Dragan Milovanović, Danica Srećković-Batoćanin, Marija Savić and Dana Popovic
Petrology of plagiogranite from Sjenica, Dinaridic Ophiolite Belt (southwestern Serbia)
The Sjenica plagiogranite occurs in the southern part of the Dinaridic Ophiolite Belt, 5 km northwest of Sjenica. The main minerals are albite with strongly altered biotite (replaced with chlorite), with occasional amphibole (magnesio hornblende to tschermakite) and quartz. An enclave of fine-grained granitic rocks with garnet grains was noted too. Secondary minerals are calcite and chlorite (daphnite). Major, trace and REE geochemistry coupled with field observations support a model by which the Sjenica plagiogranite could be formed by fractional crystallization of mantle origin mafic magma in a supra-subduction zone setting. Occurrences of calcite and chlorite nests in the Sjenica plagiogranites revealed that these rocks underwent hydrothermal alteration due to intensive sea water circulation in a sub-sea-floor environment.
Bojana Stojanović, Jelena Milovanović, Aleksandar Arsenijević, Marija Milovanovic and Miodrag L. Lukic
B cells play a dual role in the pathogenesis of autoimmune diseases. In experimental autoimmune encephalomyelitis (EAE), an experimental model for multiple sclerosis, B cells contribute to disease progression, while their regulatory role predominates in the initial phases of disease development. Several studies have identified different subsets of regulatory B cells, mostly in the spleen, which are all sources of IL-10. However, peritoneal regulatory B cells are also important producers of IL-10, can migrate towards inflammatory stimuli, and could have an immunoregulatory function. As we have observed expansion of regulatory B cells in the peritoneum of resistant mice after EAE induction, herein we discuss the regulatory roles of B cells in EAE pathogenesis and the possible role of peritoneal regulatory B cells in resistance to EAE induction.
Sasa Benazic, Zana Besser Silconi, Jelena Milovanovic, Aleksandar Arsenijevic, Bojana Stojanovic, Marija Milovanovic and Tatjana Kanjevac
Metals are essential components in indispensable biochemical processes for living organisms. This review article highlights the metals zinc and gold in the development and treatment of breast cancer. Metal compounds off er many advantages as therapeutics due to their ability to coordinate ligands in a three-dimensional configuration. In aqueous solution, they form positively charged ions that can bind to negatively charged biological molecules. Metal complexes that contain metal ions such as zinc(II) and gold have received considerable attention as potential anticancer agents. Zinc is an essential trace element that plays a critical role in a wide range of cellular processes that include structural, signalling, catalytic and regulatory functions. Zinc acts as a key structural component in many proteins and enzymes, including transcription factors, cellular signalling proteins, and DNA repair enzymes, and perturbed levels of zinc in tissues may play a role in cancer aetiology and outcome. Unlike zinc, gold is feasible as a component of compounds for effective anticancer therapy. Some progress in anticancer therapy may include interactions between zinc and gold.
Jelena Milovanovic, Aleksandar Arsenijevic, Bojana Stojanovic, Marija Milovanovic, Stipan Jonjic, Branka Popovic, Nebojsa Arsenijevic and Miodrag L. Lukic
Viral infection has been identified as the most likely environmental trigger of multiple sclerosis (MS). There are conflicting data regarding the role of cytomegalovirus (CMV) in MS pathogenesis.
We utilised experimental autoimmune encephalomyelitis (EAE)-resistant BALB/c mice and murine cytomegalovirus (MCMV), the murine homolog of CMV, to examine the mechanism by which viral infection enhances autoimmune neuroinflammation. Mice subjected to latent neonatal MCMV infection developed the typical characteristics of EAE. Similar to MS, the MCMV-infected EAE-induced mice developed infiltrates in the central nervous system (CNS) composed of similar percentages of CD4+ and CD8+ T cells. The influx of both Th 1 and Th 17 cells into the CNS of MCMV- infected EAE-induced mice was observed. Interestingly, the development of autoimmune neuroinflammation after latent MCMV infection was accompanied by a significant influx of Tc17 cells (CD8+IL-17+ and CD8+RoRγt+) but not Tc1, cells. Our results suggest that latent MCMV infection affects the development of inflammatory lymphocytes that exhibit encephalitogenic potential, thereby mediating increased CNS pathology following EAE induction, and that CMV represents a possible environmental factor in the pathogenesis of MS and other autoimmune diseases
Žana Besser Silconi, Sasa Benazic, Jelena Milovanovic, Aleksandar Arsenijevic, Bojana Stojanovic, Marija Milovanovic and Tatjana Kanjevac
Since the discovery of the antitumor activity of cisplatin by Rosenberg and co-workers, the use of metal complexes in cancer treatment has caused a huge interest. Today, platinum-based drugs are part of standard chemotherapy in the management of a variety of ca ncers, germ cell tumours, sarcomas, and lymphomas. Unfortunately, toxicity and drug resistance are major obstacles to wider clinical application of these drugs. Their use is greatly limited by severe side effects such as nephrotoxicity, ototoxicity, and neurotoxicity. Although cisplatin is one of the most successful anticancer drugs to date, its biochemical mechanism of action is still unclear. Cisplatin is generally accepted as having the ability to interact with the purine bases on the DNA, causing DNA damage, interfering with DNA repair mechanisms, and subsequently inducing apoptosis in cancer cells.
Chronic lymphocytic leukaemia is a neoplastic B cell lymphoproliferative disease characterized by a highly variable clinical course. Clinical stage at the diagnosis and biological prognostic factors are the important predictors for survival. The Rai and Binet staging systems describe three major prognostic subgroups. Commonly used prognostic biomarkers in chronic lymphocytic leukaemia can be divided into genotypic, DNA-level changes and phenotypic, expression-level changes. For chronic lymphocytic leukaemia, substantial progress in therapy has not been made over the past 40 years. The main goal of future scientific research is to find new platinum complexes that have better efficacy in cancer treatment, the ability to be administered orally, without developing a cancer-drug resistance, and reduced toxic side effects.
Dragana Dragas Milovanovic, Ivan Radosavljevic, Marija Radovanovic, Jasmina R. Milovanovic, Slobodan Obradovic, Slobodan Jankovic, Dragan Milovanovic and Natasa Djordjevic
Carbamazepine exhibits significant inter-individual variability in its efficacy and safety, which leads to unpredictable therapy outcomes for the majority of patients. Although its complex biotransformation depends on CYP3A5 activity, evidence of association between carbamazepine treatment outcomes and CYP3A5 functional variations remains inconclusive. The aim of the present study was to investigate the distribution of two of the functionally important CYP3A5 variants *2 and *3 as well as their effects on carbamazepine dose requirements, plasma concentrations and clearance in a Serbian population. The study involved 40 paediatric epileptic patients on steady-state carbamazepine treatment. Genotyping was conducted using the PCR-RFLP method, and carbamazepine plasma concentrations were determined using the HPLC method. CYP3A5*2 and *3 polymorphisms were found at frequencies of 0.0% and 97.5%, respectively, which corresponds well to previously published data for Caucasians. No differences in CYP3A5*3 allele frequencies were detected among epileptic patients in comparison to healthy volunteers within similar ethnic populations (p>0.08), indicating that CYP3A5 polymorphism does not represent a risk factor for epilepsy development. There was an observed tendency towards lower dosage requirements (mean±SD: 15.06±4.45 mg/kg vs. 18.74±5.55 mg/kg; p=0.26), higher plasma concentrations (mean±SD: 0.45±0.13 mg/kg vs. 0.38±0.03 mg/kg; p=0.47) and lower clearance (mean±SD: 0.14±0.05 mg/kg vs. 0.15±0.01 mg/kg; p=0.79) of carbamazepine in homozygous carriers of CYP3A5*3/*3 compared to heterozygous CYP3A5*1A/*3 Serbians. Because these genotype groups did not differ significantly in terms of their carbamazepine pharmacokinetics parameters, the proposed effects of CYP3A5*3 on carbamazepine metabolism could not be confirmed.
Dragana Djordjevic, Jelena Milovanovic, Milena Jurisevic, Bojana Stojanovic, Olga Cvetkovic, Marija Pergal, Elizabeta Ristanovic, Danilo Vojvodic, Milos Simic, Dragan Manojlovic, Marija Milovanovic and Nebojsa Arsenijevic
Copper serves as a limiting factor for multiple steps of tumour progression, including angiogenesis, growth and metastasis. High levels of copper have been found in a wide spectrum of human cancers. Antitumour activities of copper-chelating drugs have been reported in animal models. Organosulfur compounds (diallyl sulfi de, DAS; diallyl disulfi de, DADS; S-ethylcysteine, SEC; N-acetylcysteine, NAC) derived from garlic exhibit marked copper- chelating activity. We analysed a mixture of fi fteen n-propyl polysulfi des (DPPS) for potential antitumour activity against several murine tumour cell lines, including colon carcinoma (CT26), mammary carcinoma (4T1) and melanoma cell lines (B16F10), and compared the eff ects with the antiproliferative eff ect in highly proliferative murine mesenchymal stem cells (mMSCs). Th e eff ects of the mixture of n-propyl polysulfi des (100%) on cell viability were determined using MTT assays. Cell apoptosis was analysed using Annexin V-FITC/PI assays. Th e results of the MTT assays indicate that this standardized mixture of n-propyl polysulfi des has a strong, dose-dependent cytotoxic eff ect against all three of the tested tumour cell lines (CT26, 4T1, B16F10). Th e cytotoxic eff ect of the n-propyl polysulfi de mixture against the CT26 and B16F10 cell lines was much stronger than that of cisplatin and was signifi cantly weaker in mMSCs, which are non-cancerous and highly proliferative cells, than in cancer cells. Flow cytometric analysis of CT26 and 4T1 cells revealed that apoptosis was not the dominant mechanism of cell death induced by the n-propyl polysulfi de mixture. Th e n-propyl polysulfi de mixture exerted highly cytotoxic activity against murine colon carcinoma and melanoma cell lines, but its antiproliferative activity against mMSCs was signifi cantly lower than that of cisplatin.
Milena Jurisevic, Gordana Radosavljevic, Aleksandar Arsenijevic, Marija Milovanovic, Nevena Gajovic, Dragana Djordjevic, Jelena Milovanovic, Bojana Stojanovic, Aleksandar Ilic, Tibor Sabo and Tatjana Kanjevac
The design of platinum based drugs is not a new field of interest. Platinum complexes are widely used as anticancer agents and currently, approximately 30 platinum(II) and platinum(IV) entered into some of the phases of clinical trials. A special place in today’s research belongs to platinum complexes with diammine ligands. A large number of edda (ethylenediamine- N, N’-diacetate)-type ligands and their corresponding metal complexes has been successfully synthesized. This article summarizes recent progress in research on edda-type-platinum complexes. Some of these agents achieves better effect compared to the gold standard (cisplatin). It has been shown that there is a possible relationship between the length of the ligand ester group carbon chain and its cytotoxic effect. In most cases the longer the ester chain is the greater is the antitumor activity. Of particular interest are the noticeable effects of some new platinum compound with edda-type ligand on cell lines that are known to have a high level of cisplatin-resistance. Exanimate complexes appear to have a different mode of mechanism of action compared with cisplatin which includes apoptotic and necrotic cell death. There are indications that further investigations of these compounds may be very useful in overcoming the problems associated global cancer statistic.
Aleksandar Arsenijevic, Jelena Milovanovic, Bojana Stojanovic, Marija Milovanovic, Eric M. Gershwin, Patrick Leung, Nebojsa Arsenijevic and Miodrag L. Lukic
Primary biliary cirrhosis (PBC) is an autoimmune disease of the liver that is, characterised by destruction of the intrahepatic bile ducts and the presence of antimitochondrial antibodies (AMAs). Several murine models of PBC, with similar serological, biochemical, and histological features to human PBC, have been developed in recent years. These animal models enable investigators to study the etiology and pathophysiologic mechanism of PBC. Immune response in PBC is directed towards E2 components of the 2-oxo-acid dehydrogenase family of enzymes, which is in located in mitochondria and is an immunodominant epitope (a lipoylated peptide sequence shared by enzymes). Immunisation of mice with 2-octynoic acid coupled to bovine serum albumin (2-OA-BSA) (which is an antigen that is structurally related to the E2 subunit of the pyruvate dehydrogenase complex [PDC-E2]) produces histologic features similar to those found in human PBC. Th is model of xenobiotic induced PBC is suitable for studying the early events in PBC pathogenesis and for developing new therapeutics in PBC.
Boban Milovanović, Dušan Tomović, Slobodan M. Janković, Iva Grubor, Ljiljana Nikolić, Miloš Nikolić, Marina Mijajlović, Strahinja Mrvić, Ana Divjak, Andjela Milojević, Jelena Djoković, Andjelka Prokić, Andriana Bukonjić, Marija Sekulić, Vesna Matić, Djordje Vukmirović, Bojan Rakonjac, Tanja Dimitrijević, Nataša Nikolić, Dragutin Jovanović, Jelena Milovanović, Marija Ratković, Nevena Barudžić, Nenad Mladenović, Milan Milutinović, Ana Antanasković and Milena Nikolić
Fear of needles can significantly limit professional and social functioning of a person, and is highly prevalent in general population (4%).
The aim of our study was to reveal risk factors that are associated with fear of needles among healthy university students of medicine and pharmacy.
The study was of a cross-sectional type. In total, 301 students of medicine or pharmacy (82% female and 18% male) attending from 1st to 5th year of study were surveyed at the Faculty of Medical Sciences, University of Kragujevac, Serbia. The students were surveyed using a questionnaires (scales) for assessing the fear of needless, a visual analog scale for self-assessment intensity of the fear of needless, and a general questionnaire with questions about socio-demographic characteristics of the participants. Using a score on the scales as out-come variables, multiple regressions were employed to reveal factors that may influence the fear of needles.
Average values of Blood/Injection Fear Scale, Injection Phobia Scale-Anxiety and Medical Avoidance Survey scores were 7.89 ± 9.48, 4.46 ± 5.18 and 89.95 ± 12.73, respectively. The following factors affected significantly the score of the scales: course of study, chronic disease in the family, fear of a dentist, smell of the room phobia, sound phobia, score on the Beck’s anxiety scale and fear of a situation when medical staff give an injection. The presence of chronic disease in the family was a protective factor, while the other six factors were contributing to the fear of needles.
Fear of needles is more prevalent among the students of pharmacy than among the students of medicine. It is less frequent among students with chronic disease in their family, while fear of dentist, smell of the room phobia, sound phobia, general anxiety and fear from the situation when medical staff give an injection are all factors that predispose students of medicine or pharmacy to develop fear of needles.