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Bioactive peptides are promising cosmetic active ingredients that can improve skin healthand appearance. They exhibit a broad spectrum of activity, including anti-aging, antioxidant, an-timicrobial, and anti-inflammatory effects. The aim of this study was to develop a safe, stable, andefficacious environmentally friendly (“green”) emulsion using a milk protein hydrolysate as a modelactive ingredient. Potential emulsions were formulated with biodegradable emollients, stabilizedwith naturally derived mixed emulsifier, and prepared by cold process. They were evaluated forrheological behavior (continuous rotation and oscillation tests), physical stability (dynamic me-chanical thermal analysis—DMTA test), and texture profiles, as well as cytotoxic, antioxidant, andantimicrobial effects. Rheological characterization revealed shear-thinning flow behavior with yieldpoint from continuous rotation tests and predominantly elastic character from oscillation (amplitudeand frequency sweep) tests, with small structural change detected in the DMTA test. These resultsimplied satisfactory rheological properties and good stability. Texture analysis revealed acceptablespreadability and substantivity of the emulsions. The protein hydrolysate showed antioxidant activity.The developed emulsions showed low antibacterial activity against selected microorganisms, butthis was due to the action of preservatives, not peptides. All potential emulsions showed a desirablesafety profile. The results obtained provide the basis for the next stage of formulation development,i.e., in vivo efficacy tests.

Dry olive leaf extract (DOLE) and its active component oleuropein (OLE) were applied as reducing and stabilizing agents to prepare colloidal 20–25 nm silver nanoparticles (Ag NPs). The Ag NPs were characterized using transmission electron microscopy, X-ray diffraction analysis, and absorption spectroscopy. The cytotoxic actions of coated Ag NPs, and their inorganic and organic components, were examined against trophoblast cells and human peripheral blood lymphocytes (PBLs), Gram-positive, Gram-negative bacteria, and yeast. The genotoxic potential was evaluated in PBLs in vitro with the comet assay. Ag/DOLE and Ag/OLE induced cytotoxic effects in both types of cells after 24 h exposure when silver concentrations were 0.025–0.2 mM. However, the most pronounced cytotoxicity exhibits Ag/OLE. Both colloids also caused reduced ROS production in both cell types at 0.1 mM and 0.2 mM, while bare Ag NPs did not alter ROS levels at any of the conditions. Functionalized Ag/DOLE and Ag/OLE did not show genotoxic effects in PBLs, while bare AgNPs increased DNA damage significantly only at 0.2 mM. Regarding the antimicrobial effects, the Ag/OLE had MIC values for all evaluated microorganisms from 0.0625 to less than 0.0312 mM. Also, the antimicrobial effect of Ag/DOLE was significantly higher on Gram-negative bacteria and yeast than on Gram-positive bacteria. Obtained results indicate that Ag/OLE induced the most pronounced biological effects, beneficial for its application as an antimicrobial agent, but with potential risks from exposure to high concentrations that could induce cytotoxicity in healthy human cells.

The current study describes the experimental design guided development of PEGylated nanoemulsions as parenteral delivery systems for curcumin, a powerful antioxidant, as well as the evaluation of their physicochemical characteristics and antioxidant activity during the two years of storage. Experimental design setup helped development of nanoemulsion templates with critical quality attributes in line with parenteral application route. Curcumin-loaded nanoemulsions showed mean droplet size about 105 nm, polydispersity index <0.15, zeta potential of −40 mV, and acceptable osmolality of about 550 mOsm/kg. After two years of storage at room temperature, all formulations remained stable. Moreover, antioxidant activity remained intact, as demonstrated by DPPH (IC50 values 0.078–0.075 mg/mL after two years) and FRAPS assays. In vitro release testing proved that PEGylated phospholipids slowed down the curcumin release from nanoemulsions. The nanoemulsion carrier has been proven safe by the MTT test conducted with MRC-5 cell line, and effective on LS cell line. Results from the pharmacokinetic pilot study implied the PEGylated nanoemulsions improved plasma residence of curcumin 20 min after intravenous administration, compared to the non-PEGylated nanoemulsion (two-fold higher) or curcumin solution (three-fold higher). Overall, conclusion suggests that developed PEGylated nanoemulsions present an acceptable delivery system for parenteral administration of curcumin, being effective in preserving its stability and antioxidant capacity at the level highly comparable to the initial findings.

This study focuses on the development of biocompatible oil-in-water (O/W) nanoemulsions based on polyglycerol esters, as promising carriers for natural actives: red raspberry seed oil—RO and hydro-glycolic fruit extracts from red raspberry—RE and French oak—FE. Nanoemulsions were obtained via phase inversion composition (PIC) method at room temperature by dilution of microemulsion phase, confirmed by visual appearance, percentage of transmittance, microscopic, rheological and Differential Scanning Calorimetry (DSC) investigations. The results have shown that the basic RO-loaded formulation could be further enriched with hydro-glycolic fruit extracts from red raspberry or French oak, while keeping a semi-transparent appearance due to the fine droplet size (Z-ave: 50 to 70 nm, PDI value ≤ 0.1). The highest antioxidant activity (~92% inhibition of the DPPH radical) was achieved in the formulation containing both lipophilic (RO) and hydrophilic antioxidants (FE), due to their synergistic effect. The nanoemulsion carrier significantly increased the selective cytotoxic effect of RO towards malignant melanoma (Fem-X) cells, compared to normal human keratinocytes (HaCaT). In vivo study on human volunteers showed satisfactory safety profiles and significant improvement in skin hydration during 2 h after application for all nanoemulsions. Therefore, polyglycerol ester-based nanoemulsions can be promoted as effective carriers for red raspberry seed oil and/or hydro-glycolic fruit extracts in topical formulations intended for skin protection and hydration.

The amount of organic pomace, left behind agricultural processes, is continuously rising in accordance with industrial progress. Grape pomace, generated in the wine industry all over the world, represents a raw material for obtaining valuable products. Grape seeds are especially rich in oil containing bioactive compounds that can have various health-related effects. The aim of the study is to compare the quality of seed oils obtained from six white grapes, including two Serbian autochthonous varieties. Linoleic acid, associated with numerous health benefits, is the major fatty acid in all samples (≈66% of total); α-tocopherol is the main tocopherol homologue. Total polyphenol content ranges from 73.4 to 104.3 mg of gallic acid equivalents per 100 g. In order to provide comprehensive information about antioxidant capacity of grape seed oil (GSO), three tests are performed (ferric ion reducing antioxidant power; 2,2’-diphenyl-1-picrylhydrazyl, and 2,2’-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid) radical scavenging). Antimicrobial activity is investigated against different strains; however, GSO inhibits the growth of Staphylococcus aureus and Candida albicans. Obtained results are used to develop a novel approach for oil quality assessment. Calculated oil quality scores (OQS) reveal no significant difference between international and autochthonous varieties, although Smederevka stands out as the most potent one. Practical applications: Considering the progressive waste increase in the wine industry and keeping in mind all health-promoting effects of grape seed oil (GSO), it is clearly observed that oil production represents a profitable and sustainable utilization of grape seeds. The results of the present study show that GSO is a rich source of compounds with antioxidant and antimicrobial properties. In addition, this work provides deeper insight into a quality of Serbian autochthonous grape varieties that are still insufficiently explored. Furthermore, the prop

Mahonia aquifolium and its secondary metabolites have been shown to have anticancer potential. We performed MTT, scratch, and colony formation assays; analyzed cell cycle phase distribution and doxorubicin uptake and retention with flow cytometry; and detected alterations in the expression of genes involved in the formation of cell-cell interactions and migration using quantitative real-time PCR following treatment of lung adenocarcinoma cells with doxorubicin, M. aquifolium extracts, or their combination. MTT assay results suggested strong synergistic effects of the combined treatments, and their application led to an increase in cell numbers in the subG1 phase of the cell cycle. Both extracts were shown to prolong doxorubicin retention time in cancer cells, while the application of doxorubicin/extract combination led to a decrease in MMP9 expression. Furthermore, cells treated with doxorubicin/extract combinations were shown to have lower migratory and colony formation potentials than untreated cells or cells treated with doxorubicin alone. The obtained results suggest that nontoxic M. aquifolium extracts can enhance the activity of doxorubicin, thus potentially allowing the application of lower doxorubicin doses in vivo, which may decrease its toxic effects in normal tissues.

As the number of poorly soluble drugs is increasing, nanocrystals have become very interesting due to wide range of application possibilities. Curcuminwas used as a model active ingredient in this work. Even though it has many proven positive effects, due to its physicochemical issues, its possibilities have not been fully exploited. The goal of this work was to select optimal conditions for a top-down method for curcumin nanosuspension production, and to perform their comprehensive characterization applying complementary methodologies: dynamic light scattering, polarization and atomic force microscopy, thermal analysis, X-ray powder diffraction, antioxidant activity evaluation, release kinetics assessment, and screening of potential biological effects applying cell viability assays on normal human lung fibroblasts, human melanoma and human adenomacarcinoma cells. After 30 min of milling, nanosuspensions stabilized by polysorbate 80 and by its combinations with sucrose palmitate showed good stability, while curcumin crystal structure was unaltered. Obtained nanocrystals were well defined, with average diameter 120-170 nm and PDI of about 0.25, zeta potential was below -30 mV and pH~5 for all formulations. Nanodispersions exhibited high antioxidant potential and improved dissolution rate compared to the corresponding coarse dispersions. Although curcumin nanodispersions exhibited significant antiproliferative effect to each cancer cell line, the highest effect was towards adenocarcinoma cells.

Considering a growing demand for medicinal/cosmetic products with natural actives, this study focuses on the low-energy nanoemulsions (LE-NEs) prepared via the Phase inversion composition (PIC) method at room temperature as potential carriers for natural oil. Four different red raspberry seed oils (ROs) were tested, as follows: cold-pressed vs. CO2- extracted, organic vs. non-organic, refined vs. unrefined. The oil phase was optimized with Tocopheryl acetate and Isostearyl isostearate, while water phase was adjusted with either glycerol or an antioxidant hydro-glycolic extract. This study has used a combined approach to formulation development, employing both conventional methods (pseudo-ternary phase diagram - PTPD, electrical conductivity, particle size measurements, microscopical analysis, and rheological measurements) and the methods novel to this area, such as textural analysis and Raman spectroscopy. Raman spectroscopy has detected fine differences in chemical composition among ROs, and it detected the interactions within nanoemulsions. It was shown that the cold-pressed, unrefined, organic grade oil (RO2) with 6.62% saturated fatty acids and 92.25% unsaturated fatty acids, was optimal for the LE-NEs. Textural analysis confirmed the existence of cubic gel-like phase as a crucial step in the formation of stable RO2-loaded LE-NEs, with droplets in the narrow nano-range (125 to 135 nm; PDI ≤ 0.1). The DPPH test in methanol and ABTS in aqueous medium have revealed a synergistic free radical scavenging effect between lipophilic and hydrophilic antioxidants in LE-NEs. The nanoemulsion carrier has improved the biological effect of raw materials on HeLa cervical adenocarcinoma cells, while exhibiting good safety profile, as confirmed on MRC-5 normal human lung fibroblasts. Overall, this study has shown that low-energy nanoemulsions present very promising carriers for topical delivery of natural bioactives. Raman spectroscopy and textural analysis have proven to be a u

The complement system plays an important role in host defense. It is composed of series of plasma proteins which, when activated in a sequential reaction, unleashes a powerful destructive activity towards invading pathogens. Three major pathways exist in the activation of complement: the classical pathway, which is initiated by antibody-antigen binding, the alternative pathway, which is activated by a susceptible foreign surface, and the lectin pathways, which can be triggered by manann-binding lectins. The complement system consists of serum and cell surface proteins that interact with one another and with other molecules of the immune system in a highly regulated manner. Complement proteins are plasma proteins that are normally inactive and they are activated only under particular conditions to generate products that mediate various effector functions of the complement., Sistem komplementa ima značajnu ulogu u odbrani domaćina od patogena. Sastoji se od niza proteina plazme koji se aktiviraju u kaskadnom procesu, dovodeći do oštećenja patogena. Opisana su tri puta aktivacije sistema komplementa: klasičan (aktivira se vezivanjem C1q komponente komplementa za kompleks antigen-antitelo), alternativni (aktivira se direktnim vezivanjem C3b komponente komplementa za površinske molekule mikroorganizama) i lektinski (indukovan je vezivanjem manoza vezućeg proteina za manozne rezidue na površini mikroorganizama). Najvažnija uloga sistema komplementa u urođenom i specifičnom imunitetu je stimulisanje fagocitoze, liza mikroorganizama i pospešivanje inflamacije. Komplement ima ključnu ulogu i u uklanjanju imunskih kompleksa.

Na osnovu podataka o upotrebi vrste Mahonia aquifolium u tradicionalnoj medicini definisan je cilj našeg istraživanja, ispitivanje antitumorske i antimikrobne aktivnosti ekstrakata kore mahonije.Ispitivanjem citotoksičnosti vodenog i etanolnog ekstrakta na humanim malignim ćelijskim linijama je dokazano da ekstrakti imaju selektivnu citotoksičnu aktivnost, a najviši intenzitet dejstva su pokazali na HeLa ćelijama adenokarcinoma cerviksa. Fluorescentnom mikroskopijom i analizom faza ćelijskog ciklusa je pokazano da ekstrakti indukuju apoptozu u HeLa ćelijama. Primenom inhibitora kaspaza pokazano je da ekstrakti indukuju apoptozu preko spoljašnjeg puta aktivacije. Ispitivanja na endotelijalnim EA.hy926 ćelijama pokazala su antiangiogenetski i antimigratorni efekat ekstrakata.Primena tretmana doksorubicin/ekstrakt ukazala je na izraženo sinergističko dejstvo ekstrakta sa doksorubicinom na A549 ćelijama karcinoma pluća. Ekstrakti povećavaju zadržavanje leka u ćeliji i pojačavaju efekat doksorubicina na smanjenje migracije A549 ćelija i njihovo grupisanje u kolonije. Antimetastatski potencijal kombinacije doksorubicin/ekstrakt potvrđen je analizom ekspresije gena odgovornih za invazivnost.Oba ekstrakta ispoljavaju antimikrobni efekat, koji je najizraženiji na bakterijskoj vrsti Staphylococcus aureus. Ekstrakti dovode do smanjenja produkcije biofilma i glikokaliksa. Sa antibioticima i antimikoticima ekstrakti su delovali sinergistički.Hemijskom analizom potvrđeno je da su za aktivnost ekstrakata M. aquifolium odgovorni alkaloidi tipa berberina. Na intenzitet citotoksičnosti najviše utiču berberin, palmatin i berbamin.Rezultati su pokazali da M. aquifolium može naći svoje mesto u terapiji malignih ili infektivnih oboljenja, pojedinačno i u kombinaciji sa postojećim lekovima., The goal of our research was investigation of antitumor and antimicrobial activities of Mahonia aquifolium extracts and it was based on its use in traditional medicine. Water and ethanol extract exerted selective cytotoxic activity on examined malignant cell lines, and the best activity was observed against cervical adenocarcinoma, HeLa, cells. Fluorescence microscopy and cell cycle analysis showed that both extracts induce apoptosis in HeLa cells. Experiments with caspase inhibitors showed that extracts induce a caspase-dependent apoptosis through extrinsic pathway. Both extracts inhibit the migration of EA.hy926 cells, and exerted anti-angiogenic effect.The investigation of the doxorubicine/extract treatment showed synergistic effect of extracts with doxorubicine against lung carcinoma A549, cells. Extracts were shown to prolong doxorubicin retention time in A549 cells. A549 cells treated with doxorubicin/extract were shown to have lower migratory and colony formation potentials than the cells treated with doxorubicin alone. Antimetastatic effect of the treatment was confirmed with analysis of expression of genes responsible for malignant cells invasiveness.Extracts exerted antimicrobial effect. The best effect was observed against Staphylococcus aureus. Extracts showed potential to inhibit production of biofilm and glycocalycs. The use of extracts with antibiotics and antimycotics showed synergistic effect.Chemical analysis confirmed that berberine type alkaloids are the most responsible for activities of M. aquifolium. The compounds with the highest cytotoxic activity are: berberine, palmatine, and berbamine.The results of our research suggested that M. aquifolium may be used in therapy of malignant or infective diseases, alone or in combination with other drugs.

Na osnovu podataka o upotrebi vrste Mahonia aquifolium u tradicionalnoj medicini definisan je cilj našeg istraživanja, ispitivanje antitumorske i antimikrobne aktivnosti ekstrakata kore mahonije. Ispitivanjem citotoksičnosti vodenog i etanolnog ekstrakta na humanim malignim ćelijskim linijama je dokazano da ekstrakti imaju selektivnu citotoksičnu aktivnost, a najviši intenzitet dejstva su pokazali na HeLa ćelijama adenokarcinoma cerviksa. Fluorescentnom mikroskopijom i analizom faza ćelijskog ciklusa je pokazano da ekstrakti indukuju apoptozu u HeLa ćelijama. Primenom inhibitora kaspaza pokazano je da ekstrakti indukuju apoptozu preko spoljašnjeg puta aktivacije. Ispitivanja na endotelijalnim EA.hy926 ćelijama pokazala su antiangiogenetski i antimigratorni efekat ekstrakata. Primena tretmana doksorubicin/ekstrakt ukazala je na izraženo sinergističko dejstvo ekstrakta sa doksorubicinom na A549 ćelijama karcinoma pluća. Ekstrakti povećavaju zadržavanje leka u ćeliji i pojačavaju efekat doksorubicina na smanjenje migracije A549 ćelija i njihovo grupisanje u kolonije. Antimetastatski potencijal kombinacije doksorubicin/ekstrakt potvrđen je analizom ekspresije gena odgovornih za invazivnost. Oba ekstrakta ispoljavaju antimikrobni efekat, koji je najizraženiji na bakterijskoj vrsti Staphylococcus aureus. Ekstrakti dovode do smanjenja produkcije biofilma i glikokaliksa. Sa antibioticima i antimikoticima ekstrakti su delovali sinergistički. Hemijskom analizom potvrđeno je da su za aktivnost ekstrakata M. aquifolium odgovorni alkaloidi tipa berberina. Na intenzitet citotoksičnosti najviše utiču berberin, palmatin i berbamin. Rezultati su pokazali da M. aquifolium može naći svoje mesto u terapiji malignih ili infektivnih oboljenja, pojedinačno i u kombinaciji sa postojećim lekovima., The goal of our research was investigation of antitumor and antimicrobial activities of Mahonia aquifolium extracts and it was based on its use in traditional medicine. Water and ethanol extract exerted selective cytotoxic activity on examined malignant cell lines, and the best activity was observed against cervical adenocarcinoma, HeLa, cells. Fluorescence microscopy and cell cycle analysis showed that both extracts induce apoptosis in HeLa cells. Experiments with caspase inhibitors showed that extracts induce a caspase-dependent apoptosis through extrinsic pathway. Both extracts inhibit the migration of EA.hy926 cells, and exerted anti-angiogenic effect. The investigation of the doxorubicine/extract treatment showed synergistic effect of extracts with doxorubicine against lung carcinoma A549, cells. Extracts were shown to prolong doxorubicin retention time in A549 cells. A549 cells treated with doxorubicin/extract were shown to have lower migratory and colony formation potentials than the cells treated with doxorubicin alone. Antimetastatic effect of the treatment was confirmed with analysis of expression of genes responsible for malignant cells invasiveness. Extracts exerted antimicrobial effect. The best effect was observed against Staphylococcus aureus. Extracts showed potential to inhibit production of biofilm and glycocalycs. The use of extracts with antibiotics and antimycotics showed synergistic effect. Chemical analysis confirmed that berberine type alkaloids are the most responsible for activities of M. aquifolium. The compounds with the highest cytotoxic activity are: berberine, palmatine, and berbamine. The results of our research suggested that M. aquifolium may be used in therapy of malignant or infective diseases, alone or in combination with other drugs.

AbstrcatNew cationic tetranuclear Co(II) and neutral binuclear Cu(II) complexes with tpmc (N,N,N,N-tetrakis-(2-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane) and bridging pyromellitate ligand pma (tetraanion 1,2,4,5-benzenetetracarboxylic acid) were isolated. The composition of the compounds is proposed based on elemental analyses (C, H, N, M=Cu, Co), molar conductivity determination, UV-Vis, FTIR, EPR, LC-MS and reflectance spectroscopy, magnetic measurements, cyclic voltammetry, as well as TG and DTA. It is proposed that in [Co-4(pma)(tpmc)(2)](ClO4)(4)6H(2)O (1), cobalt(II) is six-coordinate out of cyclam rings and one OCO- from pma participates in coordination with one Co(II). In the case of [Cu-2(pma)tpmc].8H(2)O (2), one OCO- from pma bridges two Cu(II). The cytotoxic activity of 1 and 2 was tested against tumor cell lines human cervix adenocarcinoma (HeLa), estrogen-receptor-positive human breast cancer (MCF-7), human myelogenous leukemia (K562), and the human Caucasian Burkitt's lymphoma (Ramos). The IC50 values for 1 and 2 were within the range 44.66 +/- 2.39 to 152.40 +/- 2.28M, and from 140.88 +/- 3.51 to 192.05 +/- 2.09M, respectively. Both 1 and 2 were tested for antimicrobial activity. We determined that minimal inhibitory concentration for 1 against Staphylococcus aureus, Bacillus subtilis, and Klebsiella pneumoniae was 25mM. Complex 2 did not express activity against tested microbial strains.

Zoonosis is any disease or infection that is naturally transmissible from animals to human and vice-versa. Zoonoses are an important issue of many countries in the world, and more than 200 has been recognized by now. Pathogenic agents that cause zoonoses are parasites, bacteria, fungi, viruses and prions. Trichinella spiralis is a cylindric parasite that causes trichinellosis. Trichinellosis is a disease that is transmitted by ingestion of meat contaminated by larva. Treatment is often with no success, but prevention and cooperation between veterinary and human medical sector plays an important role in saving human health., Sve bolesti ili infekcije koje se prirodnim putem mogu preneti sa životinja na čoveka i obrnuto svrstavamo u zoonoze. Zoonoze su problem u brojnim državama, a do sada je opisano više od 200 ovakvih bolesti. Jedna od klasifikacija zoonoza je na osnovu uzročnika bolesti koji može biti parazit, bakterija, virus, gljivica ili prion. Trichinella spiralis je parazit valjkastog oblika koji izaziva trihinelozu. Ovo je bolest koja se prenosi ingestijom mesa koje sadrži larve trihinele. Bolest je moguće lečiti, ali primarno se radi na prevenciji trihineloze. Lečenje često nije uspešno, ali prevencija i saradnja veterinarskog sektora i sektora humane medicine igra značajnu ulogu u očuvanju zdravlja ljudi.

The aim of the present study was to reveal the potential biological activities of the dichlorometane: methanol (1:1) dry extract (DME) and the nutritional value of selected seaweeds: Cymodocea nodosa, Halimeda tuna, Cystoseira barbata and Codium bursa, collected from the Adriatic coast, Montenegro. We assessed the chemical composition and several biological activities such as: anti-a-glucosidase, antitumour, antimicrobial and antioxidative activity. H. tuna had the best cytotoxic activity against human colon carcinoma cell line, LS174 (IC50 = 17.92 +/- 1.54 mu g/mL). C. nodosa demonstrated strong cytotoxicity against human adenocarcinoma cell line, HeLa (IC50 = 13.28 +/- 0.39 mu g/mL) and human chronic myelogenous leukaemia cell line, K562 (IC50 = 19.64 +/- 1.55 mu g/mL). C. barbata had the best anti a-glucosidase (IC50 = 9.98 +/- 3.34 mu g/mL) and antimicrobial activity (minimal inhibitory concentration of 100 mu g/mL) for Staphylococcus aureus and Bacillus subtilis. C. bursa showed the highest nutritional value (490.4 kcal).

A novel and efficient synthetic route was developed for the preparation of protoberberine derivatives. A methodology, designed primarily to control the substitution patterns on the terminal rings, was used to access a small array of these compounds. An initial biological profiling suggested an anticancer potential of the synthesised derivatives, while structure-based target fishing identified their potential targets and established a rational basis for further structural modifications. Although the activities need further improvement, the study demonstrated that the described approach may be useful in the discovery of novel lead compounds.

In our previous work we showed that 3F10 monoclonal antibody (mAb), which recognizes the rat complement receptor 1-related/gene protein y (Crry), induces homotipic aggregation of thymocytes. In this work we studied the effect of 3F10 mAb on proliferation of rat thymocytes stimulated with concanavalin A (ConA) or by cross-linking the T cell receptor (TCR) by anti-alphabetaTCR mAb (R73), in vitro, and the mechanisms involved in the process. Our results show that 3F10 mAb stimulates proliferation of total thymocytes triggered by suboptimal concentrations of ConA or TCR cross-linking, in a dose-dependent manner. Maximal stimulation was observed using 10 mug/ml and 20 mug/Ml of 3F10 mAb, respectively. The 3F10-induced stimulation of thymocytes proliferation in the presence of ConA, that was followed by increased production of interleukin-2 (IL-2), up-regulation of the expression of IL-2 receptor alpha (IL-2Ralpha) and was inhibited by anti-CD11a and anti-CD 18 mAbs. Purified thymocytes did not respond by proliferation to 3F10 mAb, either alone or in combination with R73 mAb or ConA. Proliferation of these cells was achieved only in the presence of OX-6(+) antigen-presenting cells (APC) and additional signals transmitted by TCR or ConA. These results suggest that Crry is involved in the LFA-1 dependent proliferation of thymocytes, a phenomenon that has not been recognized so far.

The aim of research was to determine the effects of maximally therapeutically achievable concentrations of metformin on malignant cells and healthy peripheral blood mononuclear cells (PBMC). Eight patients with T2D or hyperglycemia and nine healthy volunteers were included in the study. For determination of the influence of metformin on the phenotype of breast carcinoma, 1,410 patients with surgically removed tumors were included. From this group 37 breast cancer patients had DM type 2 or hyperglycemia and were pretreated with metformin alone or sometimes in combination with other antidiabetic drugs. Our results proved that metformin at low concentrations induced mild decrease in survival of malignant cells and PBMC stimulated for proliferation, but it didn't affect survival of resting PBMC. The effects of plasma of hyperglycemic patients who were under metformin therapy on autologous PBMC-induced decrease in survival of MDA-MB-361 cells, was noticeable in some patients. Metformin pretreatment for 24 h of HER2+ MDA-MB-361 cells, which were subsequently treated for 48 h with Herceptin, induced additional decline in cell survival. The analysis of influence of metformin on phenotype of breast cancer cells revealed significantly lower number of diabetic cancer patients treated with metformin with overexpressed HER2+ tumors (p lt 0.013), while the number of patients with ER+PR+ tumors was not significantly changed (p lt 0.832). In conclusion, therapeutically used concentrations of metformin exhibit mild cytotoxic action on malignant and dividing normal cells pointing to its preferred role in malignant and autoimmune diseases. The use of metformin was associated with pronounced decrease in HER2 overexpressing tumors.

Lyme borreliosis is a multisystem disorder characterized by a wide spectrum of clinical manifestations. In Europe, the main aetiological agents are Borrelia afzelii, Borrelia garinii and B. burgdorferi sensu stricto, but Borrelia spielmanii, Borrelia valaisiana, Borrelia lusitaniae and Borrelia bissettii have also been reported as rare or potential causes of human disease. In North America, B. burgdorferi sensu stricto is the only human pathogen. The most common clinical manifestation of Lyme borreliosis is a skin lesion, erythema migrans, which may resolve spontaneously without antibiotic treatment. However, the pathogen can spread to other tissues and organs, causing more severe manifestations that can involve a skin, nervous system, joints, and/or heart, requiring antibiotic therapy. The most commonly used antibiotics in the treatment of Lyme borreliosis are: amoxicillin, ceftriaxone, cefuroxime, doxycycline and azithromycin., Lajmska borelioza je multisistemska bolest koju karakteriše širok spektar kliničkih manifestacija. U Evropi je primarno prouzrokovana vrstama B. afzelii, B. garinii i B. burgdorferi sensu stricto, ali Borrelia spielmanii, Borrelia valaisiana, Borrelia lusitaniae and Borrelia bissettii se takođe navode kao retki ili potencijalni uzročnici oboljenja kod ljudi. U Severnoj Americi, kao jedini humani patogen, dokazana je vrsta B. burgdorferi sensu stricto. Najčešća klinička manifestacija lajmske borelioze je kožna lezija, erythema migrans, koja može da prođe spontano, bez terapije antibioticima. Međutim, patogen se može širiti do drugih delova kože i organa i tako prouzrokovati teže manifestacije kako na koži, tako i na nervnom sistemu, zglobovima i/ili srcu, pri čemu je terapija antibioticima neophodna. Najčešće korišćeni antibiotici u terapiji lajmske borelioze su: amoksicilin, ceftriakson, cefuroksim, doksiciklin i azitromicin.

Clinical use of various biological agents (protein-based products derived from biological sources, such as bacteria, fungi or mammalian cells) have greatly improved the treatment of a wide variety of diseases in humans. Nevertheless, a variety of their adverse reactions have been observed. These adverse effects have been clasified in five types (α, β, γ, δ and ε). Type β adverse effect involves hypersensitivity reactions linked to the immunogenicity of biological agents. It is worth emphasizing that biological agents irrespective whether they contain xenoantigens may lead to development of anti-drug antibodies. Several drug-, patients-, diseaseand treatment-related factors contribute to immunogenicity of biological agents. Anti-drug antibodies can influence either the efficacy of biological agent or induce hypersensitivity reactions. One of them is immediate infusion reaction, which occurs during or within one hour after biological agent infusion. This reaction may cause mild to severe clinical manifestations. Involvement of IgE- and non-IgE isotypes in hypersentitivity reactions are confirmed by novel methods for detecting anti-drug antibodies. This manuscript summarizes the current knowledge on factors influencing immunogenicity to biological agents, and points to the mechanisms underlying the drug-induced hypersensitivity reactions., Više od dve decenije biološki lekovi (proteini dobijeni iz bioloških izvora, kao što su bakterije, gljive ili ćelije sisara) koriste se u terapiji različitih autoimunskih/ inflamatornih bolesti i tumora kod ljudi. Primena ovih lekova praćena je pojavom novih neželjenih efekata koji se mogu svrstati u pet različitih grupa koje se obeležavaju slovima grčkog alfabeta (od α do ε). Reakcije preosetljivosti koje se vezuju za imunogenost bioloških lekova su klasifikovane kao reakcije iz grupe tip β. U praksi, svi proteini koji se koriste kao biološki lekovi, pokreću imunski odgovor, a kao rezultat nastaju anti-lek antitela. Brojni faktori koji su vezani za sam lek, pacijenta ili način davanja leka mogu da utiču na imunogenost nekog biološkog leka. Anti-lek antitela mogu da se vežu za lek i smanje njegovu efikasnost ili da izazovu reakcije preosetljivosti (uglavnom tip I, ređe tip III). Infuzijska reakcija, koja se javlja već u toku davanja infuzije leka ili u okviru jednog sata od njenog završetka, jedna je od najčešćih reakcija preosetljivosti na biološke lekove. U ovom radu opisani su faktori koji mogu da utiču na imunogenost bioloških lekova i patogenetski mehanizmi reakcija preosetljivosti na biološke lekove.