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Vitamin D je lipofilni steroidni prohormon poznat po svojoj ulozi u apsorpciji kalcijuma i mineralizaciji kostiju. Poslednjih decenija veliki broj opservacionih studija ukazao je na povezanost izmeĊu nedostatka vitamina D i razliĉitih bolesti, što je podstaklo istraţivanja o potencijalnim efektima ovog molekula i u drugim organskim sistemima osim skeletnog. Pokazano je da vitamin D moţe uticati na sistemsku glukoznu homeostazu, kao i na insulinsku senzitivnost u skeletnim mišićima, jetri i adipoznom tkivu. Efekti vitamina D u srcu, kao vaţnom mestu delovanja insulina, su u jako maloj meri izuĉavani, naroĉito u fiziološkim uslovima, zbog ĉega je cilj ove doktorske disertacije bio da se analiziraju efekti vitamina D na metaboliĉke procese regulisane insulinom u srcu zdravih pacova. Muţjaci pacova Wistar soja su tretirani holekalciferolom tokom šest nedelja. U cilju izuĉavanja efekata tretmana vitaminom D na insulinom regulisanu fosforilaciju i unutarćelijsku lokalizaciju ispitivanih molekula, polovina ţivotinja je primila injekciju insulina 40 min pre ţrtvovanja. Primenom molekularno-bioloških metoda analizirana je genska ili proteinska ekspresija molekula ukljuĉenih u insulinski signalni put, transport i metabolizam glukoze i masnih kiselina, kao i molekula ukljuĉenih u transport kalcijuma u srcu. Tretman vitaminom D nije uticao na parametre sistemske glukozne homeostaze (glukoza, AUC, IPGTT) i luĉenje insulina dok je u okviru parametara lipidnog profila znaĉajno smanjio koncentraciju neesterifikovanih masnih kiselina. U srcu ţivotinja tretiranih vitaminom D uoĉena je znaĉajna redistribucija receptora za vitamin D iz citosola u jedro što ukazuje na direktan efekat vitamina D u srcu. Tretman vitaminom D je ostvario efekat na nivou kljuĉnih insulinomindukovanih fosforilacija molekula u metaboliĉkom putu PI3K/Akt (pIRS-1 Ser307, pAkt Thr308), dok na nivou efektornih molekula MAPK signalnog puta (ERK1/2) promene nisu uoĉene. Nivo glukoznih transportera (GLUT1, GLUT4) i t, Vitamin D is a lipophilic steroid prohormone known for its role in calcium absorption and bone mineralization. In recent decades, numerous observational studies have indicated the connection between vitamin D deficiency and various diseases, leading researchers to investigate the potential extraskeletal effects of this molecule. It has been shown that vitamin D can affect systemic glucose homeostasis as well as insulin sensitivity in skeletal muscle, liver and adipose tissue. The effects of vitamin D on the heart, as an important site of insulin action, have been studied only to a very limited extent, especially under physiological conditions, and therefore the aim of this dissertation was to analyze the effects of vitamin D on insulin-regulated metabolic processes in the heart of healthy rats. Male Wistar rats were treated with cholecalciferol for six weeks. To investigate the effects of vitamin D treatment on insulin-regulated phosphorylation and intracellular localization of the analyzed moleculles, half of the animals received an insulin injection 40 minutes before killing. Molecular biological methods, were used to analyze gene or protein expression of molecules involved in insulin signaling, glucose and fatty acids transport and metabolism, and calcium transport in the heart. Vitamin D treatment did not affect systemic glucose homeostasis parameters (glucose, AUC, IPGTT) and insulin secretion, whereas it significantly decreased the concentration of nonesterified fatty acids in the lipid profile. In the heart of vitamin D-treated animals, a significant redistribution of the vitamin D receptor from the cytosol to the nucleus was observed, indicating a direct effect of vitamin D in the heart. Vitamin D treatment affected the level of insulin-induced phosphorylation of key molecules of the PI3K/Akt pathway (pIRS-1 Ser307, pAkt Thr308), whereas no changes were observed at the level of the effector molecules of the MAPK signaling pathway (ERK1/2). The levels of gluc

The health-promoting benefits of walnut consumption are substantially ascribed to its fatty acid (FA) profile, which is rich in polyunsaturated FA with an exceptionally high n-3 to n-6 ratio. There are also phytonutrients in walnuts that are linked to health welfare. This review article integrates all studies on the effects of walnuts on the cardiovascular system performed on experimental animals, and thus is a source of data on the mechanisms underlying the observed effects. These studies, which are very diverse in experimental design, indicate that a diet enriched with walnuts or treating animals with walnut extract or chemical constituents of walnuts, has many favorable effects on heart and vascular system function. The cardiovascular effect of walnuts depends on the metabolic status of the organism. Among the cardiovascular effects of walnuts is that they improve the FA profile in the circulation and heart in favor of n-3 polyunsaturated FAs. In addition, a favorable effect on triglyceride and cholesterol status, which reduces cardiovascular disease risk, is observed. Intake of walnuts promotes FA catabolism and has anti-inflammatory, antioxidant, and antiarrhythmic effects. Walnuts also have a beneficial effect on vascular tone, accompanied by a decrease in blood pressure and reduced risk for atherosclerosis. In conclusion, studies on experimental animals encourage the consumption of walnuts as a simple, convenient approach to improve cardiovascular health.

The transport of cations in the cardiomyocytes, crucial for the functioning of the heart, can be affected by walnut diet due to the high content of polyunsaturated fatty acids. Healthy and metabolically compromised rats (drinking 10% fructose solution) were subjected to a diet supplemented with 2.4 g of walnuts for 6 weeks to investigate the effect on proteins involved in cation transport in the heart cells. Fructose increased the level of the a1 subunit of Na+/K+-ATPase and the phosphorylation of extracellular signal-regulated kinase 1/2 in the heart of control and walnut-eating rats, while elevated L-type calcium channel a (LTCCa), sodium–calcium exchanger 1 (NCX1), and Maxi Ka level were observed only in rats that did not consume walnuts. However, walnuts significantly increased the cardiac content of LTCC, NCX1, and Maxi Ka, as well as Kir6.1 and SUR2B subunits of KATP channel, but only in fructose-naive rats. In animals that drank fructose, a significant increasing effect of walnuts was observed only in Akt kinase phosphorylation, which may be a part of the antiarrhythmic mechanism of decreasing cation currents in cardiomyocytes. The walnut diet-induced increase in LTCC and NCX1 expression in healthy rats may indicate intense cardiac calcium turnover, whereas the effect on Kir6.1 and SUR2B subunits suggests stimulation of KATP channel transport in the cardiac vasculature. The effects of walnuts on the cation-handling proteins in the heart, mostly limited to healthy animals, suggest the possible use of a walnut-supplemented diet in the prevention rather than the treatment of cardiological channelopathies.

The study aimed to characterize the consequences of a 15-week intake of 10% fructose on the kidney, with the focus on oxidative stress markers and properties of the Na,K-ATPase enzyme. Various antioxidants naturally occurring in common food were demonstrated to be protective against fructose-induced deterioration of kidneys. Therefore, we also aimed to observe the effect of 6-week quercetin administration (20 mg/kg/day) that was initiated following the 9-week period of higher fructose intake, by determining the concentration of sodium, potassium, creatinine, urea, and glucose in blood plasma and oxidative status directly in the renal tissue. Kinetic studies of renal Na,K-ATPase were utilized for a deeper insight into the molecular principles of expected changes in this enzyme activity under conditions of presumed fructose-induced renal injury. Fructose intake led to increase in body weight gain, plasma glucose and sodium levels, and deterioration of kidney properties, although some compensatory mechanisms were observable. Quercetin administration improved glycemic control in rats exposed to fructose overload. However, an increase in plasma creatinine, a decrease in GSH/GSSG ratio in renal tissue homogenate, and a controversial effect on renal Na,K-ATPase enzyme suggest that quercetin treatment may not be beneficial in the condition of pre-existing renal pathology.

Consumption of walnuts is beneficial for cardiovascular health. To study walnut effects on proteins involved in vascular tone regulation, control and fructose-fed rats were subjected to walnut diet for 6 weeks. In contrast with increased energy intake and body mass gain, aortic protein level of L-type calcium channel alpha subunit was decreased and the level of SUR2B subunit of ATP-sensitive K + channel was increased in healthy rats subjected to walnuts, together with improved Akt phosphorylation. Upon the walnut diet in rats subjected to fructose overload, the rise in energy intake and body mass gain, was followed by an increase in blood insulin. Although SUR2B level was elevated, the level of sodium-calcium exchanger NCX1 and inducible nitric oxide synthase were reduced and increased, respectively. In summary, walnut consumption was accompanied with moderate beneficial vascular effect in healthy rats, while an effect of walnut in rats with metabolic disturbances was rather controversial.

Fruktoza je prirodni šećer, ĉiji se unos poslednjih decenija dramatiĉno povećao, najvećim delom zbog povećane upotrebe kukuruznog sirupa sa visokim sadrţajem fruktoze. Povećan unos fruktoze vodi ka razvoju metaboliĉkog sindroma kod ljudi i eksperimentalnih ţivotinja. Pored promena u jetri, adipoznom tkivu i skeletnim mišićima, ishrana bogata fruktozom je praćena i razvojem insulinske rezistencije u srcu. Poznato je da insulin ostvaruje svoje efekte na ćelije srca i da u stanju insulinske rezistencije u srcu dolazi do poremećaja u signalnom putu Akt/eNOS i balansu korišćenja energetskih supstrata. Posledice povećanog unosa fruktoze su polno zavisne, pri ĉemu je protektivni efekat pripisan estrogenim hormonima. Fiziološke koncentracije estrogena poboljšavaju osetljivost na insulin i deluju kardioprotektivno. TakoĊe, estradiol utiĉe na specifiĉno delovanje insulina u srcu. Cilj ove studije bio je analiza efekta estradiola na procese u srcu regulisane insulinom u stanju insulinske rezistencije izazvane ishranom bogatom fruktozom. Ţenke pacova su podvrgnute standardnoj ishrani ili ishrani obogaćenoj 10% rastvorom fruktoze tokom 9 nedelja i ovarijektomisane 2 nedelje pre ţrtvovanja, pri ĉemu je polovina ţivotinja na fruktoznoj ishrani dan nakon ovarijektomije podvrgnuta tretmanu estradiolom. U cilju izuĉavanja efekata ishrane bogate fruktozom i estradiola na insulinom regulisanu fosforilaciju i unutarćelijsku lokalizaciju ispitivanih molekula, polovina ţivotinja je tretirana insulinom 40 minuta pre ţrtvovanja. Analizirani su molekuli iz insulinskog signalnog puta (IRS-1, Akt i ERK1/2), kao i efektorni molekuli ĉiju funkciju reguliše insulin, kao što su eNOS, Na+/K+-ATP-aza i molekuli ukljuĉeni u transport i metabolizam energetskih supstrata u srcu (GLUT1, GLUT4, CD36, lipin 1 i CPTI) i lipidni profil srca. Ispitivana je ekspresija ovih molekula na nivou proteina, kao i njihova fosforilacija ili unutarćelijska lokalizacija. Ishrana bogata fruktozom je povećala unos teĉnost

The renin-angiotensin system has been implicated in the development of metabolic syndrome and appears to be a key in the local tissue control of normal cardiac functions. Physiological concentrations of estrogens have been shown to be cardioprotective, especially against the damaging effects of fructose-rich diet. The aim of the study was to investigate the expression of the renin-angiotensin system molecules with potentially deleterious effect on the heart (angiotensin-converting enzyme and angiotensin II type 1 receptor) and those with potentially protective effects, (angiotensin-converting enzyme 2 and angiotensin II type 2 receptor), in ovariectomized fructose fed female rats with 17-estradiol replacement. Real-time PCR and Western blot analysis were used for quantification of gene and protein expression in the heart. Fructose diet increased the expression of angiotensin-converting enzyme and angiotensin II type 1 receptor and decreased the expression of angiotensin-converting enzyme 2 and angiotensin II type 2 receptor. On the other hand, estradiol replacement seems to undo fructose diet effects on cardiac renin-angiotensin system. Downregulation of angiotensin-converting enzyme and angiotensin II type 1 receptor, and reversion of expression of both potentially protective molecules, angiotensin-converting enzyme 2 and angiotensin II type 2 receptor, to the control level in cardiac tissue took place. Obtained results suggest that estradiol may reverse the harmful effect of fructose-rich diet on the expression of renin-angiotensin system molecules. These findings may also be important in further research of phenotypes like insulin resistance, metabolic syndrome, and following cardiovascular pathology in females.