Andrija Smelcerovic

Microbial Polysaccharides and their Derivatives as Current and Prospective Pharmaceuticals

The ability to produce polysaccharides is widely found among microbial species. The structural diversity of the microbial polysaccharides (MPS) leads to a wide diversity of their applications. This review focuses pharmacological properties of MPS and their derivatives. They have been reported to possess many biological activities, such as antiviral, antitumor, antimicrobial and anticoagulant activities. So, the MPS of the type beta-1,3-D-glucans, including curdlan and scleroglucan, show antitumor and antiviral activity. A number of biological and synthetic sulfated polysaccharides, including sulfated polysaccharides from marine microalgae, inhibit viral infections. Many of MPS demonstrate a series of attractive properties as carrier materials in drug delivery systems and nonviral gene delivery. Furthermore, MPS have found an application as wound-healing agents, blood plasma expanders and vaccines. Some MPS, like chitin, chitosan and alginate have an unusual combination of biological activities and physicochemical properties leading to the development of novel or improved pharmaceuticals. They have become of a great interest not only as drug and cell carriers but also as new functional materials of high biological activity, and recent progress in MPS chemistry is quite noteworthy. This review also examines the advances in the application of MPS in the field of tissue engineering.

Do other Hypericum species have medical potential as St. John's wort (Hypericum perforatum)?

Among 484 Hypericum L. (Guttiferae/Hypericaceae) species, widespread in warm temperate areas throughout the world, only H. perforatum is widely used in official medicine. Hypericum perforatum has been reported as an antidepressant, antiviral, antimicrobial, anti-inflammatory, and a healing agent. The main constituents of the Hypericum species are naphthodianthrones, primarily represented by hypericin and pseudohypericin, phloroglucinol derivatives, especially hyperforin, and flavonoids, such as quercetin, quercitrin, hyperoside and rutin. Hypericin and pseudohypericin have been found to possess antiretroviral activity. Hyperforin may also have an important contribution to the antidepressant activity of Hypericum extracts. The content of the above active constituents in some Hypericum species is higher than in H. perforatum. Also, a number of studies of the biological activities of Hypericum species have shown that the most recognized species of this genus, H. perforatum, was not the most active. Comprehensive analysis of the published research on the chemical composition and biological activity, showed that H. richeri has a similar pharmacological potential as St. Jons wort. The species, with high content of naphtodianthrones,which might be used against viruses and retroviruses, are: H. androseamum,H. annulatum, H. barbatum, H. boissieri, H. elegans, H. hirsutum, H. hyssopifolium, H. humifusum, H. montanum. H. montbretii, H. triquetrifolium, H. richeri, H. rochelii, H. rumeliacum, H. thasium, andH. patulum. Very few species (e.g. H. inodorum and H. moseranum) contained the similar amounts of hyperforine as H. perforatum. Since hyperforin was recognized as one of the most crucial components for the antidepressive activity, it seems that H. perforatum barely has an alternative for this purpose. Plant species containing considerable amounts of other acylphloroglucinol derivatives have the potential to demonstrate antibacterial and cytotoxic activity. Some of these species are: H. sampsonii, H. ascyron, H. foliosum, H. geminiflorum and H. scabrum. However, only a few studies concerning the activity of extracts and isolated compounds were done in vivo. Also, data on the safe usage of Hypericum constituents as phytotherapeutics are scarce. Since some of Hypericum species are scarcely distributed or endemic as well as some of the secondary metabolites are presented in very small amounts, bio-production, especially endophytes, could represent an abundant and reliable source of pharmacologically active metabolites of Hypericum species for exploitation in pharmaceutical industry.

Effect of four lichen acids isolated from Hypogymnia physodes on viability of rat thymocytes.

Four lichen acids, physodalic acid (F1), physodic acid (F2), 3-hydroxyphysodic acid (F3), and isophysodic acid (F4), were isolated from Hypogymnia physodes methanol extract using preparative reversed-phase high performance liquid chromatography and their structures were determined by UV, MS, (1)H NMR and (13)C NMR. This is the first report on the isolation of F4 from H. physodes. Isolated rat thymocytes were cultivated with increasing F1-F4 concentrations (0.1, 1, 10μg/well) and proliferative activity, viability, ROS (reactive oxygen species) production and MMP (mitochondrial membrane potential) disturbances were evaluated. Obtained results show significantly decreased thymocytes proliferation was observed when cells were treated with F1 (1μg, p<0.05; 10μg; p<0.001), F2 (10μg, p<0.05) and F3 compound (10μg, p<0.05). Significantly increased cytotoxicity was detected when cells were incubated with F1 (1μg, p<0.05; 10μg, p<0.01), F2 (10μg, p<0.05) and F3 compound (10μg, p<0.001). Increased H2DCF-DA fluorescence intensity, when cells were treated with F1 (1μg, p<0.001; 1μg, p<0.01; 10μg, p<0.001) and F2 (1μg, p<0.05; 10μg, p<0.01) compound, indicating the increase of intracellular ROS production. Simultaneously, increased ROS levels were followed with significantly decreased MMP when thymocytes were cultivated with F1 (0.1μg, p<0.001; 1μg, p<0.001; 10μg, p<0.001) and F2 compound (10μg, p<0.001). Thymocytes exposure to increased (0.1, 1, 10μg) concentrations of F3 and F4 compounds did not result with significant alterations in MMP and intracellular ROS production. We have shown that higher F1 and F2 concentrations induce thymocytes toxicity mainly through induction of oxidative stress, while cytotoxicity effect of F3 is followed with altered antioxidant/oxidant balance. The rigid 11H-dibenzo[b,e][1,4]dioxepin-11-one ring in the depsidone structure may play a important role for the examined biological activities.

Phenolic constituents and the in vitro antioxidant activity of the flowers of Hypericum venustum

The phenolic constituents and antioxidant activity of ethanol and water extract of the flowers of Hypericum venustum, collected in Turkey, were investigated. The extracts possess strong reducing power, free radicals and hydrogen peroxide scavenging activity, as well as metal chelating ability.

The Effect of Camphor and Borneol on Rat Thymocyte Viability and Oxidative Stress

Camphor and borneol are wildly distributed in the essential oils of medicinal plants from various parts of the World. Our study has been carried out to evaluate the effect of these two bicyclic monoterpenes on rat thymocytes. Camphor and borneol at concentrations of 0.5 and 5 µg/mL did not induce significant toxicity on the immune system cells, while a significant increase of thymocyte viability was detected when cells were incubated with 50 µg/mL of camphor. A significant increase of cell viability was similarly detected when thymocytes were cultivated with borneol at concentrations of 0.5 and 5 µg/mL. The role of camphor and borneol in reactive oxygen species (ROS) production and mitochondrial membrane potential (MMP) disturbances in rat thymocytes as well as their potential mechanism(s) of action were also discussed.

HPLC-MS Analysis and Anti-Oedematogenic Activity of Hypericum grandifolium Choisy (Hypericaceae)

A study has been carried out on the chemical composition and in vivo anti-oedematogenic activity of several extracts from Hypericum grandifolium Choisy (Hypericaceae) collected in Tenerife (Canary Islands). The HPLC-MS analysis (HPLC-ESI/MS and HPLC-FT/MS) revealed the presence of hyperforin, flavonoids and probably benzophenone derivatives, while naphthodianthrones were absent. Pharmacological results revealed that the methanol extracts and the aqueous, butanol and chloroform fractions obtained therefrom possess anti-oedematogenic activity against TPA-induced ear oedema and carrageenan-induced paw oedema, the chloroform fraction being the most active. Subfractions derived from the chloroform fraction also showed anti-oedematogenic activity. From these results, it can be suggested that different constituents, such as the flavonoids and the benzophenone derivatives, could be responsible, at least in part, for the anti-oedematogenic effects observed for this species.

Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: Potential impact of dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase-4 (DPP-4), glycyl-prolyl-naphthylamidase, is a serine protease that catalyzes the hydrolysis of various proline-containing polypeptides. It is involved in the inactivation of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor (CXCR4) and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. DPP-4 inhibition has received considerable attention because of its significant therapeutic benefits in the regulation of insulin secretion and tissue insulin sensitivity, the regulation of tumor growth and metastasis, angiogenesis, tissue repair, especially after myocardial infarction, and regulation of endocrine function. Inhibition of circulating proteases appears to maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. In the present article, we present an overview of some basic facts about the role of DPP-4 in glucose homeostasis, the mechanism of its inhibition, and a brief summary of available DPP-4 inhibitors. Furthermore, since protection against the overactivity of proteases is important for restorating cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.

Two 6-(propan-2-yl)-4-methyl-morpholine-2,5-diones as new non-purine xanthine oxidase inhibitors and anti-inflammatory agents

Two cyclodidepsipeptides, 3-(2-methylpropyl)-6-(propan-2-yl)-4-methyl-morpholine-2,5-dione (1) and 3,6-di(propan-2-yl)-4-methyl-morpholine-2,5-dione (2), were evaluated for inhibitory activity against commercial enzyme xanthine oxidase (XO) in vitro and XO in rat liver homogenate as well as for anti-inflammatory response on human peripheral blood mononuclear cells (PBMCs). Both of cyclodidepsipeptides were excellent inhibitors of XO and significantly suppressed the nuclear factor of κB (NF-κB) activation. Allopurinol, a widely used XO inhibitor and drug to treat gout, relevated stronger inhibitory effect on rat liver XO activity than those of compounds 1 and 2. Molecular docking studies were performed to gain an insight into their binding modes with XO. The studied morpholine-diones derivatives exerting XO inhibition and anti-inflammatory effect may give a promise to be used in the treatment of gout and other excessive uric acid production or inflammatory conditions.

Recent Advances in Analysis of Essential Oils

This review provides an overview of the emerging trends in analysis of essential oils and indicates future trends. Since early human history the essential oils have been used in folk medicine, food and cosmetic industries in various parts of the world. GC-FID is the traditional method for essential oils quantification while GC-MS is the most common analytical method for qualitative analysis. Chiral GC allowed the identification of a great number of chiral essential oil constituents. An alternative to GC analysis is HPLC chromatography. The use of hyphenated techniques, such as LC-MS-MS provides important information about the structure of essential oils constituents. However, only a comparatively small number of reports on essential oil analyses by HPLC can be found in the literature. Multidimensional chromatography is an approach capable of providing greater resolution.13C-NMR spectroscopy is a complementary tool for analysis of essential oils. Advantage of this method compared to mass spectrometry is identification of stereoisomers and thermally unstable compounds while its disadvantage is inability to identify the minor oils constituents. 1H-NMR as an online tool for GC analysis showed promising results but requires further research to be applied on the analysis of essential oils. The range of information obtained from essential oils analysis enables the application of chemometrics (review).

Antimicrobial activity and cytotoxicity of some 2-amino-5-alkylidene-thiazol-4-ones.

We report a small, focused library of 30 diverse 2-amino-5-alkylidene-thiazol-4-ones that was assayed in a whole-cell antibacterial screen against a panel of several bacterial strains and a yeast. Most of the compounds exhibited modest to significant antibacterial activity against Pseudomonas aeruginosa, Bacillus subtilis and Staphylococcus aureus, and no activity against Salmonella typhimurium and Escherichia coli. The antibacterial activity depends markedly upon substituents on the thiazol-4-one core, and the most potent compound assayed (