The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice

Background: Genome-wide association studies in asthma have repeatedly identified single nucleotide polymorphisms in the ORM (yeast)-like protein isoform 3 (ORMDL3) gene across different populations. Although the ORM homologues in yeast are well-known inhibitors of sphingolipid synthesis, it is still unclear whether and how mammalian ORMDL3 regulates sphingolipid metabolism and whether altered sphingolipid synthesis would be causally related to asthma risk. Objective: We sought to examine the in vivo role of ORMDL3 in sphingolipid metabolism and allergic asthma. Methods: Ormdl3-LacZ reporter mice, gene-deficient Ormdl3(-/-) mice, and overexpressing Ormdl3(Tg/wt) mice were exposed to physiologically relevant aeroallergens, such as house dust mite (HDM) or Alternaria alternata, to induce experimental asthma. Mass spectrometry-based sphingolipidomics were performed, and airway eosinophilia, T(H)2 cytokine production, immunoglobulin synthesis, airway remodeling, and bronchial hyperreactivity were measured. Results: HDM challenge significantly increased levels of total sphingolipids in the lungs of HDM-sensitized mice compared with those in control mice. In Ormdl3(Tg/wt) mice the allergen-induced increase in lung ceramide levels was significantly reduced, whereas total sphingolipid levels were not affected. Conversely, in liver and serum, levels of total sphingolipids, including ceramides, were increased in Ormdl3(-/-) mice, whereas they were decreased in Ormdl3(Tg/wt) mice. This difference was independent of allergen exposure. Despite these changes, all features of asthma were identical between wildtype, Ormdl3(Tg/wt), and Ormdl3(-/-) mice across several models of experimental asthma. Conclusion: ORMDL3 regulates systemic ceramide levels, but genetically interfering with Ormdl3 expression does not result in altered experimental asthma

The university-industry cooperation: The role of employers in quality assurance of Education

The purpose of the study is to discuss the role of employers’ engagement in the educational process of universities in assuring the quality of educational services and preparing quality graduates. Realization of the principle of integrating education, science and industry in modern conditions ensures a balance between the content of educational programmes, results of R&D and industry. Thus, the paper discusses the current launched mechanisms of Kazakh National University in Kazakhstan aimed at promoting an establishment of mutual trust between the university and the employer community to ensure the quality of provided educational services. The results of the paper could serve as a guide to the most necessary aspects of cooperation practices between universities and employers for potential academy managers and practitioners in quality management processes

Вивчення впливу соків з дикорослої сировини Північного Казахстану на хімічний склад сироваткових напоїв

In deep processing technologies whey is a more "valuable" product than cheese, cottage cheese. Even though whey has a low energy value among dairy products, it is at the same time very valuable biologically. Recently, the consumption of berries has increased markedly everywhere. This growth is explained by the growing attention of the population to health and the appearance on the market of many canned products "saturated with berries". In addition, there are many scientific studies concerning the composition of biologically active components in the composition of berries. Thus, scientific developments to produce new foods enriched with berries are of crucial importance for berry producers, food processors and consumers. The scientific novelty of this study is to investigate the possibility of using wild plant raw materials of Northern Kazakhstan (chokeberry and saskatoon berry) in milk beverages’ technology, that will be described for the first time. This berries despite their rich chemical composition, are rarely used in the food industry. The study describes the nutritional value and chemical composition of whey drinks enriched with juice from saskatoon berries, black chokeberry. In our study it is proposed thermosaltic coagulation as a primary treatment for whey. The comparative analyses of natural whey and treated one shows the expediency and benefit of using thermosaltic coagulation. At the same time, juices from wild berries increase the biological and nutritional value of whey drinks Thus, the described advantages are confirmed with assays and confirm the expediency of using this combined technology in the production of drinks from whey with berry juices. The obtained research results will be used to develop a new technology to produce juice drinks based on whey and will also be described in a patent for a utility model for the production of beverages from wheyУ технологіях глибокої переробки сироватка є більш "цінним" продуктом, ніж сир, сир. Незважаючи на те, що сироватка має низьку енергетичну цінність серед молочних продуктів, в той же час вона дуже цінна біологічно. Останнім часом споживання ягід помітно зросло у всьому світі. Таке зростання пояснюється зростаючим увагою населення до здоров'я і появою на ринку великої кількості консервованих продуктів, "насичених ягодами". Крім того, існує безліч наукових досліджень, що стосуються складу біологічно активних компонентів в складі ягід. Таким чином, наукові розробки з виробництва нових харчових продуктів, збагачених ягодами, мають вирішальне значення для виробників ягід, переробників харчових продуктів і споживачів. Наукова новизна даного дослідження полягає у вивченні можливості використання дикорослої рослинної сировини Північного Казахстану (чорноплідної горобини і саскатунської ягоди) в технології молочних напоїв, яка буде описана вперше. Ці ягоди, незважаючи на їх багатий хімічний склад, рідко використовуються в харчовій промисловості. У дослідженні описана харчова цінність і хімічний склад сироваткових напоїв, збагачених соком з ягід саскатуна, горобини і обліпихи. У нашому дослідженні ми пропонуємо термосолеву коагуляцію як первинну обробку молочної сироватки. Порівняльний аналіз натуральної сироватки і обробленої сироватки показує доцільність і перевага використання термосолевой коагуляції. У той же час соки з лісових ягід підвищують біологічну і поживну цінність сироваткових напоїв. Таким чином, описані переваги підтверджуються проведеними нами аналізами і підтверджують доцільність використання цієї комбінованої технології при виробництві напоїв з молочної сироватки з ягідними соками. Отримані результати досліджень будуть використані для розробки нової технології виробництва сокових напоїв на основі молочної сироватки, а також будуть описані в патенті на корисну модель для виробництва напоїв з молочної сироватки

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I – A link to metabolic control

BACKGROUND: 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). METHODS: In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. RESULTS: 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ± 129 vs 35 ± 14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ± 182 vs 398 ± 90 μmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ± 22 vs 110 ± 18 μmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. CONCLUSION: In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism

Disturbed sphingolipid metabolism with elevated 1-deoxysphingolipids in glycogen storage disease type I – A link to metabolic control

Background 1-Deoxysphingolipids (1-deoxySLs) are atypical sphingolipids. They are formed during sphingolipid de novo synthesis by the enzyme serine palmitoyltransferase, due to the alternate use of alanine over its canonical substrate serine. Pathologically elevated 1-deoxySL are involved in several neurological and metabolic disorders. The objective of this study was to investigate the role of 1-deoxySL in glycogen storage disease type I (GSDI). Methods In this prospective, longitudinal observational study (median follow-up 1.8y), the plasma 1-deoxySL profile was analyzed in 15 adult GSDI patients (12 GSDIa, 3 GSDIb), and 31 healthy controls, along with standard parameters for monitoring GSDI. Results 1-Deoxysphinganine (1-deoxySA) concentrations were elevated in GSDI compared to controls (191 ± 129 vs 35 ± 14 nmol/l, p < 0.0001). Concordant with the mechanism of 1-deoxySL synthesis, plasma alanine was higher (625 ± 182 vs 398 ± 90 μmol/l, p < 0.0001), while serine was lower in GSDI than in controls (88 ± 22 vs 110 ± 18 μmol/l. p < 0.001). Accordingly, serine, alanine and triglycerides were determinants of 1-deoxySA in the longitudinal analysis of GSDIa. 1-deoxySA concentrations correlated with the occurrence of low blood glucose (area under the curve below 4 mmol/l) in continuous glucose monitoring. The 1-deoxySL profile in GSDIb was distinct from GSDIa, with a different ratio of saturated to unsaturated 1-deoxySL. Conclusion In addition to the known abnormalities of lipoproteins, GSDI patients also have a disturbed sphingolipid metabolism with elevated plasma 1-deoxySL concentrations. 1-DeoxySA relates to the occurrence of low blood glucose, and may constitute a potential new biomarker for assessing metabolic control. GSDIa and Ib have distinct 1-deoxySL profiles indicating that both GSD subtypes have diverse phenotypes regarding lipid metabolism

Novel Mouse Models of Methylmalonic Aciduria Recapitulate Phenotypic Traits with a Genetic Dosage Effect

Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects. Transgenic Mut(ki/ki) and Mut(ko/ki) mice survive post-weaning, show failure to thrive, and show increased methylmalonic acid, propionylcarnitine, odd chain fatty acids, and sphingoid bases, a new potential biomarker of MMAuria. Consistent with genetic dosage, Mut(ko/ki) mice have lower Mut activity, are smaller, and show higher metabolite levels than Mut(ki/ki) mice. Further, Mut(ko/ki) mice exhibit manifestations of kidney and brain damage, including increased plasma urea, impaired diuresis, elevated biomarkers, and changes in brain weight. On a high protein diet, mutant mice display disease exacerbation, including elevated blood ammonia, and catastrophic weight loss, which, in Mut(ki/ki) mice, is rescued by hydroxocobalamin treatment. This study expands knowledge of MMAuria, introduces the discovery of new biomarkers, and constitutes the first in vivo proof of principle of cobalamin treatment in mut-type MMAuria

Novel mouse models of methylmalonic aciduria recapitulate phenotypic traits with a genetic dosage effect

Methylmalonic aciduria (MMAuria), caused by deficiency of methylmalonyl-CoA mutase (MUT), usually presents in the newborn period with failure to thrive and metabolic crisis leading to coma or even death. Survivors remain at risk of metabolic decompensations and severe long term complications, notably renal failure and neurological impairment. We generated clinically relevant mouse models of MMAuria using a constitutive Mut knock-in (KI) allele based on the p.Met700Lys patient mutation, used homozygously (KI/KI) or combined with a knockout allele (KO/KI), to study biochemical and clinical MMAuria disease aspects. Transgenic Mutki/ki and Mutko/ki mice survive post-weaning, show failure to thrive, and show increased methylmalonic acid, propionylcarnitine, odd chain fatty acids, and sphingoid bases, a new potential biomarker of MMAuria. Consistent with genetic dosage, Mutko/ki mice have lower Mut activity, are smaller, and show higher metabolite levels than Mutki/ki mice. Further, Mutko/ki mice exhibit manifestations of kidney and brain damage, including increased plasma urea, impaired diuresis, elevated biomarkers, and changes in brain weight. On a high protein diet, mutant mice display disease exacerbation, including elevated blood ammonia, and catastrophic weight loss, which, in Mutki/ki mice, is rescued by hydroxocobalamin treatment. This study expands knowledge of MMAuria, introduces the discovery of new biomarkers, and constitutes the first in vivo proof of principle of cobalamin treatment in mut-type MMAuria

Propofol (Diprivan®) and Intralipid® Exacerbate Insulin Resistance in Type-2 Diabetic Hearts by Impairing GLUT4 Trafficking

BACKGROUND The IV anesthetic, propofol, when administered as fat emulsion-based formulation (Diprivan) promotes insulin resistance, but the direct effects of propofol and its solvent, Intralipid, on cardiac insulin resistance are unknown. METHODS Hearts of healthy and type-2 diabetic rats (generated by fructose feeding) were aerobically perfused for 60 minutes with 10 μM propofol in the formulation of Diprivan or an equivalent concentration of its solvent Intralipid (25 μM) ± insulin (100 mU•L). Glucose uptake, glycolysis, and glycogen metabolism were measured using [H]glucose. Activation of Akt, GSK3β, AMPK, ERK1/2, p38MAPK, S6K1, JNK, protein kinase Cθ (PKCθ), and protein kinase CCβII (PKCβII) was determined using immunoblotting. GLUT4 trafficking and phosphorylations of insulin receptor substrate-1 (IRS-1) at Ser307(h312), Ser1100(h1101), and Tyr608(hTyr612) were measured. Mass spectrometry was used to determine acylcarnitines, phospholipids, and sphingolipids. RESULTS Diprivan and Intralipid reduced insulin-induced glucose uptake and redirected glucose to glycogen stores in diabetic hearts. Reduced glucose uptake was accompanied by lower GLUT4 trafficking to the sarcolemma. Diprivan and Intralipid inactivated GSK3β but activated AMPK and ERK1/2 in diabetic hearts. Only Diprivan increased phosphorylation of Akt(Ser473/Thr308) and translocated PKCθ and PKCβII to the sarcolemma in healthy hearts, whereas it activated S6K1 and p38MAPK and translocated PKCβII in diabetic hearts. Furthermore, only Diprivan phosphorylated IRS-1 at Ser1100(h1101) in healthy and diabetic hearts. JNK expression, phosphorylation of Ser307(h312) of IRS-1, and PKCθ expression and translocation were increased, whereas GLUT4 expression was reduced in insulin-treated diabetic hearts. Phosphatidylglycerol, phosphatidylethanolamine, and C18-sphingolipids accumulated in Diprivan-perfused and Intralipid-perfused diabetic hearts. CONCLUSIONS Propofol and Intralipid promote insulin resistance predominantly in type-2 diabetic hearts