Prenatal Glucocorticoids: Short-Term Benefits and Long-Term Risks

Glucocorticoids are steroid hormones synthesized in the adrenal gland cortex, and most of their physiological effects are mediated by the glucocorticoid receptor (GR), that acts as a ligand-dependent transcription factor. Coordinate changes in metabolism under glucocorticoid influence provide energy that is instantly and selectively available to vital organs, an enables them to deal with immediate environmental demands, at the expense of anabolic pathways, such as bone formation, reproduction, immunological responses and other, that are being blunted or delayed, under glucocorticoid influence [1-3]. During fetal development the synthesis of adrenal glucocorticoids precedes the establishment of a definitive structure of the gland. In rats, secretion of the main glucocorticoid – corticosterone starts as early as on day 13 of development [4] (term=22 days, short gestation period), while in humans secretion of the main glucocorticoid – cortisol starts in the 8th week of pregnancy (term=40 weeks, long gestation period) [5]. Glucocorticoid receptor mRNA is present in the tissue derivatives of all three germ layers from fetal day 13 onwards, and increases gradually during rat fetal development [6]. Human fetal tissues express GR at the gestational age of 6 weeks, meaning that the machinery for hormone action is prepared at the early stages of development [5]. These facts suggest that endogenous glucocorticoids produced by the fetal adrenal glands have a crucial role in fetal growth and the development of individual fetal tissues [7]. In response to the prepartum rise in glucocorticoids a wide variety of changes known as “preparation for birth” occurs, meaning that the maturational changes in many fetal tissues, essential for neonatal survival, are intensified during the last third of gestation. Namely, circulating glucocorticoids induce fetal lung maturation and surfactant production, trigger a variety of physiological effects on brain cell differentiation and synaptogenesis, stimulate the production of hepatic gluconeogenic enzymes, affect pancreatic -cell development and insulin content, influence renal development and affect the maturation of the immune system [8-10]. Metabolic, cardiovascular and immune adaptations under glucocorticoid influence are fundamental to successfully overcoming birth-related stress and postnatal adaptation of the newborn to environmental challenges [11, 12]. Environmental conditions influence the prevailing nutritional and endocrine status in mothers and fetuses. Numerous animal and human studies have shown that adverse environmental conditions during pregnancy, such as maternal undernutrition [13, 14], stress [15, 16], illness, placental insufficiency [17, 18], as well as prenatal glucocorticoid exposure [19, 20] affect fetal development and postnatal outcome. Changes in the maternal hypothalamic-pituitary-adrenal (HPA) activity, transplacental diffusion of nutrients, hormones and growth factor supply, potently affect the fetal HPA axis influencing glucocorticoid output as well as other developing systems [21, 22]. Gestational age, at which an insult occurs, its nature and intensity, determines the specific tissue or organ which will be affected by the insult. Glucocorticoids are the key mediators between maternal environment and the fetus, and as such are involved in adaptations of the fetus to predicted postnatal environment. Even transient changes in glucocorticoid levels could have longlasting consequences. The outcome might be growth retardation and change in the developmental trajectory, in the direction that best suited to the expected environment [23, 24]. This phenomenon is known as programming. The adaptations caused by suboptimal intrauterine conditions are appropriate if the predicted and actual postnatal environments match, and lead to survival to reproduce in a deprived environment [25, 26]. If there is a mismatch between the environment predicted and the actual environment experienced postnatally, adaptations are inappropriate and result in the development of disease like hypertension, ischemic heart disease, glucose intolerance, insulin resistance and type 2 diabetes [27-29]. In this chapter the latest findings, with clear statements from the literature, as well as own results regarding the endocrine mechanisms of intrauterine programming mediated by glucocorticoids will be analyzed. The causal relationship between a prenatally programmed endocrine axes and their postnatal functioning that affect growth, stress response, metabolism and reproduction will be discussed. In order to better understand mechanisms of fetal glucocorticoid programming of endocrine axes, special attention will be paid to key points of their development

An overview of encapsulation technologies for food applications

Encapsulation is a process to entrap active agents within a carrier material and it is a useful tool to improve delivery of bioactive molecules and living cells into foods. Materials used for design of protective shell of encapsulates must be food-grade, biodegradable and able to form a barrier between the internal phase and its surroundings. Among all materials, the most widely used for encapsulation in food applications are polysaccharides. Proteins and lipids are also appropriate for encapsulation. Spray drying is the most extensively applied encapsulation technique in the food industry because it is flexible, continuous, but more important an economical operation. Most of encapsulates are spray-dried ones, rest of them are prepared by spray-chilling, freeze-drying, melt extrusion and melt injection. Molecular inclusion in cyclodextrins and liposomal vesicles are more expensive technologies, and therefore, less exploited. There are number of reasons why to employ an encapsulation technology and this paper reviews some of them. For example, this technology may provide barriers between sensitive bioactive materials and the environment, and thus, to allow taste and aroma differentiation, mask bad tasting or smelling, stabilize food ingredients or increase their bioavailability. One of the most important reasons for encapsulation of active ingredients is to provide improved stability in final products and during processing. Another benefit of encapsulation is less evaporation and degradation of volatile actives, such as aroma. Furthermore, encapsulation is used to mask unpleasant feelings during eating, such as bitter taste and astringency of polyphenols. Also, another goal of employing encapsulation is to prevent reaction with other components in food products such as oxygen or water. In addition to the above, encapsulation may be used to immobilize cells or enzymes in food processing applications, such as fermentation process and metabolite production processes. There is an increasing demand to find suitable solutions that provide high productivity and, at the same time, satisfy an adequate quality of the final food products. This paper aims to provide a short overview of commonly used processes to encapsulate food actives

Development of pituitary ACTH and GH cells in near term rat fetuses

This study describes the development of ACTH and GH cells in 19- and 21-day-old rat fetuses using immunohistochemistry and morphometric measurements. Between days 19 and 21 of pregnancy, the total volume of fetal ACTH cells was unchanged, while their volume density and number per unit of area decreased significantly. ACTH-like immunopositivity in the pars intermedia increased during the examined period. The cell volume, volume density and number of GH cells per unit of area all markedly increased in parallel with fetal development, i.e., from gestational days 19 to 21. GH-like immunopositivity is demonstrated in the pars intermedia of 21-day-old fetuses for the first time.Prezentovano istraživanje opisuje razvoj ACTH i GH ćelija hipofize fetusa pacova, neposredno pred rođenje korišćenjem imunohistohemije i morfometrijskih merenja. Od 19. do 21. dana gestacije volumen ACTH ćelija fetusa bio je nepromenjen, dok su volumenska gustina i broj ćelija po jedinici površine značajno smanjeni. Intenzitet ACTH imunopozitivnosti u pars intermedia povećavn je tokom ispitivanog perioda. Volumen GH ćelija, volumenska gustina i brojnost po jedinici površine značajno su povećani tokom završnog perioda fetalnog razvoja, tj. od 19. do 21. dana gestacije. GH imunopozitivnost prvi put je demonstrirana u ćelijama pars intermedia kod fetusa starih 21 dan.nul

Inhibitory effect of SRIH-14 on ACHT cells in neonatal female rats

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The effect of SRIH-14 or octreotide on the morphological characteristics of adrenal medulla using newcast

The effects of chronic treatments with either SRIH-14 or octreotide on the adrenal medulla of male Wistar rats were examined. Adult males received subcutaneous (s.c.) injections of 20 μg/100 g body weight of either SRIH-14 or octreotide twice a day for 28 consecutive days. The absolute weights and the absolute volumes of the adrenal glands significantly (p<0.05) decreased after either treatment. The adrenal medulla was analyzed by histological and stereological methods using newCAST. Compared to the control, the relative volumes of the vascular tissues significantly (p < 0.05) decreased - by 40% and 25% in the SRIH-14- and octreotide-treated groups, respectively. In the SRIH-14- and octreotide-treated groups the relative volumes of chromaffin and interstitial tissue increased by 6% and 5% (p < 0.05), respectively. These findings show that both SRIH-14 and octreotide affect the morphological characteristics of the adrenal zona medullaris in a similar manner.Projekat ministarstva br. 143007

Adverse effect of dexamethasone on development of the fetal rat ovary.

Dexamethasone (Dx) is often used in obstetric practice to promote fetal lung maturation and to prevent respiratory distress syndrome when the risk of preterm delivery persists. This therapy enables survival of the newborn, but also is associated with deleterious effects on the offspring, such as reproductive disorders. The aim of this study was to determine specifically whether prenatal exposure to Dx disturbs the physiological balance between proliferation and apoptosis of germinative cells (GC) in the ovary of 19 and 21 day old fetuses and thus induces developmental programing of the female reproductive system. Pregnant Wistar rats (n = 10/group), separated into control (vehicle) and Dx-treated (0.5 mg/kg body mass) groups, received injections on gestational days 16, 17 and 18. Exposure to Dx lowered the volume of the fetal ovary by 30% (p<0.05) in 21 day old fetuses, as well as the total number of GC in the ovary by 21% (p<0.05). When compared to the controls, in Dx-exposed fetuses the total number of PCNA positive GC was 27% lower at 19 days and 71% lower at 21 day old (p<0.05), while total numbers of caspase-3 positive GC were 2.3 fold and 34% higher respectively, (p<0.05). Our results demonstrate that prenatal exposure to Dx diminished proliferation but increased the rate of germinative cell apoptosis, with consequently reduced total germinative cell number and ovary volume. Impairment of fetal oogenesis and fewer GC in the fetal ovary compromise the oogonial stock and thus may constitute a risk for female fertility. This article is protected by copyright. All rights reserved.This is the peer reviewed version of the following article: Ristić N, Nestorović N, Manojlović-Stojanoski M, Trifunović S, Ajdžanović V, Filipović B, Pendovski L, Milošević V. Adverse effect of dexamethasone on development of the fetal rat ovary. Fundam Clin Pharmacol. 2018, which has been published in final form at [http://doi.org/10.1111/fcp.12415]. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions

Histomorphometric evaluation of bone regeneration using autogenous bone and beta-tricalcium phosphate in diabetic rabbits

Background/Aim. The mechanism of impaired bone healing in diabetes mellitus includes different tissue and cellular level activities due to micro- and macrovascular changes. As a chronic metabolic disease with vascular complications, diabetes affects a process of bone regeneration as well. The therapeutic approach in bone regeneration is based on the use of osteoinductive autogenous grafts as well as osteoconductive synthetic material, like a β-tricalcium phosphate. The aim of the study was to determine the quality and quantity of new bone formation after the use of autogenous bone and β-tricalcium phosphate in the model of calvarial critical-sized defect in rabbits with induced diabetes mellitus type I. Methods. The study included eight 4-month-old Chincilla rabbits with alloxan-induced diabetes mellitus type I. In all animals, there were surgically created two calvarial bilateral defects (diameter 12 mm), which were grafted with autogenous bone and β-tricalcium phosphate (n = 4) or served as unfilled controls (n = 4). After 4 weeks of healing, animals were sacrificed and calvarial bone blocks were taken for histologic and histomorphometric analysis. Beside descriptive histologic evaluation, the percentage of new bone formation, connective tissue and residual graft were calculated. All parameters were statistically evaluated by Friedman Test and post hock Wilcoxon Singed Ranks Test with a significance of p < 0.05. Results. Histology revealed active new bone formation peripherally with centrally located connective tissue, newly formed woven bone and well incorporated residual grafts in all treated defects. Control samples showed no bone bridging of defects. There was a significantly more new bone in autogeonous graft (53%) compared with β-tricalcium phosphate (30%), (p < 0.030) and control (7%), (p < 0.000) groups. A significant difference was also recorded between β-tricalcium phosphate and control groups (p < 0.008). Conclusion. In the present study on the rabbit grafting model with induced diabetes mellitus type I, the effective bone regeneration of critical bone defects was obtained using autogenous bone graft.Vojnosanitetski pregled (2016), 73(12): 1132-113

The effect of ovariectomy on thyroid c cells of adult rats

The structure and function of C cells of adult female rats after ovariectomy (Ovx) were investigated. Intact control and Ovx rats were i.p. treated with sterile olive oil for 4 weeks. Peroxidase-antiperoxidase (PAP) immunohistochemical procedure was applied to localize calcitonin (CT) in thyroid C cells while its serum content was determined by RIA method. Morphometric analyses of the C cells volume, that of their nuclei and relative volume density included stereological method with the multipurpose test system M42. Also, the average number of C cells number per mm2 was calculated. Ovx led to a significant increase in body weight (21%; p<0.005). At the same time the C cells of Ovx rats had a significantly decreased cell volume (13%; p<0.005) and their number per mm2 was increased by 59% (p<0.001) in comparison with the controls. Ovx resulted in reduction of serum CT level by 45% comparing to the corresponding controls. Based on these data it can be concluded that Ovx inhibits both the structure and function of the C cells.U ovom radu ispitivana je struktura i funkcija C ćelija adultnih ženki pacova posle ovarijektomije (Ovx). Intaktne kontrolne i Ovx životinje su tretirane i.p. sterilnim maslinovim uljem u trajanju od četiri nedelje. Za lokalizaciju kalcitonina (CT) u C ćelijama štitaste žlezde korišćena je imunohistohemijska metoda peroksidaze- antiperoksidaze (PAP). Nivo CT-a u serumu određen je RIA metodom. Morfometrijska ispitivanja volumena C ćelija, njihovih jedara i relativne volumenske gustine ćelija vršena su višenamenskim testnim sistemom M42. Takođe je izračunat broj C ćelija po mm2. Statistička obrada podataka vršena je Studentovim t-testom. Posle Ovx-a telesna masa životinja značajno je povećana za 21% (p<0.005). Volumen C ćelija Ovx pacova značajno je smanjen za 13% (p<0.005), njihov broj po mm2 povećan za 59% (p<0.001), a nivo CT-a u serumu smanjen za 45% u poređenju sa intaktnom kontrolom. Na osnovu dobijenih rezultata možemo zaključiti da Ovx deluje inhibitorno na strukturu i funkciju C ćelija štitaste žlezde kod pacova

Koncentracija trans- i cis-rezveratrola u vinima proizvedenim u Srbiji

Resveratrol, which occurs in two isomeric forms, trans and cis, is a phytoalexin with numerous pharmacological activities, such as anti-cancer, antiviral, neuroprotective and anti-aging. Red wine is the main source of the compound and an easy way of including resveratrol in the human diet. In this study, the most popular commercial Serbian wines (red, white and rose-type) were analyzed for their content of trans- and cis-resveratrol. The analysis was performed by HPLC with a UV detector. Prior to the injection, phenolic compounds were extracted onto a LiChrolut RP18 bonded silica cartridge. The concentration of trans-resveratrol ranged from 0.11 to 1.69 mg L-1 and cis-resveratrol from 0.12 to 1.49 mg L-1.Metodom tečne hromatografije (HPLC) ispitan je sadržaj slobodnog oblika trans- i cis-rezveratrola u osamnaest komercijalnih uzoraka (10 crvenih, 7 belih i 1 roze) srpskih vina. Svi uzorci su pre hromatografije ekstrahovani SPE tehnikom na LiChrolut RP18 koloni. trans-Rezveratrol je detektovan u 17 od 18 analiziranih uzoraka vina sa prosečnom koncentracijama od 0,78 mg l-1 za crvena vina i 0,23 mg l-1 za bela vina. Najviša koncentracija trans-rezveratrola je nađena u uzorku crvenog vina Cabernet Sauvignon berbe 2002 godine. cis-Rezveratrol je detektovan u 12 od 18 analiziranih uzoraka vina sa prosečnom koncentracijom 0,55 mg l-1 za crvena vina, dok je u belim vinima od analiziranih 7 uzoraka detektovan samo u 2 uzorka sa koncentracijama 0,12 i 0,49 mg l-1. Visok sadržaj cis-rezveratrola u nekim uzorcima je verovatno posledica izomerizacije trans- u cis-rezveratrol tokom procesa proizvodnje vina