<p>Дефинисани су експeримeнтaлни поступци за oдрeђивaњe губитака и стeпeнa искoришћeњa пoстрojeњa у зaвиснoсти oд рeлaтивнoг oптeрeћeњa кaбинe (кoшa) у експлоатационим условима, као и за oдрeђивaњe мeхaничких кaрaктeристикa чeличних ужaди.<br />Дата је мoгућнoст примeнe мeтoдa нумeричкe aнaлизe зa рeшaвaњe систeмa ПДЈ хипeрбoличнoг типa са константним параметрима и граничним условима што одговара случајевима осциловања кабине (коша) након заустављања (кочења) погонског мотора.<br />Развијени су aдeквaтни прoрaчунски мoдeли који омогућују комплексну динaмичку aнaлизу лифтoвa и извoзних пoстрojeњa у функцији прoмeнљиве крутoсти и граничних услова. Дефинисан је утицај променљиве крутости нa стaбилнoст крeтaњa, кроз прoмeну слободне дужине ужади.</p> / <p>Definisani su eksperimentalni postupci za određivanje gubitaka i stepena iskorišćenja postrojenja u zavisnosti od relativnog opterećenja kabine (koša) u eksploatacionim uslovima, kao i za određivanje mehaničkih karakteristika čeličnih užadi.<br />Data je mogućnost primene metoda numeričke analize za rešavanje sistema PDJ hiperboličnog tipa sa konstantnim parametrima i graničnim uslovima što odgovara slučajevima oscilovanja kabine (koša) nakon zaustavljanja (kočenja) pogonskog motora.<br />Razvijeni su adekvatni proračunski modeli koji omogućuju kompleksnu dinamičku analizu liftova i izvoznih postrojenja u funkciji promenljive krutosti i graničnih uslova. Definisan je uticaj promenljive krutosti na stabilnost kretanja, kroz promenu slobodne dužine užadi.</p> / <p>We have defined the experimental procedures for defining the dissipation and the utility factor of vertical transport machines depending on the relative loading of the cabin (cage) in exploiting conditions, as well as for the setting the mechanical charactristics of the steel ropes.<br />There is given the option of applying the numerical analyses methods for solving the PDE systems of the hyperbolic type with constant parameters and boundary conditions, which is suitable for the cases when there are oscillations of the cabin (cage) after stopping (braking) the driving motor.<br />The adequate calculation models have been developed and they enable a complex dynamic analyses of elevators and mine elevators in the function of variable stiffness and boundary conditions. We also defined the influence of the variable stiffness on the stability of movement, through a change in the ropes&rsquo; free length.</p>

<p>Bor je bilo koji četinar roda Pinus koji pripada porodici Pinaceae. U Republici Srbiji nalaze se prirodne i ve&scaron;tačke &scaron;ume crnog bora Pinus nigra Arnold. Kora bora se vekovima koristila u tradicionalnoj medicini, međutim tek u novije vreme su otkriveni i potvrđeni njeni pozitivni biolo&scaron;ki efekti u medicini. Najpoznatiji komercijalni preparat kore bora je piknogenol, standardizovani ekstrakt kore francuskog primorskog bora Pinus pinaster Aiton, koji raste duţ obale jugozapadne Francuske. Pozitivni efekti koje ispoljava piknogenol, kao &scaron;to su antioksidativno, hipoglikemijsko, hipolipidemijsko delovanje, zasnovani su na njegovom visokom sadržaju fenolnih jedinjenja. Danas, i pored saznanja da je kora bora bogata sekundarnim metabolitima ona najče&scaron;će zavr&scaron;ava kao nusproizvod drvne industrije. Ciljevi ovog rada bili su ispitivanje kvalitativnih i kvantitativnih karakteristika i biohemijskih aktivnosti ekstrakata kore crnog bora Pinus nigra sa Mokre gore i Tare, dobijenih različitim rastvaračima; upoređivanje glikemijskog i lipidnog delovanja ekstrakta kore bora Pinus nigra sa komercijalnim preparatom piknogenol; uticaj ekstrakta kore bora Pinus nigra i piknogenola na delovanje standardnih antidijabetika metformina i gliklazida; kao i uticaj na parametre oksidativnog stresa nakon izlaganja životinja toksičnoj dozi paracetamola. In vitro ispitivanja su uključivala analizu ekstrakata dobijenih različitim rastvaračima. Ukupni sadržaj fenola, tanina, flavonoida i proantocijanidna, kao i ispitivanje antioksidativne aktivnosti kroz pet različitih metoda, određivani su spektrofotometrijski. Vr&scaron;ena je analiza ekstrakata kore bora visokoefikasnom tečnom hromatografijom (HPLC). In vivo ispitivanje je rađeno na 156 albino laboratorijska pacova soja Wistar. Eksperimentalne ţivotinje su tokom 7 dana per os primale ekstrakt kore crnog bora poreklom sa Mokre gore 100 mg/kg, koji je pokazao najbolju aktivnost, piknogenol 50 mg/kg, metformin 100 mg/kg, gliklazid 10 mg/kg, kao i njihove kombinacije. Za ispitivanje uticaja primenjivanih supstanci na glikemiju ţivotinja kori&scaron;ćeni su test oralnog podno&scaron;enja glukoze i indukcija trajne hiperglikemije aloksanom. Od biohemijskih parametara u serumu je određivana koncentracija lipida, kao i parametric pokazatelji funkcije bubrega i jetre. Ex vivo ispitivanja uključivala su određivanje intenzitet lipidne peroksidacije i anktivnosti enzima antioksidativne za&scaron;tite u homogenatu jetre ispitivanih ţivotinja, nakon primene toksične doze paracetamola. HPLC analizom ekstrakata kore crnog bora utvrđeno je da ekstrakti poreklom sa Mokre gore i Tare u najvećoj meri sadrţe taksifolin, a zatim katehin, njegove derivate, kafenu kiselinu i epikatehin. PotvrĎen je visok antioksidativni kapacitet piknogenola, ali takođe i značajan antioksidativni kapacitet ekstrakata kore crnog bora, sa najboljim rezultatima kod ekstrakta poreklom sa Mokre gore. Sedmodnevni tretman ekstraktom kore bora 100 mg/kg, metforminom 100 mg/kg, gliklazidom 10 mg/kg i piknogenolom 50 mg/kg, kod ţivotinja sa aloksanski izazvanim dijabetesom, doveo je do sniženja glikemije u krvi. Uočeno je povećanje konentracije HDL holesterola i značajno sniženje serumskih triglicerida kod dijabetičnih i normoglikemičnih ţivotinja koje su primale piknogenol, ekstrakta kore bora, gliklazid i metformin u poređenju sa kontrolnom grupom ţivotinja. Zajednička primena ekstrakta kore bora i standardnih antidijabetika značajno je snizila vrednosti AST, ALP i direktni bilirubin u grupi dijabetičnih i normoglikemičnih ţivotinja u odnosu na kontrolnu grupu, čime se ukazuje na potencijalno hepatoprotektivno delovanje ekstrakta kore crnog bora. O&scaron;tećenje jetre izazvano toksičnom dozom paracetamola je potvrđeno ispitivanim parametrima, uključujući oksidativni status u homogenatu jetre i histolo&scaron;ka ispitivanja. Rezultati na&scaron;eg istraživanja su pokazali da piknogenol 50 mg/kg, kao i ekstrakt kore crnog bora 100 mg/kg značajno smanjuju nivo MDA u poređenju sa kontrolnom grupom i grupom koja je primala paracetamol. Na osnovu rezultata istraţivanja može se zaključiti da primena piknogenola i ekstrakta kore crnog bora: ublaţava poremećaj homeostaze glukoze, utiče povoljno na lipidni status, značajno potencira antihiperglikemijsko delovanje metformina i hipoglikemijski efekat gliklazida, sprečava poremećaj biohemijskih parametara pokazatelja funkcije jetre i bubrega u serumu ispitivanih životinja i ispoljava značajno in vitro antioksidativno delovanje i sprečava o&scaron;tećenje jetre laboratorijskih životinja izazvano toksičnom dozom paracetamola.</p> / <p>A pine is any conifer in the genus Pinus of the family Pinaceae. In the Republic of Serbia there are natural and artificial forests of black pine Pinus nigra Arnold. Pine bark has been used for centuries in traditional medicine, but only recently its positive biological effects has been revealed and confirmed in medicine. The most famous commercial pine bark product is Pycnogenol, a standardized extract of the French maritime pine bark (Pinus pinaster Aiton), which grows along the coast of southwestern France. The positive effects of Pycnogenol, such as antioxidant, hypoglycemic, hypolipidemic, are based on its high content of phenolic compounds. Nowdays, despite the knowledge that the pine bark is rich in secondary metabolites, it usually ends up as a by-product of the wood industry. The objectives of this dissertation were to investigate the qualitative and quantitative characteristics and biochemical activities of the black pine (Pinus nigra) extracts from Mokra gora and Tara, obtained by different solvents; comparison of glycemic and lipid action of Pinus nigra bark extract with commercial product Pycnogenol; the influence of black pine bark extract and Pycnogenol on the action of standard antidiabetics metformin and gliclazide; as well as the influence on the parameters of oxidative stress in animals exposed to the toxic dose of paracetamol. In vitro analyses included the analysis of extracts obtained with different solvents. The total phenolic, tannin, flavonoid and proanthocyanidin content, as well as the antioxidant activity tests, were determined spectrophotometrically. High-efficiency liquid chromatography (HPLC) was performed in order to determine black pine bark extract content. In vivo analyses was performed on 156 albino Wistar laboratory rats. Experimental animals received for 7 days per os: black pine bark extract obtained from Mokra gora 100 mg/kg, which showed the best activity; Pycnogenol 50 mg/kg; metformin 100 mg/kg; gliclazide 10 mg/kg; and their combinations. An oral glucose tolerance test and the aloxan-induced hyperglycaemia were used to examined the effects of the substances on experimental animals. Biochemical parameters, the lipids concentration and parameters of the kidney and liver function, were determined in animal serum. Ex vivo analyses included determination of lipid peroxidation activity and the activity of antioxidant protection enzymes in liver homogenates of the test animals, after administration of a toxic dose of paracetamol. HPLC analysis of black pine bark extracts obtained from Mokra gora and Tara showed the greatest content of taxifolin, then catechin, and its derivatives, caffeic acid and epicatechin. A high antioxidative capacity of Pycnogenol was confirmed, but also a significant antioxidant capacity of black pine bark extract, with the best results in the extract obtained from Mokra gora. Seven-day treatment in aloxan-induced diabetes animals with 100 mg/kg black pine bark extract, metformin 100 mg/kg, gliclazide 10 mg/kg and Pycnogenol 50 mg/kg led to a decrease of serum glycemic index. There was an increase in the HDL cholesterol concentration and a significant reduction in serum triglycerides in diabetic and normoglycemic animals which received Pycnogenol, black pine bark extract, gliclazide and metformin compared to the control group. Concomitant usage of the black pine bark extract and standard antidiabetics significantly reduced the levels of AST, ALP and direct bilirubin in the group of diabetic and normoglycemic animals compared to the control group, indicating the potential hepatoprotective action of the black pine bark extract. Damage to the liver caused by the toxic dose of paracetamol was confirmed by the liver homogenate oxidative status and histological examination. The results of our study have shown that Pycnogenol 50 mg/kg, as well as 100 mg/kg black pine bark extract significantly reduce the level of MDA in comparison with the control and the paracetamol treated group. Based on the results of the dissertation, it can be concluded that the use of Pycnogenol and black pine bark extract alleviate glucose homeostasis disorder; positively affects the lipid status; significantly increases the antihyperglycemic effect of metformin and the hypoglycemic effect of gliclazide; prevents impairment biochemical parameters of the liver and kidney function in the serum of the experimental animals; significantly exhibits in vitro antioxidant activity and prevents liver damage caused by toxic dose of paracetamol in experimental animals.</p>

<p>Uvod: Ko&scaron;arka je naizmeničan, dominantno anaerobni timski sport koji igraju sportisti na različitim nivoima. Iako je primarno američki sport, ko&scaron;arka je ubrzo postala i međunarodni, a danas gotovo da nema zemlje u kojoj se ne igra. Razlog za podizanje svesti o ko&scaron;arka&scaron;koj igri je taj &scaron;to je to dru&scaron;tvena igra čijim upražnjavanjem se može zadovoljiti niz sociolo&scaron;kih, fiziolo&scaron;kih, psiholo&scaron;kih i mnogih drugih aspekata. U trenažnom procesu, samo pravilnim izborom trenažnih programa, raznovrsnosti trenažnih sadržaja, izborom trenažnih metoda i sredstava rada može se očekivati razvoj svih kretnih, funkcionalnih i drugih sposobnosti ko&scaron;arka&scaron;a. Prethodno navedeno utiče na izbor vežbi koje će biti primenjene na sportiste odnosno ko&scaron;arka&scaron;e, a koje su osnovno sredstvo u trenažnoj tehnologiji za prevođenje sportiste iz nižeg u vi&scaron;i nivo sportske forme.<br />Cilj: Cilj istraživanja je da se kroz odabranu bateriju testova ustanovi efekat zadatog tretmana na transformaciju morfo-funkcionalnih, motoričkih i specifično motoričkih sposobnosti studenata ko&scaron;arka&scaron;a sprovedenog u pripremnom delu sezone (predtakmičarski ili bazični deo).<br />Metodologija: Uzorak ispitanika činio je ukupno 95 studenata mu&scaron;kog pola, Severoistočnog federalnog univerziteta u Jakutsku (Rusija) koji broji oko 20000 studenata pretežno iz azijatskog dela sveta. Uzrast ispitanika je od 18-23 godine gde je prosečna starost 20.841.26 godina. Naveden uzorak je metodom slučajnog uzorka podeljen u dve grupe: prva grupa je bila eksperimentalna (N=45), dok je druga grupa bila kontrolna (N=50). Eksperimentalna grupa je realizovala eksperimentalni plan i program. Kontrolna grupa je realizovala &bdquo;Op&scaron;ti program treninga ko&scaron;arka&scaron;kih performansi&ldquo; koji se primenjuje u KK&ldquo;Borac&ldquo; iz Čačka.<br />Za svaku dobijenu varijablu izračunati su centralni i disperzioni parametri. Za procenu normalnosti distribucije svih varijabli primenjen je Kolmogorov-Smirnov test. U cilju utvrđivanja razlika u morfo-funkcionalnim i motoričkimi specifično motoričkim sposobnostima studenata ko&scaron;arka&scaron;a u inicijalnom i finalnom merenju između kontrolne i eksperimentalne grupe primenjena je multivarijatna analiza varijanse (MANOVA) i univarijatna analiza varijanse (ANOVA). Struktura razlika između grupa i hijerarhija antropometrijskih i motoričkih varijabli na inicijalnom i na finalnom merenju utvrđena je primenom Diskriminativne analize. Stvarni efekti eksperimentalnog i kontrolnog tretmana, na finalnom merenju utvrđeni su uz pomoć univarijatne analize kovarijanse (ANCOVA) i multivarijatne analize kovarijanse (MANCOVA).<br />Rezultati: Rezultati multivarijatne analize varijanse ukazuju da u sistemu primenjenih varijabli postoje statistički značajne razlike između kontrolne i eksperimentalne grupe na finalnom merenju u varijablama za procenu morfolo&scaron;kih karakteristika (p = .000), funkcionalnih sposobnosti (p = .000), motoričkih (p = .000) i specifično motoričkih sposobnosti (p = .000). Rezultati diskriminativne analize (p = .000) ukazuju da postoji jasno definisana granica između subuzoraka kada su u pitanju varijable za procenu morfolo&scaron;kih karakteristika (p = .000), funkcionalnih sposobnosti (p = .000), motoričkih (p = .000) i specifično motoričkih sposobnosti na finalnom merenju. Primenom ANOVA analize utvrđeno je da postoje statistički značajne razlike između subuzoraka studenata ko&scaron;arka&scaron;a u varijablama za procenu morfolo&scaron;kih karakteristika i u varijablama za procenu funkcionalnih sposobnosti ispitanika. ANOVA je takođe potvrdila statistički značajne razlike u varijablama za procenu motoričkih i specifično motoričkih sposobnosti. Statistički značajne razlike u gore navedenim varijablama je uočena u korist eksperimentalne grupe.<br />Putem MANCOVA analize utvrđena je statistički značajna razlika između eksperimentalne i kontrolne grupe studenata ko&scaron;arka&scaron;a u sistemu primenjenih varijabli za procenu morfolo&scaron;kih karakteristika ispitanika (p=.000), za procenu funkcionalnih sposobnosti (p=.000), za procenu motoričkih sposobnosti (p=.000) i za procenu specifično motoričkih sposobnosti ispitanika (p=.000) na finalnom merenju, na kraju primenjenog eksperimentalnog tretmana u korist eksperimentalne grupe. Rezultati diskriminativne analize (p = .000) ukazuju da postoji jasno definisana granica između subuzoraka kada su u pitanju varijable za procenu morfolo&scaron;kih karakteristika (p = .000), funkcionalnih sposobnosti (p = .000), motoričkih&nbsp;&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; (p = .000) i specifično motoričkih sposobnosti na na kraju primenjenog eksperimentalnog tretmana.<br />Zaključak: Kako je uočena statistički značajna razlika u celom ispitivanom prostoru, može se zaključiti da postoji statistički značajan efekat eksperimentalnog tretmana na određene morfolo&scaron;ke karakteristike, funkcionalne, motoričke i specifično motoričke sposobnosti ispitanika. Efekti eksperimentalnog tretmana na ko&scaron;arka&scaron;e su bili bolji od efekata konvencionalnog ko&scaron;arka&scaron;og treninga.</p> / <p>Introduction: Basketball is an alternate, dominant anaerobic team sport that plays athletes at different levels. Although it is&nbsp; the US primarily sport, basketball soon became international, and today there is almost no country in which it is not played. The reason for raising awareness about the basketball game is that it is a social game whose practice can satisfy a range of sociological, physiological, psychological and many other aspects. In the training process, only the correct selection of training programs, variety of training contents, choice of training methods and training tools can be expected to develop all the locomotional, functional and other abilities of basketball players. The aforementioned influences the selection of exercises that will be applied to athletes or basketball players, which are the basic instrumentality in the training technique for translating an athlete from a lower to a higher level of sports form.<br />Objective: The aim of the research is to determine the effect of the given treatment on the transformation of the morpho-functional, motor and specific motor skills of basketball players conducted during the preparatory part of the season (pre-competitive or basic part) through the selected battery of tests.<br />Methodology: The sample of respondents consisted of a total of 95 male students, Northeastern Federal University in Yakutsk (Russia), which has about 20000 students predominantly from the Asian region. The age of the respondents is from 18-23 years, where the average age is 20.841.26 years. The sample was randomly divided into two groups: the first group was experimental (N = 45), while the second group was control group (N = 50). The experimental group realized the experimental plan and program. The control group realized the &quot;General Basketball Performance Training Program&quot;, which is being applied in BC &quot;Borac&quot; from Cacak.<br />For each obtained variable, the central and dispersion parameters. The Kolmogorov-Smirnov test was used to estimate the normal distribution of all variables. In order to determine the differences in the morpho-functional, motor and specific motor skills of basketball students in the initial and final measurement between the control and the experimental group, a multivariate variance analysis (MANOVA) and a univariate variance analysis (ANOVA) were applied. The structure of differences between groups and the hierarchies of anthropometric and motor variables on initial and final measurement was determined using the Discrimination Analysis. The actual effects of experimental and control treatment were determined at the final measurement using a univariate covariance analysis (ANCOVA) and multivariate covariance analysis (MANCOVA).<br />Results: The results of the multivariate analysis of variance indicate that in the system of applied variables there are statistically significant differences between the control and the experimental group at the final measurement in variables for estimating morphological characteristics (p = .000), functional abilities (p = .000) .000), motor skills (p = .000) and specific motor skills (p = .000). The results of the discriminant analysis (p = .000) indicate that there is a clearly defined boundary between subunits when it comes to variables for assessing morphological characteristics (p = .000), functional abilities (p = .000), motor (p = .000) and specific motor skills in final measurement.<br />Using ANOVA analysis it was determined that there are statistically significant differences between subsamples of students in variables for evaluation of morphological characteristics and variables for assessing the functional abilities. ANOVA also confirmed statistically significant differences in variables for assessing motor abilities and specific motor skills. In the above mentioned variables statistically significant differences were observed in favor of the experimental group.<br />The MANCOVA analysis showed a statistically significant difference between the experimental and control group of basketball students in the system of applied variables for assessing the morphological characteristics of the respondents (p = .000), for assessment functional abilities (p = .000), for the assessment of motor abilities (p =. 000) and for the assessment of the specific motor abilities of the subjects (p = .000) at the final measurement, at the end of the applied experimental treatment, in favor of the experimental group. The results of the discriminant analysis (p = .000) indicate that there is a clearly defined boundary between subunits when it comes to variables for assessment morphological characteristics (p = .000), functional abilities (p = .000), motor (p = .000) and specific motor abilities, at the end of the applied experimental treatment.<br />Conclusion: As a statistically significant difference was observed in the entire study area, it can be concluded that there is a statistically significant effect of experimental treatment on certain morphological characteristics, functional, motor and specific motor abilities of the respondents. The effects of experimental treatment on basketball players were better than the effects of conventional basketball training.</p>

<p>Žučne kiseline (ŽK) su strukturno raznoliki molekuli, koji pored uloge koju ostvaruju putem žuči, deluju i kao signalni molekuli i ostvaruju kako endokrina tako i parakrina dejstva. Činjenica da je do sada u terapijske svrhe primenjivana samo ursodeoksiholna kiselina (UDK), posledica je brojnih ograničenja u mogućnosti primene ostalih prirodnih ŽK, i ističe potrebu za otkrivanjem novih sintetskih ŽK i liganda. Cilj istraživanja bio je ispitivanje sintetske 12-monoketoholne kiseline (MK) i prirodne UDK u modelu holestaze i aloksanom izazvanog dijabetesa. Ispitivanja su vr&scaron;ena na pacovima soja Wistar. Analizirana je telesna masa, glikemija, pokazatelji jetrene funkcije (AST; ALT, &gamma;-GT, ukupni i direktni bilirubin), a iz homogenate jetre određen je intenzitet lipidne peroksidacije i aktivnost antioksidativnih enzima (CAT, GSH-Px, GSH-R, GSH-ST). Isečci tkiva jetre su histolo&scaron;ki obrađeni i bojeni hematoksilin-eozin metodom i histohemijskim metodama (retikulin, Mallory, Periodic Acid Schiff- Alcian Blue (PAS/AB)). Imunohistohemijski je ispitana proliferacija hepatocita (Ki-67), markeri apoptoze (p53, Bcl-2, Bcl-X, Bax) i ekspresija nuklearnog farnesoid X receptora (FXR). Rezultati istraživanja pokazuju da ispitivane ŽK pomažu očuvanje telesne mase u holestazi i dijabetesu, i značajno snižavaju glikemiju kod dijabetičnih jedinki. Parametri jetrene funkcije u holestazi i dijabetesu su regulisani primenom MK i UDK. Obe ŽK u značajnoj meri smanjuju intenzitet lipidne peroksidacije i pojačavaju enzimsku antioksidativnu odbranu hepatocita u holestazi i dijabetesu. Ekspresija markera apoptoze nije značajno promenjena izazvanjem modela holestaze i dijabetesa, kao ni primenom ispitivanih ŽK. Nasuprot tome, izazivanje holestaze i dijabetesa značajno smanjuje proliferaciju hepatocita, dok primena MK i UDK poni&scaron;tava ovaj efekat i značajno povećava proliferaciju hepatocita. Hiperglikemija u aloksanskom dijabetesu nije dovela do pojačane ekspresije FXR. Izazivanje holestaze kod zdravih i dijabetičnih životinja dovelo je do porasta ekspresije FXR, koja je redukovana primenom MK i UDK. Na osnovu dobijenih rezultata može se zaključiti da sintetska 12-monoketoholna kiselina pokazuje slična hipoglikemijska, hepatoprotektivna i antioksidativna dejstva kao i prirodna ursodeoksiholna kiselina.</p> / <p>Bile acids (BAs) are structurally diverse molecules, which have theroles in the digestive system, which are exercised through the bile. Beside those, BAs act as a signaling molecules and achieve endocrine and paracrine effects. In addition to its own metabolism, bile acids modulate the metabolism of lipids and glucose. The fact that so far only ursodeoxycholic acid (UDC) is used for therapeutic purposes, speak clearly about of numerous limitations on the application of other natural BAs, and highlights the need to develop new synthetic Bas and ligands. The aim of this study was to investigate the influence of synthetic 12-monoketocholic acid (MC) and natural bila acid UDC in the model of cholestasis and alloxan-induced diabetes. Tests were performed on male Wistar rats. We analyzed the body mass, glucose, liver function tests (AST, ALT, &gamma;-GT, total and direct bilirubin). Using liver tissue homogenates we determined intensity of lipid peroxidation (by concentration of malondilaldehyde) and the activity of antioxidant enzymes (CAT, GSH-Px, GSH -R, GSH-ST). Liver tissue were histologically processed and stained with hematoxylin-eosin method and histochemical methods (reticulin, Mallory, Periodic Acid Schiff- Alcian Blue (PAS / AB)). Imunohistochemical examination included hepatocyte proliferation (Ki-67), markers of apoptosis (p53, Bcl-2, Bcl-X, Bax), and expression of the nuclear farnesoid X receptor (FXR). Results of the research show that MC prevented decrease in body mass during cholestasis and diabetes, and significantly reduced glycemia in diabetic animals. The liver function tests in cholestasis and diabetes are normalised by MC and UDC aplication. Both BAs significantly reduce lipid peroxidation and enhance enzymatic antioxidant defense of hepatocytes in cholestasis and diabetes. The expression of markers of apoptosis was not significantly changed in models of cholestasis and diabetes, as well as the application of the tested BAs. In contrast, in cholestasis and diabetes model, the proliferation of hepatocytes was significantly reduced, while the use of MC and UDC reversed this effect and significantly increased the proliferation of hepatocytes. Hyperglycemia in alloxan-induced diabetes did not lead to overexpression of FXR. Induction of cholestasis in healthy and diabetic animals resulted in an increase in the expression of FXR, which is reduced by using the MK and the UDC. Based on these results we can conclude that a synthetic 12-monoketocholic acid shows similar hypoglycemic, hepatoprotective and antioxidant effects as natural ursodeoxycholic acid.</p>

<p>Uvod: U pro&scaron;losti žučne kiseline su uglavnom razmatrane sa stanovi&scaron;ta njihove funkcije koju obavljaju u crevima jer posreduju u varenju masti i apsorpciji liposolubilnih vitamina. Nedavne studije potvrđuju da žučne kiseline ne igraju samo ulogu u varenju masti, nego se pona&scaron;aju i kao signalni molekuli koji stupaju u interakciju sa raznim receptorima uključujući nuklearne receptore i receptore vezane za G-proteine. Kao amfipatični molekuli one su sposobne da reaguju sa fosfolipidima ćelijskih membrana i da pobolj&scaron;avaju prolazak lekova kroz njih. Stoga se žučne kiseline razmatraju kao promoteri u bukalnim, okularnim i nazalnim farmaceutskim formulacijama. Cilj: Svrha ovog istraživanja je bila da se ispitaju žučne kiseline i njihovi okso derivati kao jedinjenja koja utiču na propustljivost ćelijskih membrana i prolazak lekova do ciljnih tkiva. Materijal i metod: Interakcije makrolidnih antibiotika i žučnih kiselina su ispitivane uz pomoć NMR difuzionih merenja i relaksacije paramagnetičnim jonima. Retencioni parametri odabranih žučnih kiselina su dobijeni kori&scaron;ćenjem hromatografije na normalnim fazama i evaluisani su primenom pet različitih softvera. In vivo ekaperimenti su sprovedeni na 126 eksperimentalnih životinja koje su bile podeljene u 21 grupu. Rezultati: Vezivanje žučnih kiselina za micele je indikovano razlikama u hemijskom pomeranju makrolida i pro&scaron;irenju signala kao posledica redukovane mobilnosti unutar micela. Dodatak micela žučnih kiselina povećava solubilizaciju makrolida za faktor približno 2-3. Sprovedena korelaciona analiza pokazala je značajnu zavisnost između faktora retencije i intestinalne apsorpcije, prodora u MDCK epitelne ćelije, permeabilnost kroz kožu, logBB i PPB%. Putem implementacije in vivo eksperimentalnog dela pokazano je da žučne kiseline utiču na prolazak makrolida u tkivo mozga, bubrega i jetre. Zaključak: Ispitivane žučne kiseline pokazuju dobre farmakokinetske karakteristike i olak&scaron;avaju prolazak makrolida kroz različite ćelijske membrane.</p> / <p>Introduction: In the past, bile acids were mostly considered to function in the intestine where they play a role in digestion of fats and mediate absorption of fat-soluble vitamins. Recent studies confirm that bile acids not only facilitate solubilization of fats but behave as signal molecules that interact with various receptors including nuclear receptors and G protein-coupled receptors. As amphipathic molecules they are able to interact with phospholipids of cells membranes and enhance drugs permeation. Thus, bile acids are considered as drug promoters in buccal, ocular, nasal, and transdermal dosage forms. Purpose: The purpose of this research was to investigate bile acids and its oxo derivatives as enhancers in drug permeability. Three research methods to evaluate the characteristics of bile acids and its properties were used. Material and method: The interaction between macrolide antibiotics and bile acids was investigated by NMR chemical-shift titration, self-diffusion measurements and paramagnetic relaxation enhancements. Retention parameters of selected bile acids are acquired by normal-phase thin layer chromatography and evaluated using five different softwares. In vivo experiments were conducted on 126 animals which were divided in 21 groups. Results: Binding bile acids to the micelles is indicated by differences in the chemical shift of the macrolides and line broadening as a consequence of reduced mobility in the micelle. Addition of bile micelles increases the solubility of macrolide antibiotics by a factor of approximately 2&ndash;3. Examined correlation analysis confirmed significant dependence between retention factor and intestinal absorption, MDCK epithelial cells, skin permeability, logBB and PPB%. Through the implementation of in vivo experiments it is shown that bile acids promote penetration of macrolides in brain tissue, kidney and liver. Conclusion: Investigated bile acids showed good pharmacokinetic properties and facilitate in macrolides permeation through various membranes.</p>

<p>Mnogi lekovi registrovani za razne druge indikacije mogu da deluju selektivno na tumorske receptore, signalne puteve, metaboličke procese, bioenergetske faktore, enzime, proteine, gene koji reguli&scaron;u proliferaciju, apoptozu i neoangiogenezu tumora ne pogađajući ove procese kod zdravih ćelija. Uvođenje novih lekova je izrazito dug, složen i skup proces istraživanja. Kori&scaron;ćenjem principa otkrivanja antikancerskog efekta kod već registrovanih lekova za druge indikacije, direktno se utiče na skraćivanje vremena i tro&scaron;kova istraživanja. Eksperimentalno je ispitana efikasnost antitumorskog delovanja mebendazola, metformina, itrakonazola, diklofenaka, nitroglicerina i deoksiholne kiseline na fibrosarkom hrčka izazvan BHK21/C13 tumorskom ćelijskom linijom praćenjem veličine i histologije lečenih tumora. Eksperimentalno je ispitana mogućnost primene deoksiholne kiseline, nitroglicerina, kofeina i itrakonazola kao adjuvansa u kombinaciji sa pojedinim ispitivanim lekovima (metformin, itrakonazol, diklofenak) za lečenje fibrosarkoma hrčka. Kako je ispitivanje vr&scaron;eno na mladuncima imladim hrčkovima i kako su sarkomi najče&scaron;ći u dečijem uzrastu, definisanje potencijalne antikancerske uloge ispitivanih lekova se odnosi prvenstveno na njihovu primenu u pedijatriji. Pokazano je da metformin, kombinacije metformina sa kofeinom, metformina sa itrakonazolom i metformina sa nitroglicerinom deluju u pogledu svih ispitivanih parametara tumora antitumorski na fibrosarkom hrčka. Kofein, itrakonazol i nitroglicerin pojačavaju antitumorsko dejstvo metformina na fibrosarkom hrčka. Tokom svih eksperimenata realizovanih u okviru ove disertacije, pokazalo se da nije bilo delotvornog tretmana, koji ne sadrži metformin.</p> / <p>Many drugs registered for various other indications can act selectively to tumor receptors, signaling pathways, metabolic processes, bioenergetic factors, enzymes, proteins, genes that regulate proliferation, apoptosis, and neoangiogenesis of the tumor without affecting these processes in the healthy cells. The introduction of new drugs is a very long, complex and expensive process of research. Using the principle of detecting the anticancer effect in already registered drugs for other indications, directly affects the reduction of time and cost of research. The efficacy of mebendazole, metformin, itraconazole, diclofenac, nitroglycerin and deoxycholic acid antitumor activity on hamster fibrosarcinoma induced experimentally by the BHK21/C13 tumor cell line was tested by monitoring the size and histology of the treated tumors. The possibility of using deoxycholic acid, nitroglycerin, caffeine and itraconazole as an adjuvant in combination with investigated drugs (metformin, itraconazole, diclofenac) for the treatment of hamster fibrosarcoma has been experimentally tested. As the examination was carried out on young cubs and young hamsters and that sarcomas are the most common in childhood, defining the potential anti-cancer role of the investigated drugs relates primarily to their application in pediatrics. Metformin, combinations of metformin with caffeine, metformin with itraconazole and metformin with nitroglycerin have shown antitumor action on the hamster fibrosarcoma in terms of all tested tumor parameters. Caffeine, itraconazole and nitroglycerin increase the antitumor effect of metformin on the hamster fibrosarcoma. During all the experiments carried out within this dissertation, there has been no effective treatment, which does not contain metformin.</p>