The effects of estradiol on the regulation of sodium-potassium pump and heart morphology in normally fed and obese rat

Hormon estradiol, pored svojih efekata koje ostvaruje na reprodukciju i razviće, uključen je i u regulaciju metaboličkih procesa u različitim organima, uključujući i srce. Pored sistemskog efekta koje estradiol ostvaruje na kardiovaskularni sistem zapažen je, ali i nedovoljno razjašnjen, uticaj estradiola na srce i kardiomiocite. U literaturnim podacima koji se odnose na efekte estradiola na morfologiju srca uglavnom su izučavani efekti estradiola u patofiziološkim stanjima hipertenzije i traume, dok je uloga estradiola na morfologiju srca u patofiziološkim stanjima gojaznost i rezistencije na insulin (IR) još uvek nedovoljno izučena. Estradiol svoje efekte ostvaruje genomskim i negenomskim signalnim putevima posredstvom specifičnih receptora za estrogen (ER), pri čemu dolazi do aktivacije složene mreže međuzavisnih intracelularnih signalnih puteva uključujući i fosfatidilinozitol-3 kinazu (PI3K), protein kinazu B (Akt), kao i ekstracelularnim signalima regulisane kinaze 1 i 2 (ERK1/2). Natrijum-kalijum adenozin trifosfataza (Na+/K+-ATPaze) je membranski protein koji ima ulogu u održavanju elektrohemijskog gradijenta Na+ i K+ jona kroz ćelijsku membranu, a takođe ima i važnu ulogu u regulaciji tonusa glatkih mišića vaskulature, kao i regulaciji kontrakcija srca. Poremećaji u funkciji Na+/K+-ATPaze uočeni su u različitim patofiziološkim stanjima kao što su stanja hipertenzije, gojaznosti i IR. Signalni putevi koji su uključeni u estradiolom regulisanoj ekspresiji i aktivnosti Na+/K+-ATPaze uključuju i aktivaciju Akt i ERK1/2 kinaza. Stimulišući aktivnost Na+/K+-ATPaze, estradiol ostvaruje direktan uticaj na srce povećavajući kontraktilnost ćelija srca. Nedostatak podataka u literaturi o in vivo efektima estradiola na regulaciju Na+/K+-ATPaze i morfologiju srca, kao i mehanizmi kojima estradiol ostvaruje svoje efekte na ćelije srca u patofiziološkim stanjima (gojaznost i IR), ukazuju na značaj realizovanih istraživanja u okviru ove doktorske disertacije. U ovoj doktorskoj disertaciji izučavani su molekularni mehanizmi in vivo efekata estradiola na regulaciju Na+/K+-ATPaze i morfologiju srca, u koje su uključene Akt i ERK1/2 kinaze, kako u fiziološkim tako i u patofiziološkim uslovima kao što su stanja gojaznosti i IR. U eksperimentima su korišćeni adultni pacovi Wistar soja. Dve grupe pacova za ishranu su koristile standardnu laboratorijsku hranu za pacove (normalno uhranjeni pacovi), dok su druge dve grupe hranjene standardnom laboratorijskom hranom obogaćenom sa 42% masti (gojazni pacovi)...Hormone estradiol is also involved in the regulation of metabolic processes in various organs, including the heart. The systemic effects of estradiol on cardiovascular system, was observed, but the effect of estradiol on the heart still is not known in detail. The effects of estradiol on the morphology of the heart are mainly studied the effects of estradiol in pathophysiological conditions of hypertension and trauma, whereas the role of estradiol on the morphology of the heart in pathophysiological conditions such are obesity and insulin resistance (IR) is still insufficiently explored. Estradiol exert its effect by nongenomic and genomic signaling pathways, through specific receptors for estrogen (ER), via the activation of a complex network of dependent intracellular signaling pathways including phosphatidylinositol 3 - kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinases 1 and 2 (ERK1/2). Sodium-potassium adenosine triphosphatase (Na+/K+-ATPase ) is a membrane protein that plays a role in maintaining the electrochemical gradient of Na+ and K+ ions across the cell membrane, and also plays an important role in the regulation of muscle tone of smooth muscle vasculature , as well as in the regulation of heart contraction. Disturbances in the Na+/K+-ATPase function have been observed in various pathophysiological conditions such as hypertension, obesity and IR. Estradiol regulates Na+/K+-ATPase activity and expression via the activation of Akt and ERK1/2 signaling pathways. Stimulating the activity of the Na+/K+-ATPase, estradiol has direct effect on the heart by increasing the contractility of cardiac cells. The lack of literature data about in vivo effects of estradiol on the Na+/K+-ATPase regulation, the heart morphology, and the mechanisms by which estradiol achieves its effects on heart cells in pathophysiological conditions (obesity and IR) stresses the importance of the research within the framework of this doctoral dissertation. In this doctoral thesis, the molecular mechanisms of in vivo effects of estradiol on the regulation of Na+/K+-ATPase and the morphology of the heart, via Akt and ERK1/2 kinase, both in physiological and in pathophysiological conditions such as obesity and IR, were studied and for these experiments adult Wistar rats were used. Two groups of rats were fed with standard laboratory rats’ foods (normally fed), while the other two groups were used standard laboratory food enriched with 42% fat (obese rats)..

Concerning the Security Activities of the Peoples\u27 Liberation Councils during the Peoples\u27 Liberation War and Revolution

In the course of the Peoples\u27 Liberation War (NOR) and socialist revolution, the country was liberated and the Yugoslav bourgeois society transformed into a new socialist society. The government, which consisted of the army of occupation and counter-revolutionaries, was overthrown and a revolutionary government of the armed masses, in the form of the Peoples\u27 Liberation Councils (NOO) was put in its place. The NOO were responsible for every phase of government and thus developed an intelligence and counter-intelligence service. The Fascist invaders (Germans, Italians, Bulgarians and Hungarians) and the counter-revolutionary forces, having failed by military means to destroy the revolutionary forces and crush the armed uprising, took to the use of espionage and subversive means of combat. All organized revolutionary forces therefore made use of espionage and counter-espionage with the aim of resisting the enemy, preserving the purity of their ranks and protecting human life and property. In this the NOO played an important part. They secured order in the ranks and organized guards in the villages. They introduced registration and issued passes to travellers. They took active measures against enemy propaganda, limiting trade with enemy occupied towns, stopping the spread of rumours and false information and opposing smuggling. They instructed the population in matters of security, thus increasing watchfulness while they worked on the development of brotherhood and unity and showed practical concern for the people

A quality of life assessment and the correlation between generic and disease-specific questionnaires scores in outpatients with chronic liver disease-pilot study

Introduction. Chronic liver diseases (CLD) are an important cause of morbidity and mortality in general population. The aim of this study was to analyze potential differences between patients with CLD and healthy control group, and to estimate the severity of CLD by using simple questionnaires: general health questionnaire (GHQ-12) and chronic liver disease questionnaire (CLDQ). Methods. A cross-sectional pilot study was performed in Zemun Clinical Hospital during years 2014 and 2015. Sixty participants were divided into 4 groups (15 per group): chronic alcoholic hepatitis, other chronic hepatitis, liver cirrhosis, and healthy control group. Entire study population chose one of four offered answers of structured questionnaires GHQ-12 and CLDQ, based on which mean model of end-stage liver disease (MELD) and Child-Turcotte-Pugh (CTP) scores were calculated. Results. Mean GHQ12 and CLDQ scores were 10.5 and 5.21 +/- 1.11 respectively. Regarding certain CLDQ domain scores, a significant difference between alcoholic and non-alcoholic hepatitis groups in the worry domain was observed. Mean MELD score was 7.42 +/- 2.89 and did not differ between chronic hepatitis groups, while mean CTP score was 5.73 +/- 0.88. A statistically significant correlation was observed between GHQ12 and CLDQ scores (rho = -0.404, p LT 0.01), but not between subjective and objective scores. Conclusions. Mean GHQ12 and CLDQ scores pointed out to general psychological no-distress condition of the studied participants, as well as scarcely expressed CLD-specific complaints. Mean MELD and CTP scores indicated stable chronic liver diseases, with low three-month mortality rates in the cases of chronic hepatitis, as well as determination to Child A group in the case of liver cirrhosis

Antioxidant enzymes and vascular diseases

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a fundamental role in regulating endothelial function and vascular tone in the physiological conditions of a vascular system. However, oxidative stress has detrimental effects on human health, and numerous studies confirmed that high ROS/RNS production contributes to the initiation and progression of cardiovascular diseases. The antioxidant defense has an essential role in the homeostatic functioning of the vascular endothelial system. Endogenous antioxidative defense includes various molecules and enzymes such as superoxide dismutase, catalase, glutathione reductase, and glutathione peroxidase

The role of the liver in glucose and lipid metabolism in obesity

Jetra ima važnu ulogu u održavanju metaboličke homeostaze i predstavlja mesto kompleksne regulacije metabolizma supstrata (ugljenih hidrata, lipida i proteina) od strane insulina i drugih hormona. Proteklih decenija ističe se značaj metaboličkih funkcija jetre u brojnim patološkim stanjima. Mehanizmi kojima gojaznost dovodi do poremećaja metaboličkih procesa u jetri su danas predmet mnogobrojnih istraživanja. Metaboličke i hormonske promene koje su posledica prevashodno visceralne gojaznosti, dovode vremenom do nagomilavanja lipida u jetri. Povećana učestalost gojaznosti i razvoj metaboličkog sindroma doprinose pojavi patofizioloških promena u jetri i razvoju nealkoholne bolesti masne jetre (NAFLD), jednoj od najčešćih bolesti jetre u zapadnoevropskim zemljama. U ovom preglednom članku razmotrili smo najnovije literaturne podatke koji se odnose na ulogu jetre u metabolizmu glukoze i lipida u stanju gojaznosti.The liver plays a vital role in metabolic homeostasis and represents a major site for complex regulation of substrates (carbohydrates, lipids, and proteins) by insulin and other hormones. The significance of liver metabolic functions in many pathophysiological conditions is highlighted over the past decades. Mechanisms of obesity-induced metabolic disturbance in the liver are the topic of numerous research studies. Metabolic and hormonal changes which are caused primarily by visceral obesity lead to hepatic lipid accumulation. Increased prevalence of obesity and the development of metabolic syndrome contribute to pathophysiological changes in the liver and development of non-alcoholic fatty liver disease (NAFLD), one of the most common diseases in Western societies. In this review, we discussed most recent literature data related to the role of the liver in glucose and lipid metabolism in obesity

ارزیابی کیفیت آزمون های چهار گزینه ای دروس تئوری عمومي گروه اندودانتیکس دانشکده دندانپزشکی قزوین در طی سال های تحصیلی 1388 تا 1396

Svrha je ovoga rada bila ispitati citotoksični, proapoptotski, antimigratorni i pro-antioksidacijski učinak metanolnih, acetonskih i etil-acetatnih ekstrakata dvaju vrsta lišaja, i to: Pseudevernia furfuracea i Platismatia glauca na tumorske stanične linije debelog crijeva (HCT-116 i SW-480). Citotoksični efekti na tumorskim staničnim linijama debelog crijeva uspoređeni su s onima na staničnoj liniji normalnih humanih fibroblasta (MRC-5). Citotoksičnost je ispitana MTT testom, stanična migracija Transwell esejom, dok je apoptoza praćena fluorescentnom metodom pomoću akridin narančastog bojila i etidijevog bromida. Prooksidacijski/antioksidacijski učinak praćen je spektrofotometrijskim mjerenjem koncentracije redoks parametara. Ispitani ekstrakti imali su značajan citotoksični učinak na tumorske stanične linije, bez zapaženog utjecaja na normalnu staničnu liniju. Najjača citotoksičnost postignuta je nakon 72 h obrade staničnih linija ekstraktima vrste P. furfuracea (IC50= (21,2±1.3) µg/mL pri obradi HCT-116 stanica etil-acetatnim ekstraktom i IC50=(51.3±0.8) µg/mL pri obradi stanica SW-480 acetonskim ekstraktom). Ekstrakti P. furfuracea imali su značajan proapoptotski i prooksidacijski učinak, dok je metanolni ekstrakt te vrste imao najjači antimigratorni učinak na ispitane tumorske stanične linije. Svi ispitani ekstrakti vrste P. glauca imali su znatan citotoksični učinak na stanice HCT-116 nakon 72 h tretmana (IC50<40 μg/mL), dok su metanolni i acetonski ekstrakti imali citotoksični učinak na stanice SW-480 nakon 24 h, s izraženom proapoptotskom/nekrotskom aktivnošću. Svi navedeni efekti posljedica su induciranog oksidacijskog stresa u tretiranim stanicama. Može se zaključiti da ekstrakti lišaja bitno mijenjaju vijabilnost i migratorni potencijal ispitanih tumorskih staničnih linija karcinoma debelog crijeva. Dobiveni rezultati pokazuju da su stanice HCT-116 osetljivije na ispitane ekstrakte, pri čemu ekstrakti vrste P. furfuracea pokazuju bolji proapototski i antimigratorni učinak. Ispitane vrste lišaja mogu se smatrati izvorima antikancerogenih aktivnih tvari.The aim of this study is to investigate cytotoxic, proapoptotic, antimigratory and pro-antioxidant effects of methanol, acetone and ethyl acetate extracts of lichens Pseudevernia furfuracea and Platismatia glauca on colorectal cancer (HCT-116 and SW-480) cell lines. We compared the cytotoxic effects on colorectal cancer cells with the effects obtained from normal human fibroblast (MRC-5) cell line. Tetrazolium (MTT) test evaluated the cytotoxic effects, Transwell assay evaluated cell migration, acridine orange/ethidium bromide (AO/EB) fluorescent method followed the apoptosis, while prooxidant/antioxidant effects were determined spectrophotometrically through concentration of redox parameters. The tested extracts showed considerable cytotoxic effect on cancer cells with no observable cytotoxic effect on normal cells. Ethyl acetate and acetone extract of P. furfuracea induced the highest cytotoxicity (IC50=(21.2±1.3) μg/mL on HCT-116, and IC50=(51.3±0.8) μg/mL on SW-480 cells, respectively, after 72 h), with noteworthy apoptotic and prooxidant effects, and antimigratory potential of methanol extract. P. glauca extracts induced cytotoxic effects on HCT-116 cells after 72 h (IC50<40 μg/mL), while only methanol and acetone extracts had cytotoxic effects on SW-480 cells after 24 h, with proapoptotic/necrotic activity, as a consequence of induced oxidative stress. In conclusion, lichen extracts changed to a great extent cell viability and migratory potential of colorectal cancer cell lines. HCT-116 cells were more sensitive to treatments, P. furfuracea had better proapoptotic and antimigratory effects, and both investigated lichen species might be a source of substances with anticancer activity

Regulation of nitric oxide production in hypothyroidism

Hypothyroidism is a common endocrine disorder that predominantly occurs in females. It is associated with an increased risk of cardiovascular diseases (CVD), but the molecular mechanism is not known. Disturbance in lipid metabolism, the regulation of oxidative stress, and inflammation characterize the progression of subclinical hypothyroidism. The initiation and progression of endothelial dysfunction also exhibit these changes, which is the initial step in developing CVD. Animal and human studies highlight the critical role of nitric oxide (NO) as a reliable biomarker for cardiovascular risk in subclinical and clinical hypothyroidism. In this review, we summarize the recent literature findings associated with NO production by the thyroid hormones in both physiological and pathophysiological conditions. We also discuss the levothyroxine treatment effect on serum NO levels in hypothyroid patients. © 2020 The Author

The Na+/K+-ATPase: A potential therapeutic target in cardiometabolic diseases

Cardiometabolic diseases (CMD) are a direct consequence of modern living and contribute to the development of multisystem diseases such as cardiovascular diseases and diabetes mellitus (DM). CMD has reached epidemic proportions worldwide. A sodium pump (Na + /K + -ATPase) is found in most eukaryotic cells’ membrane and controls many essential cellular functions directly or indirectly. This ion transporter and its isoforms are important in the pathogenesis of some pathological processes, including CMD. The structure and function of Na + /K + -ATPase, its expression and distribution in tissues, and its interactions with known ligands such as cardiotonic steroids and other suspected endogenous regulators are discussed in this review. In addition, we reviewed recent literature data related to the involvement of Na + /K + -ATPase activity dysfunction in CMD, focusing on the Na + /K + -ATPase as a potential therapeutic target in CMD

Late Phase Cell-Cycle Proteins in Postmitotic Neurons: Relation to Alzheimer’s Disease?

Cell cycle re-entry has become a well established model of neuropathogenesis in Alzheimer’s disease (AD). We and others have demonstrated expression of early phase cell cycle-related proteins in the vulnerable neurons in AD. Evidence that this represents a bona fide mitotic event is verified by the observation that DNA replication does in fact occur in these cells. Notably, the relatively early occurrence of cell cycle events in AD suggests that a mitotic cell cycle related mechanism may play a pivotal role in the disease. Still, a number of features of the cell cycle re-entry phenotype have remained elusive to the role of ectopic protein expression in the process of neuronal cell death. Late phase cell cycle proteins regulate separation and segregation of chromosomes. The centromere region is crucial to this process. Until recently there has been no data on the role of proteins controlling the centromere region in postmitotic neurons. This new data suggests that cohesin complexes that mediate sister–chromatid cohesion in dividing cells may also contribute to gene regulation in postmitotic cells. Therefore, centromere-cohesin proteins may play a secondary role in the cell, i.e. one that is independent of their role in cohesion and chromosome segregation. Evidence demonstrating that instability of centromere-cohesion dynamics in the early phases of the cell cycle which coincide with re-entry alteration of cortical neurons enables the possibility to further elucidate initial processes leading to AD