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    64CU-COMPLEX OF THE BIFUNCTIONAL CHELATOR WITH PSMA TARGETING MOLECULE IN EX VIVO BIODISTRIBUTION STUDY IN HEALTHY RATS
    (Macedonian Medical Association, 2021)
    Chochevska, Maja
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    Nikolovski, Sasho
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    Jolevski, Filip
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    Тhe development of new diagnostic radioactive biochemical products and effective therapeutic radiopharmaceuticals is very important in the era of a personalized approach in the management of cancer patients. Consistent expression of prostate specific membrane antigen (PSMA) in metastatic prostate cancer helps us in finding the relevant radioactive prostate-specific membrane antibody. The radiopharmaceuticals used in molecular imaging require a simple radiolabeling (radiosynthesis) procedure, good target-to-organ sensitivity, and metabolic stability. The aim of this study was to label bifunctional chelator, DOTA, covalently bound to a PSMA targeting vector (DOTAGA-(I-y)fk(Sub-KuE)) with Copper-64 (64Cu) and to examine its physicochemical properties and pharmacokinetic characteristics. Healthy adult rats of Wistar strain were used to carry out experiments through ex vivo biodistribution with intravenous radiopharmaceutical administration of (7±1.5) MBq. Target organs and tissues were harvested 60 min post-injection. Also, in vitro radiochemical stability of radiolabeled molecule 64Cu-DOTA-PSMA was studied with TLC method, 24 h post preparation of the product. The obtained data showed a low uptake (≤0.45 % IA g-1) in the majority of organs, except for the liver (1.21±0.48 % IA g-1) and the kidneys (6.10±0.98 % IA g-1),indicating them as clearance organs. The in vitro stability study confirmed a relatively highstability and the product can be safely used during thatperiod.
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    NEPHROPROTECTIV EFFECTS OF CANDESARTAN ON DIABETIC NEPHROPATHY IN RATS
    (Macedonian Association of Anatomists and Morphologists, 2023)
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    Kolovchevski, Nikola
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    Shikole, Emilija
    Diabetic nephropathy (DN) stands out as a primary contributor to end-stage kidney damage. The renin-angiotensin system (RAS) plays a pivotal role in the advancement of DN, making angiotensin receptor blockers (ARBs) particularly noteworthy due to their influence on angiotensin II in DN development. This study investigated the impact of the angiotensin receptor blocker candesartan (CAN) on rats with streptozotocin (STZ)-induced DN, characterized by albuminuria, renal hypertrophy, and mild glomerulosclerosis.DN was induced in normotensive Wistar rats through a single injection of STZ (60 mg/kg ip). STZ administration led to diabetes mellitus (DM) symptoms and DN indicators, such as poor general condition, weight loss, increased kidney weight, elevated serum creatinine levels and BUN, augmented diuresis, and notable albuminuria. These manifestations were prominent at 4 weeks, intensifying further at 8 and 12 weeks post-STZ injection. Commencing candesartan treatment (5 mg/kg BW) at the 4-week mark post-STZ injection significantly alleviated all DN symptoms, reducing serum creatinine values and BUN, albuminuria, and diuresis. Histopathological examination at 8 and 12 weeks revealed that candesartan effectively mitigated glomerulopathy progression, improved the glomerulosclerotic index, and attenuated renal histological abnormalities induced by STZ. In conclusion, candesartan treatment ameliorates STZ-induced nephropathic changes in DM rats.
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    RENOPROTECTIVE EFFECTS OF DUAL BLOCKADE OF RENIN-ANGIOTENSIN SYSTEM WITH CANDESARTAN AND PERINDOPRIL IN STREPTOZOTOCIN INDUCED DIABETIC NEPHROPATHY
    (Македонско лекарско друштво = Macedonian medical association, 2013)
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    Introduction. Renin-angiotensin system (RAS) inhibition exerts a renoprotective effect independent of blood pressure reduction. Several studies suggest that combination therapy with angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blockers (ARBs) provides a greater antiproteinuric effect than monotherapy, perhaps because of more prolonged and complete RAS inhibition. The aim of the present study was to determine if a combination therapy with perindopril and candesartan at lower doses than monotherapy would confer greater renoprotection in streptozotocin (STZ) induced diabetic nephropathy. Methods. Wistar rats (n=125) were used in this study. Diabetes was induced by a single i.p. injection of STZ (60 mg/kg). The diabetic rats (n=100) were randomly assigned to receive vehicle, ARB-Candesartan (5 mg/kg/per d), ACE-I -Perindopril (6 mg/kg/per d), or a combination of low dose Candesartan+Perindopril (2,5 mg/kg/per d and 3 mg/kg/ per d) respectively, from weeks 4-12. Pathological changes of the kidney were examined with optical and transmission electron microscope.Results. Albumin excretion rate, kidney/body weight ratio and renal structural changes increased significantly in untreated diabetic rats compared to normal control rats. Treatment with candesartan, perindopril, or both decreased these changes. Addition of the candesartan to perindopril was more effective in reducing renal structural changes and improvement of renal function than monotherapy with either drug. Conclusion. Combination therapy has the additional benefit of requiring only low doses of ACE-I and ARBs to achieve superior renoprotective effects in this diabetic nephropathy model, possibly due to dual inhibitory effect on the RAS.
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    The role of TGF-β1 in the development of diabetic nephropathy experimentally induced by Streptozotocin and the nephroprotective effects of Candesartan
    (Macedonian Association of Anatomists and Morphologists, 2023-12)
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    Shikole Emilija
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    Kolovchevski, Nikola
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    Labachevski, Bojan
    Diabetic nephropathy (DN) stands as a prevalent and severe complication of diabetes mellitus (DM), lacking adequate medical therapy. The molecular mechanisms contributing to glomerular membrane damage involve the overactivity of angiotensin II, heightened expression of nephrin, vascular endothelial growth factor (VEGF), and notably, intraglomerular transforming growth factor TGF-β1. Pharmaceutical treatments targeting hemodynamic disturbances in diabetic nephropathy, such as ACE inhibitors and angiotensin receptor blockers (ARBs), hold promise for DN therapy. This study aimed to assess the role of intraglomerular TGF-β expression in experimentally induced DN in rats and explore the nephroprotective effects of candesartan. Diabetes mellitus was induced through a single intraperitoneal injection of streptozotocin (STZ) at 60 mg/kg, and DN was allowed to develop over four weeks. DM rats were randomly assigned to two groups: STZ (untreated) and STZ+CAN (treated with candesartan at 5 mg/kg/day from week 4 to week 12). STZ administration led to a substantial increase in TGF-β1 expression in the glomeruli, exceeding control levels by 5-6 times. Candesartan treatment demonstrated a significant reduction in glomerular proliferation and subsequent expansion of the mesangial matrix, suggesting a potential mechanism by which these drugs achieve therapeutic effects.
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    Effects of different dietary fatty acid supplements upon lipoprotein metabolism and lipid peroxides production in hyperlipidemic rats.
    (Македонска академија на науките и уметностите, Одделение за биолошки и медицински науки = Macedonian Academy of Sciences and Arts, Section of Biological and Medical Sciences, 2006)
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    Ðošić-Markovska, Bozidarka
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    Zafirova-Roganović, Danica
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    It has been well documented that hypercholesterolemia represents both a common and a dominant, although non-obligatory, risk factor in the progression of atherosclerosis. Research was conducted upon experimentally induced hyperlipidemic animals by means of a custom-tailored atherogenic diet. Cell susceptibility to nonenzyme-induced oxidative stress appears to be influenced by membrane fatty acid composition. This study was undertaken to determine whether differences in lipid peroxidation in steady-state and induced lipid peroxidation is a result of a different fatty acid supplementation. Adult Wistar strain rats of male gender were exposed to an atherogenic diet for a period of 160 days, before randomization into 6 dietary groups with different intragastral oil supplementation. Lipid peroxidation products were measured in 2.5% (w/v) of fresh liver homogenates (Tris-HCl, pH 7.4), by the assay of a thiobarbituric acid reactive substances (TBARS) formation using the procedures described by Okhawa (1979), including modifications (1989) in three different experimental conditions: steady-state (which corresponds to concentration of lipid peroxides in vivo ), spontaneous and metal-stimulated lipid peroxidation. Results were expressed as nmol TBARS per g of liver homogenate, calculated from the absorbency at 532 nm, using TEP as an external standard. This study shows that prolonged atherogenic dietary treatment causes moderate hypercholesterolemia and enhanced hypertriglyceridemia (+34.1% and +114.8, p < 0.001, respectively). Despite the lowering effects of the lipoprotein profiles, resulting from a fatty acid supplementation, at the end of each supplementation period, ω-6 fatty acids (soybean and corn oil) revealed an enhancement in the production of lipid des (TBARS formation) measured in steady-state levels (+22.9%, p < 0.05 and +22.6%, p < 0.05, respectively). When liver homogenates were exposed to Fe2+ and ascorbic acid-induced oxidative stress, lipid peroxidation (LPO) was enhanced in the group treated with soybean oil (ω-6) and fish oil (ω-3; +48.4 %, p < 0.001 and +44.1%, p < 0.001, respectively), but not in the group receiving corn oil. The achieved results support the hypothesis that the process of lipid peroxidation is not always in correlation with the number of double bonds in fatty acids esterified in phospholipid molecules. Consequently, it can be concluded that supplementation of unsaturated fatty acids, in the therapy of cardiovascular diseases, should include the administration of antioxidants, in order to prevent fatty acid decomposition in the case of oxidative insult.