanism of antiglycative activity of verapamil was assessed using in silico docking to study its interaction with BSA, glycosidases, and seventeen AGE pathway proteins.Results: In all in vitro models, biomarkers of protein glycation, oxidation, and glycoxidation were significantly ameliorated under the influence of verapamil. The glycoxidation inhibition rate by verapamil is comparable to that of potent antiglycating agents and antioxidants. The molecular docking simulations showed that verapamil bound preferentially to amino acids prone to glycoxidative damage out of an α-glucosidase’s active center. Among all AGE pathway proteins, verapamil was best docked with the Janus kinase 2 (JAK2) and nuclear factor-κB (NF-κB).Discussion: The results of our study confirm the antiglycoxidant properties of verapamil. The drug’s action is comparable to recognized substances protecting against oxidative and glycation modifications. Verapamil may be particularly helpful in patients with cardiovascular disease and concomitant diabetes. Studies in animal models and humans are needed to confirm verapamil’s antiglycative/antidiabetic activity

Risk factors of colorectal cancer: the comparison of selected nutritional behaviors of medical and non-medical students

Abstract Background The aim of the study was to compare the diet of medical and non-medical students in relation to colorectal cancer risk factors. Material and methods The study included 239 students of various universities in Bialystok, Poland. Respondents were divided into four groups: students of dietetics at the Medical University (SD), students of other fields of study at the Medical University (SMUB), students of the University of Technology (SBUT) and students of the University of Bialystok (SUB). The research tool was an anonymous questionnaire in an electronic form, designed by the authors of this paper. Results Overweight was the least common among students of dietetics. Products that may increase the risk of developing colorectal cancer were most frequently consumed by students of non-medical universities. Everyday consumption of processed meat products was declared by 2.08% of SD, 24.00% of SMUB, 16.13% of SBUT and 25.93% of SUB. Red meat was consumed several times a week or every day by 25% of SD, 25.33% of SMUB, 48.39% of SBUT and 35.19% of SUB. Fast-food meals consumption once or several times a week was confirmed by 4.17% of SD, 18.67% of SMUB, 27.42% of SBUT and 38.89% of SUB. Conclusion The study conducted shows that students expose themselves to colorectal cancer risk factors through their diet

Metabolism, Physiological Role, and Clinical Implications of Sphingolipids in Gastrointestinal Tract

Sphingolipids in digestive system are responsible for numerous important physiological and pathological processes. In the membrane of gut epithelial cells, sphingolipids provide structural integrity, regulate absorption of some nutrients, and act as receptors for many microbial antigens and their toxins. Moreover, bioactive sphingolipids such as ceramide or sphingosine-1-phosphate regulate cellular growth, differentiation, and programmed cell death—apoptosis. Although it is well established that sphingolipids have clinical implications in gastrointestinal tumorigenesis or inflammation, further studies are needed to fully explore the role of sphingolipids in neoplastic and inflammatory diseases in gastrointestinal tract. Pharmacological agents which regulate metabolism of sphingolipids can be potentially used in the management of colorectal cancer or inflammatory bowel diseases. The aim of this work is to critically the review physiological and pathological roles of sphingolipids in the gastrointestinal tract