The intestine of intrauterine growth retarded (IUGR) neonates showed different morphology compared to neonates born with normal body weight (NBW). The aim of the present study was to investigate the ultrastructure and proteomic profile of the gut epithelium in IUGR pig neonates with special attention to the digestive and absorptive function. Intestine tissue samples were investigated in 7-day-old IUGR and NBW littermate piglets using histometry, immunofluorescence, scanning electron microscopy (SEM), and mass spectrometry analysis. IUGR piglets have shown reduced mucosa and muscularis thickness and an enhanced number of foetal type enterocytes (FTE). SEM studies have shown the lack of the characteristic large-size vacuole in IUGR's enterocytes. Delayed removal of FTE in IUGR neonates was probably due to the inhibited apoptosis in the apical part of villi and increased apoptosis and reduced mitosis in the crypt region. In the expression of proteins in the intestinal mucosa such as hexokinase I, histones, and prelamin A/C, carbamoyl phosphate was reduced in IUGR neonates. Finally, IUGR intestines showed higher expression of HSPA9 and HSPA5 as apoptosis markers. The data indicate modifications of gut mucosa in IUGRs that may result in slower gut mucosa maturation and reduced utilisation of nutrient as compared to NBW pig neonates.
Genome-wide association studies in the FTO gene have identified SNPs correlating with obesity and type 2 diabetes. In mice, lack of Fto function leads to intrauterine growth retardation and lean phenotype, whereas in human it is lethal. The aim of this study in a pig model was to determine the localization of the FTO protein in different tissues and cell compartments, in order to investigate potential targets of FTO action. To better understand physiological role of FTO protein, its expression was studied in pigs of different age, metabolic status and nutrition, using both microscopic methods and Western blot analysis. For the first time, FTO protein was found in vivo in the cytoplasm, of not all, but specific tissues and cells e.g. in the pancreatic β-cells. Abundant FTO protein expression was found in the cerebellum, salivary gland and kidney of adult pigs. No FTO protein expression was detected in blood, saliva, and bile, excluding its role in cell-to-cell communication. In the pancreas, FTO protein expression was positively associated with energy intake, whereas in the muscles it was strictly agerelated. In IUGR piglets, FTO protein expression was much higher in the cerebellum and kidneys, as compared to normal birth body weight littermates. In conclusion, our data suggest that FTO protein may play a number of distinct, yet unknown intracellular functions due to its localization. Moreover, it may play a role in animal growth/development and metabolic state, although additional studies are necessary to clarify the detailed mechanism(s) of action. Genome-wide association studies (GWAS) have shown that single nucleotide polymorphisms (SNPs) in intron 1 of the FTO (Fat mass and obesity associated) gene are strongly correlated with an increased risk of obesity in humans 1-4. In the human FTO gene, the mutation (alteration p. Arg316 Gln) that inhibits catalytic activity of the protein, results in an autosomal recessive lethal syndrome 5. In Fto knockout mice, body weight and fat mass decrease 6 , while in animals overexpressing FTO they increase 7. Evidence from genetic epidemiology studies, life-course modeling, and diet-induced fetal programming data suggests that the FTO gene plays an important role in these complex biological interactions. It may provide the missing link in the developmental regulation of energy metabolism. The FTO variants associated with intrauterine growth retardation (IUGR) and, in consequence, low birth weight, confer a predisposition to obesity later in life. This finding favors the hypothesis of the existence of a common genetic denominator that predisposes to low birth weight and obesity in adults 8-10. Specifically, Fto deletion caused delayed growth, decreased white body fat, increased energy metabolism, and systemic sympathetic activation 6. For example, in wild-type mice, fasting reduced Fto mRNA levels and the number of Fto-immunoreactive cells in the hypothalamus. Interestingly, glucose treatment reversed this effect 11. However, another group of researchers showed that palatable ...
Low molecular weight natural mediators, 2'-5'-linked oligoadenylates, play an important role in interferon-based antiviral mechanism; participate in growth, apoptosis and other important cellular processes. Taking into account their concentration within living cells, the 2'-5'A 3 oligoadenylates may act as additional biologically active substrates, capable of regulating the S100A1 protein functioning in vivo. Aim. Find the evidence for the interaction of human apo-S100A1 with 2'-5'-linked oligoadenylates. Methods. Using the circular dichroism (CD) and heteronuclear NMR spectroscopy. Results. The obtained results demonstrated the occurrence of the secondary structure changes in human S100A1 protein upon the interaction with 2'-5'-linked oligoadenylates as well as indicated specific residues involved in this process. Conclusions. Our study points to the 2'-5'-linked oligoadenylates as possible additional elements of the complex system of fine regulation of the Ca 2+ -signal transduction pathway in human cells.
FTO is an N6-methyladenosine demethylase removing methyl groups from nucleic acids. Several studies indicate the creation of FTO complexes with other proteins. Here, we looked for regulatory proteins recognizing parts of the FTO dioxygenase region. In the Calmodulin (CaM) Target Database, we found the FTO C-domain potentially binding CaM, and we proved this finding experimentally. The interaction was Ca2+-dependent but independent on FTO phosphorylation. We found that FTO–CaM interaction essentially influences calcium-binding loops in CaM, indicating the presence of two peptide populations—exchanging as CaM alone and differently, suggesting that only one part of CaM interacts with FTO, and the other one reminds free. The modeling of FTO–CaM interaction showed its stable structure when the half of the CaM molecule saturated with Ca2+ interacts with the FTO C-domain, whereas the other part is disconnected. The presented data indicate calmodulin as a new FTO interactor and support engagement of the FTO protein in calcium signaling pathways.
На сьогодні відомо, що олігоаденілати відіграють ключову роль у так званому олігоаденілатному шляху активації інтерферону, механізм якого полягає в активації останнім ферменту 2′-5′-олігоаденілатсинтетази. Фермент, у свою чергу, використовує внутрішньоклітинний пул АТФ для синтезу особливого класу сполук -2′-5′-олігоА n , де n = 2÷6, серед яких кількісно переважають тричленні сполуки. У подальшому олігоА n активують латентну РНКазу L, що здатна гідролізувати вірусні та матричні РНК [1].Крім того, клітинний пул 2′-5′-олігоА n також містить і дефосфорильовані олігоаденілати, які утворюються в результаті ензиматичного відщеплення фосфатних груп. Біологічна роль дефосфорильованих олігоА n на сьогодні залишається незрозумілою.Раніше було виявлено, що природний 2′-5′-А 3 та його епоксимодифікований аналог 2′-5′-А 3 -epo здатні впливати на процес скорочення препаратів судин гладеньких м'язів in vivo [2]. Таку активність можна пояснити декількома шляхами, одним з яких є можлива взаємодія олігоаденілатів з білками, що беруть участь у м'язовому скороченні, зокрема кальмодуліну та S100A1, і, як наслідок, модуляція їх активності певним чином. І справді, можливість утворення комплексу 2′-5′-А 3 -CaM in vitro вже було показано раніше [3]. Виявилося,
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