Biomedical Scientific Productivity of the Mostar University Faculty of Medicine and University Hospital Mostar in 1999–2008

The aim of this study was to investigate the scientific productivity of the Mostar University Faculty of Medicine and University Hospital Mostar. All articles that were indexed by PubMed with the keyword Mostar were included in the analysis. During 1999–2008, a total of 76 articles were published, with a total of 366 authorships contributed by a total of 228 unique authors, whereas a total of 161 of these authors (70.6%) coauthored a single article only. The average number of co-authors was 4.6 per article. There was a strong increasing linear trend in the total number of published articles. The most published articles were related to clinical research, whereas the least were recorded in the basic biomedical sciences, suggesting the need to increase the research capacity in basic biomedical sciences. The large percent of single-authorship authors that were recorded suggest almost a sporadic rather than systematic publication output. Likely improvements to this situation include the creation of the newly formed doctoral (PhD) course due to start next year and several other ways in which scientific research in biomedicine can be increased in basic, clinical and public health sciences

Farmakogenetika i farmakogenomika - uticaj jednonukleotidnih polimorfizama na odgovor na lekove

Individual variation in response to drugs is an important clinical problem, which ranges from failure to respond to the drug, over adverse reactions to drugs, to interactions among drugs being administered concurrently. Numerous findings indicate that the differences in the patients response on the same drug are caused by genetic variations. This is the subject of pharmacogenetics. Although pharmacogenetics generally equated with the concept of pharmacogenomics, pharmacogenetics is primarily related to variations in a single gene that influence the on drug response, while pharmacogenomics is a broader term, which studies how all of the genes (the genome) can influence responses to drugs. In focus of this paper will be individual variation in response to drugs arising from single nucleotide polymorphisms in genes encoding the drug target proteins, enzymes that metabolize drugs, drug transporters, and polymorphisms of genes responsible for toxicity and hypersensitivity to drugs. Determination of pharmacogenetic profile of patients could point out patients who are at increased risk of adverse drug effects (for which drug should be applied at lower doses or other drugs can be used) and those in which are likely to achieve the desired therapeutic effect, and so to enable individualization of therapy.Individualne varijacije u odgovoru na lekove važan su klinički problem i mogu dovesti do potpunog odsustva reakcije na lek i pojave neželjenih reakcija na lekove. Brojni nalazi ukazuju da su razlike u odgovoru bolesnika na isti lek uslovljene genetskim varijacijama, i predmet su istraživanja farmakogenetike. Iako se farmakogenetika uglavnom izjednačuje sa pojmom farmakogenomika, farmakogenetika se uglavnom odnosi na varijacije u jednom genu koje utiču na odgovor na lek, dok je farmakogenomika šira oblast, koja ispituje kako svi geni u genomu povezani sa metabolizmom određenog leka mogu uticati na odgovor na dati lek. U ovom radu prevashodno će biti opisane individualne varijacije u odgovoru na lekove koje nastaju usled jednonukletidnih polimorfizama u genima koji kodiraju ciljne proteine lekova, enzime koji metabolišu lekove, transportere lekova, kao i polimorfizmi gena koji su odgovorni za toksičnost i preosetljivost na lekove. Određivanje farmakogenetskog profila bolesnika moglo bi da ukaže na bolesnike koji su u povećanom riziku od pojave neželjenih efekata lekova (kod kojih bi trebalo da se primene niže doze ili drugi lekovi) i na one kod kojih će se najverovatnije postići željeni terapijski efekat, odnosno da omogući individualizaciju terapije

Neuroimunski aspekti efekata vodećih jedinjenja/lekova kandidata koji deluju preko gabaa i/ili sigma‐2 receptora na raspoloženje, anksioznost i kogniciju: in vitro/in vivo delineacija primenom nano‐ i hipsc platformi

Mood, anxiety and cognitive symptoms in psychiatry and neurology represent a significant worldwide burden. Due to difficulties in disease modeling and drug delivering to the site of action, as well as gaps in in vitro/in vivo extrapolation, the efforts to elucidate the roles of stress and neuroimmune pathways in both, etiology and therapy of these symptoms are challenging, but may nevertheless result in novel mechanisms of action. Recent preclinical studies provided novel leads/drug candidates with promising mood, anxiety and cognitive effects, the intellectual property rights of which are co-owned by the project beneficiary. We aim to: (1) incorporate the selective ligands of GABAA and/or sigma-2 receptors, with code names GL-II-73, DK-I-56, MM-I-03 and CW-02-79, together with two reference sigma-2 receptor ligands (siramesine and RHM-1), into the optimized nanoparticles and target their delivery to the human induced pluripotent stem cell (hiPSC)- based tri-culture cell neuroinflammation model, or rat brain; (2) quantify the immunological/morphological/neurochemical markers in immunologically challenged hiPSC-derived neurons, astrocytes and glia cells, and (3) assess their effects on behavior and biological markers in immunologically challenged animals of both sexes subjected to chronic mild unpredictable stress. We assume that the targeted nanodelivery of selected compounds to the brain will improve their pharmacokinetic profile, fortify their beneficial effect on mood, anxiety and cognition, and help delineate the contributing neuroimmune effects presumably arising mainly from microglia. The familiarization with neuroimmune aspects and pharmacokinetic optimization will support the preclinical progress of these compounds and might provide a rationale for designing clinical trials.Raspoloženje, anksioznost i kognitivni simptomi u psihijatriji i neurologiji predstavljaju značajno opterećenje za zdravstvene sisteme na globalnom nivou. Usled poteškoća u modelovanju bolesti i isporuci lekova na mesto delovanja, kao i jaza u in vitro/in vivo ekstrapolaciji, potreba da se osvetle uloge stresa i neuroimunskih puteva u etiologiji i terapiji ovih simptoma je izazov, i može rezultovati u novim mehanizmima delovanja. Nedavne prekliničke studije obezbedile su nova vodeća jedinjenja/lekove kandidate sa obećavajućim efektima na raspoloženje, anksioznost i kogniciju, rezultujući prihvatanjem patentnih prava čiji je suvlasnik predlagač projekta. Cilj projekta je da: (1) inkorporiramo ligande selektivne za GABAA i/ili sigma-2 receptore, sa kodiranim imenima GL-II-73, DK-I56, MM-I-03 i CW-02-79, zajedno sa dva referentna liganda za sigma-2 receptore (siramesin i RHM-1), u optimizovane nanočestice i da omogućimo njihovu ciljnu isporuku u hiPSCbazirani trićelijski model neuroinflamacije, ili mozak pacova; (2) kvantifikujemo imunološke/morfološke/neurohemijske markere u imunološki izazvanim hiPSC-derivisanim neuronima, astrocitima i glija ćelijama, i (3) procenimo njihove efekte na ponašanje i biološke markere u imunološki izazvanim životinjama oba pola podvrgnutim blagom neočekivanom stresu. Procenjujemo da će ciljana isporuka odabranih jedinjenja pomoću nanonosača poboljšati njihove farmakokinetičke (FK) profile, ojačati njihove korisne efekte na raspoloženje, anksioznost i kogniciju i pomoći delineaciji doprinosa neuroimunskih efekata, po svemu sudeći, poreklom uglavnom od mikroglija ćelija. Upoznavanje sa neuroimunskim aspektima i FK optimizacija mogu da podrže napredak u prekliničkom razvoju ovih jedinjenja i obezbede osnov za dizajniranje prospektivnih kliničkih studija.Link to the lecture: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/4298

Neuroimmune aspects of mood, anxiety and cognitive effects of leads/drug candidates acting at GABAA and/or sigma-2 receptors: In vitro/in vivo delineation by nano- and hiPSC-based platforms

Mood, anxiety and cognitive symptoms in psychiatry and neurology represent a significant worldwide burden. Due to difficulties in disease modeling and drug delivering to the site of action, as well as gaps in in vitro/in vivo extrapolation, the efforts to elucidate the roles of stress and neuroimmune pathways in both, etiology and therapy of these symptoms are challenging, but may nevertheless result in novel mechanisms of action. Recent preclinical studies provided novel leads/drug candidates with promising mood, anxiety and cognitive effects, the intellectual property rights of which are co-owned by the project beneficiary. We aim to: (1) incorporate the selective ligands of GABAA and/or sigma-2 receptors, with code names GL-II-73, DK-I-56, MM-I-03 and CW-02-79, together with two reference sigma-2 receptor ligands (siramesine and RHM-1), into the optimized nanoparticles and target their delivery to the human induced pluripotent stem cell (hiPSC)- based tri-culture cell neuroinflammation model, or rat brain; (2) quantify the immunological/morphological/neurochemical markers in immunologically challenged hiPSC-derived neurons, astrocytes and glia cells, and (3) assess their effects on behavior and biological markers in immunologically challenged animals of both sexes subjected to chronic mild unpredictable stress. We assume that the targeted nanodelivery of selected compounds to the brain will improve their pharmacokinetic profile, fortify their beneficial effect on mood, anxiety and cognition, and help delineate the contributing neuroimmune effects presumably arising mainly from microglia. The familiarization with neuroimmune aspects and pharmacokinetic optimization will support the preclinical progress of these compounds and might provide a rationale for designing clinical trials.Link to the conference object: [https://farfar.pharmacy.bg.ac.rs/handle/123456789/4297

Estimation of endotoxin level in nanocrystal dispersion of DK-I-56-1 intended for parenteral administration

Estimation of endotoxin level in nanocrystal dispersion of DK-I-56-1 intended for parenteral administration Jelena Mitrović1, Tanja Ilić1, Ivan Jančić2, Biljana Bufan2, Miroslav Savić3, Snežana Savić1 1 Department of Pharmaceutical Technology and Cosmetology, University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia 2 Department of Microbiology and Immunology, University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia 3 Department of Pharmacology, University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, 11000 Belgrade, Serbia Estimation of endotoxin level in parenteral formulations is a prerequisite for numerous in vitro tests in preclinical studies and for future clinical development. However, the Limulus amoebocyte lysate (LAL) test in formulations containing nanoparticles could often lead to misinterpretation of results. Therefore, we tested if endotoxins could be detected in nanocrystal dispersions by the commercial gel clot assay kit. Nanocrystals of DK-I-56-1 (7‑methoxy‑2-(4‑methoxy‑d3-phenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one) were prepared by wet-ball milling, lyophilized and reconstituted with water for injection prior experiment. Different dilutions of nanocrystal dispersion in LAL reagent water were prepared as well as positive and negative control. Despite difficulties to detect gel clots, they were visible in the sample at dilutions 1:75 and below. According to the protocol, the endotoxin limit was estimated to be 25.00 EU/ml, which corresponds to <12.50 EU/mg of DK-I-56-1. This value relates to the endotoxin limit for diazepam, with the similar dosing regimen as proposed for DK-I-56-1

Reward-related impulsivity as a possible surrogate marker of motivation in aging Sprague-Dawley rats

Introduction: Impulsivity is an umbrella term that encompasses many subdomains, most of which rely on the decision-making processes. It is reported that in the process of healthy aging, the two dimensions of impulse control, cognition and motivation, are preserved or even improved. On the other hand, the attentive efficiency seems to decrease with age. Therefore, we aimed to investigate the effects of healthy aging on impulsivity in rats and the influence of food deprivation on impulsivity in aged rats as a strategy to enhance motivation. Additionally, we wanted to assess the gene expression for the alpha5 GABAA receptor subunit during aging, which plays a role in cognitive processes. Methodology: The variable-delay-to-signal (VDS) paradigm adapted to a touchscreen environment was used to assess impulsivity and attention in Sprague-Dawley rats at 2, 3, 5, 8, and 14 months of age. After one week of training, animals were tested at different ages in 3-stage testing protocol. Additionally, prior to testing, animals were fed a restricted diet (16 g/animal). The first stage included 20 trials with inter-trial interval of 6s (ITI6si) that reflected motor impulsivity. The second stage, with 60 randomly distributed trials of ITI9s or 15s, was related to delay intolerance, while the final stage (ITI6sf), similar to the first, was related to reflection impulsivity. The strict 3-day restriction diet (24h food deprivation followed by 10g/day/animal and 8g/day/animal) was applied to 14-month-old animals before testing. Gabra5 expression in the hippocampus was determined by qPCR. Results were analyzed by one-way ANOVA with or without repeated measures, followed by Sidak post-hoc test for impulsivity and attention parameters and by t-test for PCR parameters. Results: Animals aged 8 and 14 months had reduced motor impulsivity (p<0.01 for both groups) and delay intolerance (p<0.05 for both groups) and higher number of omissions (p<0.05 for both groups) compared to animals aged 2, 3 and 5 months of age. In addition, half of the animals were unable to successfully complete a task after 14 months. After rigorous food restriction in 14-month-old animals, the level of impulsivity (ITI9s and ITI15s) and attention (number of omissions) returned to the control level (2 and 3 months of age) compared to the performance of 14-month-old animals prior to rigorous food restriction (p<0.05). Further, the peak of reflection impulsivity (ITI6sf) was reached at 5 months compared to all other groups (p<0.01). No changes in Gabra5 expression in hippocampus were detected in 14-month-old compared to 3-month-old animals. Conclusion: From 8 months of age onwards, rats showed reduced impulsivity in the VDS stages where motor impulsivity and delay intolerance were tested, followed by attention deficits. After strict food restriction in 14-month-old animals, delay intolerance and attention were restored, suggesting the prominent role of motivation in controlling these processes, independently of Gabra5 expression levels in the hippocampus. Since the VDS paradigm aims to assess reward-related impulsivity based on cognition and motivation, it is suspected that results related to impaired cognition in older animals in other cognitive tests should be interpreted with caution, and with additional observation of motivation

Multifunkcionalni kompoziti na bazi alginatnih hidrogelova za potencijalnu primenu u oblogama za rane

Alginate hydrogels are widely used in wound dressings due to hydrophilicity, biocompatibility, flexibility, and high sorption capacity, providing effective moisture regulation in wounds and inducing rapid granulation and reepithelization of the damaged tissue. However, these dressings are not bioactive so that different methodologies have been investigated to extend functionality of alginate hydrogels. In the present work, we show several approaches to achieve this aim by addition of different biologically active components. These include incorporation of silver nanoparticles as potent antimicrobial agents (1), bioactive honey components (2), activated charcoal (AC) particles as carriers of therapeutically active agents (3) as well as the use of Zn-alginate hydrogels that release zinc ions (4). The obtained composites were comprehensively characterized regarding composition, cytotoxicity, antibacterial activity, release kinetics of active agents and wound treatment in a rat model. Ag/alginate nanocomposite hydrogels releasing silver ions and/or nanoparticles exhibited high bactericidal activity against a broad spectrum of standard and multi-drug resistant clinical bacterial strains (Escherichia coli, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus – MRSA, Acinetobacter baumannii and Pseudomonas aeruginosa). Especially interesting results were obtained against 13 clinical isolates of A. baumannii, which were completely extinguished over 48 h in 6 cases (2). However, in 3 clinical isolates, antibacterial effects were not noticed implying possibility for development of bacterial resistance to silver. In the treatment of 2nd degree burns in rats Ag/alginate nanocomposites exhibited the same efficiency as commercial medical products (5). Composite alginate hydrogels with immobilized AC particles impregnated with povidone iodine (PVP-I) as a model therapeutically active agent, were developed with the aim to provide controlled particle release in the wound without actually releasing the adsorbed substance, thus achieving the desired activity without adverse effects by systemic absorption. The composite Ca-alginate hydrogels induced strong bactericidal effects against two standard bacterial strains and clinical multi-resistant wound isolates (MRSA, E. coli, P. aeruginosa, Еnterococcus faecalis and Proteus mirabilis) without releasing PVP-I in the environment (3). Furthermore, composite Zn-alginate hydrogels released zinc ions in addition to AC particles with adsorbed PVP-I, which induced additional microbicidal effects on one wild yeast strain (Candida albicans). The obtained bactericidal effects were ascribed to effective adsorption of bacteria onto AC particles and further direct contact with the adsorbed iodine, while the antifungal activity against C. albicans was assigned to released Zn 2+. Overall, the developed composite alginate hydrogels have shown high potentials for utilization in variety of multifunctional wound dressings according to the specific needs.Alginatni hidrogelovi se široko koriste u oblogama za rane zbog svoje hidrofilnosti, biokompatibilnosti, fleksibilnosti i velikog sorpcionog kapaciteta čime obezbeđuju efikasnu regulaciju vlažnosti rane i podstiču brzu granulaciju i reepitelizaciju oštećenog tkiva. Međutim, ove obloge nisu bioaktivne tako da su istraživane različite metodologije kako bi se proširila funkcionalnost alginatnih hidrogelova. U ovom radu je prikazano nekoliko pristupa ostvarivanju tog cilja dodatkom različitih biološki aktivnih komponenata. Ovi pristupi uključuju inkorporaciju nanočestica srebra kao potentnog antimikrobnog agensa (1), bioaktivnih komponenata meda (2), čestica aktivnog uglja (AU) kao nosača terapeutski aktivnih agenasa (3), kao i primenu hidrogelova Zn-alginata koji otpuštaju jone cinka. Dobijeni kompoziti su sveobuhvatno karakterisani u pogledu sastava, citotoksičnosti, antibakterijske aktivnosti, kinetike otpuštanja aktivnih agenasa i tretmana rana u eksperimentalnom modelu opekotina na pacovima. Ag/alginatni nanokompozitni hydrogelovi su usled otpuštanja jona i/ili nanočestica srebra, pokazali izraženu baktericidnu aktivnost prema širokom spektru standardnih i kliničkih multi- rezistentnih bakterijskih sojeva (Escherichia coli, Staphylococcus aureus, meticilin-resistentni Staphylococcus aureus – MRSA, Acinetobacter baumannii i Pseudomonas aeruginosa). Posebno interesantni rezultati su dobijeni u kulturama 13 kliničkih izolata A. baumannii, gde je u 6 slučajeva postignut potpun baktericidan efekat u toku 48 h (2). Ipak, kod 3 klinička izolata nije postignuto antibakterijsko dejstvo što ukazuje na mogućnost razvoja bakterijske rezistencije na srebro. U tretmanu opekotina drugog stepena na pacovima, Ag/alginatni nanokompoziti su pokazali istu efikasnost kao komercijalni medicinski proizvodi. Kompozitni alginatni hidrogelovi sa imobilisanim česticama AU impregniranih povidon-jodom kao model terapeutski aktivnom komponentom, su razvijeni sa ciljem da obezbede kontrolisano otpuštanje čestica AU u rani bez otpuštanja adsorbovane supstance kako bi se na taj način postiglo željeno dejstvo bez neželjenih efekata sistemske apsorpcije. Kompozitni Ca-alginatni hidrogelovi su pokazali jake baktericidne efekte na dva standardna bakterijska soja i nekoliko kliničkih multi- rezistentnih izolata iz rana (MRSA, E. coli, P. aeruginosa, Еnterococcus faecalis i Proteus mirabilis) bez otpuštanja povidon-joda u okolinu (3). Isto tako, kompozitni Zn-alginatni hidrogelovi su otpuštali jone cinka uz otpuštanje AU čestica sa adsorbovanim povidon-jodom što je prouzrokovalo dodatno mikrobicidno dejstvo na jedan divlji soj gljivice Candida albicans. Dobijeni baktericidni efekti su pripisani efikasnoj adsorpciji bakterija na čestice AU i daljem direktnom kontaktu adsorbovanog joda sa ćelijskom membranom bakterija, dok je antifungalna aktivnost u odnosu na C. albicans pripisana otpuštenim Zn 2+ jonima. Može se zaključiti da su razvijeni kompozitni alginatni hdrogelovi pokazali veliki potencijal za primenu u raznovrsnim multifunkcionalnim oblogama za rane prilagođenim specifičnim potrebama.Drugi naučni simpozijum Saveza farmaceutskih udruženja Srbije sa međunarodnim učešćem, 28. 10. 2021. Beogra

Influence of promoter polymorphisms of the TNF-α (-308G/A) and IL-6 (-174G/C) genes on therapeutic response to etanercept in rheumatoid arthritis

Uvod: Genetički faktori su značajni za predviđanje ishoda lečenja bolesnika sa reumatoidnim artritisom (RA). Cilj studije bio je da se ispita uticaj-308G/A TNF-α (rs 1800629) i -174G/C IL-6 (rs1800795) promotorskih polimorfizama na terapijski odgovor na etanercept. Metode: U studiju su bila uključena 73 pacijenta sa aktivnim RA. Terapijski odgovor je procenjivan posle 6 i 12 meseci terapije po kriterijumima Evropske lige protiv reumatizma. Genotipizacija pacijenata za polimorfizme -308G/A TNF-α i -174G/C IL-6 urađena je PCR-RFLP metodom i procenjivan je uticaj genotipova na odgovor na etanercept. Rezultati: Nije bilo razlike u procentu respondera (pacijenti kod kojih se DAS28 popravio gt 1,2) između pacijenata sa TNF-α -308GG, GA i AA genotipom ni posle 6 ni posle 12 meseci tretmana. Posle 12 meseci lečenja procenat respondera je bio značajno veći kod pacijenata sa IL-6 -174GG u odnosu na pacijente sa GC ili CC genotipom (p= 0,006, x2 test). Poređenje pacijenata prema kombinovanim IL-6/TNF-α genotipovima pokazalo je da je IL-6 -174GG / TNF-α -308GG genotip učestaliji kod respondera u odnosu na druge kombinovane genotipove (p= 0.022, x2 test). Tačnije, svi pacijenti sa kombinovanim IL-6 -174GG / TNF-α -308GG genotipom bili su responderi posle 12 meseci terapije etanerceptom. Zaključak: Studija pokazuje da bolesnici sa genotipovima koji se povezuju sa manjom produkcijom TNF-α i IL-6 najbolje odgovaraju na terapiju etanerceptom.Background: The study was undertaken to assess the influence of functional -308G /A TNF-α (rs 1800629) and -174G/C IL-6 (rs1800795) promoter polymorphisms on the therapeutic response to etanercept, a TNF-α blocker, in patients with rheumatoid arthritis (RA). Methods: Seventy-three patients suffering from active RA were studied, at baseline and 6 and 12 months after therapy. The therapeutic response was estimated according to the European League Against Rheumatism response criteria. Patients were genotyped for -308G /A TNF-α and -174G/C IL-6 polymorphisms by the PCR-RFLP method, and the influence of genotype on etanercept response was assessed. Results: No difference in the percentage of responders (patients who had DAS28 improvement gt 1.2) between patients with the TNF-α -308GG and GA and AA genotype was detected after 6 and 12 months of treatment. After 12 months of treatment the percentage of responders was significantly increased in patients with the IL-6 -174GG genotype compared with those with the GC or CC genotype (p=0.006 by Chi-square test). Evaluation of the patients according to their combined IL-6/TNF-α genotypes showed that patients with the IL-6 -174GG / TNF-α -308GG genotype were more frequent among the responders compared to those with other combined genotypes (p=0.022 by Chisquare test). More precisely, all patients with the combined IL-6 -174GG / TNF-α -308GG genotype were responders after 12 months of etanercept treatment. Conclusions: The study suggests that patients who are genetically low TNF-α and IL-6 producers are the best responders to etanercept therapy

Udruženost polimorfizama gena za katehol-O- metiltransferazu sa terapijskim odgovorom i komplikacijama izazvanim levodopom kod Parkinsonove bolesti: Rezime sadašnjih saznanja

Catechol-O-methyltransferase (COMT) is one of the cardinal enzymes in the degradation of catecholamines and levodopa. Genetic variants of the COMT gene may affect COMT enzyme activity. The most examined COMT gene polymorphism is the nonsynonymous single nucleotide polymorphism (SNP) in exon 4 (Val108/158Met; rs4680). This highly functional polymorphism is responsible for fourfold variations in enzyme activity and dopamine catabolism. Recent data suggested that even synonymous SNPs of the COMT gene can lead to changes in enzyme activity. Genetically determined COMT activity can affect an individual's response to levodopa therapy and carries the risk of complications from prolonged levodopa use in Parkinson's disease (PD) patients. Identifying at-risk individuals through genetic susceptibility markers could help to prevent the development of levodopa-induced complications in PD.Katehol-O-metiltransferaza (engl. catechol-O-methyltransferase, COMT) je jedan od glavnih enzima u razgradnji kateholamina i levodope. Genetske varijante COMT gena mogu uticati na aktivnost COMT enzima. Polimorfizam COMT gena koji je najviše proučavan je nesinonimni jednonukleotidni polimorfizam (engl. single nucleotide polymorphism, SNP) u egzonu 4 (Val108/158Met; rs4680). Ovaj visoko funkcionalni polimorfizam odgovoran je za četvorostruke varijacije u aktivnosti enzima i katabolizmu dopamina. Nedavni podaci sugerišu da čak i sinonimni SNP COMT gena mogu da dovedu do promena u aktivnosti enzima. Genetski određene razlike u COMT aktivnosti mogu uticati na odgovor pojedinca na terapiju levodopom i nose rizik od komplikacija dugotrajne primene levodope kod pacijenata sa Parkinsonovom bolešću (PB). Identifikacija osoba u riziku putem markera genetske osetljivosti može pomoći u prevenciji komplikacija izazvanih levodopom kod PB

Quercetin Ameliorates Experimental Autoimmune Myocarditis in Rats

Purpose. Experimental autoimmune myocarditis (EAM) in rats is an animal model of human giant cell myocarditis and post-myocarditis dilated cardiomyopathy. The pathogenesis of EAM has not been elucidated, but there is accumulating evidence that cytokines secreted from monocytes/macrophages and T cells play a crucial role in the induction and progression of disease. Flavonoids are a large group of polyphenolic compounds abundantly present in the human diet, which scavenge oxygen radicals and have anti-inflammatory activities. Having in mind in vivo beneficial effects of flavonoid quercetin in different animal models of immunoinflammatory diseases such as experimental autoimmune encephalomyelitis and adjuvant arthritis, on the one side, and its in vitro suppressive effect on production of tumor necrosis factor-alpha (TNF-alpha), on the other side, we investigated the effects of quercetin on EAM in rats. Methods. Myocarditis was induced in Dark Agouti (DA) rats by injection of porcine cardiac myosin and quercetin at doses of 10 or 20 mg/kg was orally administered from days 0 to 21 after induction of disease. The severity of myocarditis was evaluated by determination of heart weight/body weight ratio (Hw/Bw) and histopathological examination of hearts. The levels of cytokines (TNF-alpha, IL-12, IL-17 and IL-10) in serum and lymph node cells (LNC) culture supernatants were measured by ELISA. Results. The rats treated with 20 mg/kg of quercetin had significantly decreased incidence of EAM, Hw/Bw, macroscopic and microscopic scores of hearts. Further, in EAM rats treated with quercetin levels of TNF-alpha and IL-17 were significantly lower, while the level of IL-10 was significantly higher both in serum and culture supernatants of LNC stimulated with concanavalin A compared with vehicle-treated animals. Conclusions. The present study suggests that quercetin ameliorates EAM, at least in part, by interfering production of proinflammatory (TNF-alpha and IL-17) and/or anti-inflammatory (IL-10) cytokines