P.Tretjakovs, A.Jurka, I.Bormane, I.Mikelsone, D.Reihmane, K.Elksne, G.Krieviņa, J.Verbovenko, G.Bahs, D.Fuchs. Alterations of neopterin and inflammatory biomarkers in patients with coronary atherosclerosis. American Journal of Cardiology (Ref. No.: AJC-D-10-02592).
Mandrika I, Petrovska R, Klovins J: Evidence for constitutive dimerization of niacin receptor subtypes. Biochem Biophys Res Commun, 2010, 395(2):281-287.
http://www.ncbi.nlm.nih.gov/pubmed/20380810
Kopsavilkums
The recently deorphanized niacin receptor subtypes NIACR1 (GPR109A) and NIACR2 (GPR109B) play an essential role in the regulation of metabolic processes and immune reactions. Both receptors belong to the G-protein-coupled receptor (GPCR) family, whose members have traditionally been treated as monomeric entities, but now appear to exist and function as both homodimers and heterodimers. In this study, a close physical interaction is shown between the highly homologous niacin receptor subtypes, NIACR1 and NIACR2, using bioluminescence resonance energy transfer (BRET(2)) in living cells. The extent of homo- and hetero-dimerization of the niacin receptors did not vary after activation of the receptors with selective agonists, indicating that the dimerization state of NIACR1 and NIACR2 is not regulated by ligand binding. Moreover, detection of niacin receptor dimers in both plasma membrane- and endoplasmic reticulum-enriched fractions suggests that they are formed early in the biosynthetic pathway. Taken together, these results demonstrate that niacin receptor dimerization is a constitutive process occurring early during biosynthesis.
Fridmanis D, Petrovska R, Kalnina I, Slaidina M, Peculis R, Schioth HB, Klovins J: Identification of domains responsible for specific membrane transport and ligand specificity of the ACTH receptor (MC2R). Mol Cell Endocrinol, 2010, 321(2):175-183.
http://www.ncbi.nlm.nih.gov/pubmed/20206229
Kopsavilkums
The adrenocorticotropic hormone (ACTH) receptor has highly specific membrane expression that is limited to adrenal cells; in other cell types the polypeptide fails to be transported to the cell surface. Unlike other evolutionarily related members of the melanocortin receptor family (MC1R-MC5R) that recognize different melanocortin peptides, ACTHR (MC2R) binds only ACTH. We used a mutagenesis approach involving systematic construction of chimeric ACTHR/MC4R receptors to identify the domains determining the selectivity of ACTHR membrane transport and ACTH binding. In total 15 chimeric receptors were created by replacement of selected domains of human ACTHR with the corresponding regions of human MC4R. We developed an analytical method to accurately quantify cell-membrane localization of recombinant receptors fused with enhanced green fluorescent protein by confocal fluorescence microscopy. The chimeric receptors were also tested for their ability to bind ACTH (1-24) and the melanocyte-stimulating hormone (MSH) analog, Nle4, DPhe7-alpha-MSH, and to induce a cAMP response. Our results indicate that substitution of the MC4R N-terminal segment with the homologous segment of ACTHR significantly decreased membrane transport. We also identified another signal localized in the third and fourth transmembrane regions as the main determinant of ACTHR intracellular retention. In addition, we found that the fourth and fifth transmembrane domains of the ACTHR are involved in ACTH binding selectivity. We discuss the mechanisms involved in bypassing these arrest signals via an interaction with melanocortin 2 receptor accessory protein (MRAP) and the possible mechanisms that determine the high ligand-binding specificity of ACTHR.
Christensen M. K., Erichsen K. D., Trojel-Hansen C., Tjørnelund J., Nielsen S. J., Frydenvang K., Johansen T. N., Nielsen B., Sehested M., Jensen P. B., Ikaunieks M., Zaichenko A., Loza E., Kalvinsh I., and Björkling F. Synthesis and Antitumor Effect in Vitro and in Vivo of Substituted 1,3-Dihydroindole-2-ones. J. Med. Chem. 2010, 53, 7140-7145.
http://www.ncbi.nlm.nih.gov/pubmed/20845961
Kopsavilkums
Optimization of the anticancer activity for a class of compounds built on a 1,3-dihydroindole-2-one scaffold was performed. In comparison with recently published derivatives of oxyphenisatin the new analogues exhibited an equally potent antiproliferative activity in vitro and improved tolerability and activity in vivo. The best compounds from this series showed low nanomolar antiproliferative activity toward a series of cancer cell lines (compound (S)-38: IC(50) of 0.48 and 2 nM in MCF-7 (breast) and PC3 (prostate), respectively) and potent antitumor effects in well tolerated doses in xenograft models. The racemic compound (RS)-38 showed complete tumor regression at a dose of 20 mg/kg administered iv on days 1 and 7 in a PC3 rat xenograft.
Augustyniak A.; Bartosz G.; Čipak A.; Duburs G.; Horakova Ļ.; Luczaj W.; Majekova M.; Odysseos A.D.; Rackova L.; Skrzydlewska E.; Stefek M.; Štrosova M.; Tirzitis G.; Venskutonis P.R.; Viskupicova J.; Vraka P.S.; Žarkovic N. Natural and synthetic antioxidants: An updated overview [Review Article]. Free Radical Res. 2010, 44(10), 1216-1262.
http://www.ncbi.nlm.nih.gov/pubmed/20836663
Kopsavilkums
The current understanding of the complex role of ROS in the organism and pathological sequelae of oxidative stress points to the necessity of comprehensive studies of antioxidant reactivities and interactions with cellular constituents. Studies of antioxidants performed within the COST B-35 action has concerned the search for new natural antioxidants, synthesis of new antioxidant compounds and evaluation and elucidation of mechanisms of action of both natural and synthetic antioxidants. Representative studies presented in the review concern antioxidant properties of various kinds of tea, the search for new antioxidants of herbal origin, modification of tocopherols and their use in combination with selenium and properties of two promising groups of synthetic antioxidants: derivatives of stobadine and derivatives of 1,4-dihydropyridine.
P.Tretjakovs, A.Jurka, I.Bormane, I.Mikelsone, D.Reihmane, K.Elksne, G.Krieviņa, J.Verbovenko, G.Bahs, D.Fuchs. Alterations in serum levels of neopterin, cellular adhesion molecules and myeloperoxidase in metabolic syndrome patients with stable and unstable angina pectoris. European Heart Journal (submission number: EURHEARTJ-S-10-04019).
P.Tretjakovs, A.Jurka, I.Bormane, I.Mikelsone, D.Reihmane, K.Elksne, G.Krieviņa, J.Verbovenko, G.Bahs, D.Fuchs. Changes of neopterin and inflammatory biomarkers in metabolic syndrome patients with coronary artery disease. International Journal of Cardiology (Ref. No.: IJC-D-10-02868).
L. Tarasova, I. Kalnina, A. Bumbure, K. Geldnere, R. Ritenberga, L. Nikitina-Zake, I. Vaivade, V. Pirags and J. Klovins: The effects of genetic polymorphisms in the organic cation transporters OCT1, OCT2 and multidrug and toxin extrusion 1 transporter protein on the metformin intolerance and weight lowering in patients of type 2 diabetes Pharmacogenetics and genomics
http://www.endocrine-abstracts.org/ea/0026/ea0026OC4.3.htm
Kopsavilkums
Objective: Metformin is one of the most widely used drugs in primary therapy for the treatment of type 2 diabetes (T2D). Despite its overall efficiency in T2D treatment metformin shows significant proportion of patients suffering from number of side effects. So far number of polymorphisms mainly in genes coding for various metformin transporter proteins have been described in association with metformin efficiency. However, no information exists on influence of genetic variation of metformin transporters on metformin side effects. OCT1, OCT2 and MATE1 transporters are involved in pharmacokinetics of metformin. In this study, we assessed whether 5 SNP and 2 indel polymorphisms are associated with metformin side effects in Latvian patients of type 2 diabetes.
Methods: We used information from Genome Database of Latvian Population and METFOGENE study to identify all metformin users and their response to metformin intake. Polymorphisms in SLC22A1 - rs12208357, rs34059508, rs628031; rs36056065 and rs72552763; SLC22A2 - rs316019; SLC47A1 - rs2289669 were compared between 74 type 2 diabetes patients with metformin intolerance and 236 metformin users without symptoms of metformin intolerance.
Results: We found a statistically significant association between A allele of rs628031 (P=0.008175, OR=0.558, CI 95% (0.3848-0.8703))) as well as 8 bp insertion (rs36056065) (P=0.008527, OR=0.546, CI 95% (0.3929-0.8749)) and presence of metformin intolerance. Additionally carriers of rs2289669 A allele (SLC47A1) displayed significantly lower (P=0.002114) mean BMI (32.67 kg/m2) compared to wt GG genotype (36.49 kg/m2) among regular metformin users.
Conclusion: Genetic variation in OCT1 encoded by SLC22A1 may predispose to increased incidence of metformin intolerance in patients with type 2 diabetes. Our results may also suggest that rs2289669 located in SLC47A1 gene coding for MATE1 transporter may be associated with increased efficiency of metformin effect on the weight lowering, which is in accordance with MATE1 function in hepatocytes.
V. Ignatovica, K. Megnis, H.B. Schioth and J. Klovins Identification and detailed analysis of functionally important amino acid residues in human purinergic 12 receptor using yeast Saccharomyces cerevisiae expression system. The British Journal of Endocrinology
http://www.ncbi.nlm.nih.gov/pubmed/22044483
Kopsavilkums
12 receptor (P2Y12) is a major drug target for The purinergic anticoagulant therapies, but little is known about the regions involved in ligand binding and activation of this receptor. We generated four randomized P2Y12 libraries and investigated their ligand binding cerevisiae model characteristics. P2Y12 was expressed in a Saccharomyces system. Four libraries were generated with randomized amino acids at positions 181, 256, 265 and 280. Mutant variants were screened for functional activity in yeast using the natural P2Y12 ligand ADP. Activation results were investigated using quantitative structure-activity relationship (QSAR) models and ligand-receptor docking. We screened four positions in P2Y12 for functional activity by substitution with amino acids with diverse physiochemical properties. This analysis revealed that positions E181, R256 and R265 alter the functional activity of P2Y12 in a specific manner. QSAR models for E181 and R256 mutant libraries strongly supported the experimental data. All substitutions of amino acid K280 were completely inactive, highlighting the crucial role of this residue in P2Y12 function. Ligand-receptor docking revealed that K280 is likely to be a key element in the ligand-binding pocket of P2Y12. The results of this study demonstrate that positions 181, 256, 265 and 280 of P2Y12 are important for the functional integrity of the receptor. Moreover, K280 appears to be a crucial feature of the P2Y12 ligand-binding pocket. These results are important for rational design of novel antiplatelet agents.
Beķere L.; Krauze A.; Šestakova I.; Domračeva I.; Andžāns Z.; Duburs G. Synthesis and properties of methyl 6-alkylsulfanyl-4-(2-chlorophenyl)-1,4-dihydropyridine-3-carboxylates. Latvijas ķīmijas žurnāls. 2010(2), 146-151.
http://versita.metapress.com/content/q70g3v5367842842/
Kopsavilkums
6-Alkilsulfanil-5-ciano-4-(2-hlorfenil)-2-metil-1,4-dihidropiridīn-3-karbon-skābes metilesteri 7, kas raksturojas ar optimālo lipofilitāti, iegūti 5-ciano-4-(2-hlorfenil)-2-metil-6-tiokso-1,4,5,6-tetrahidropiridīn-3-karbonskābes metilestera (5) alkilēšanas reakcijās ar halogēnalkāniem 6. Uzlabots mērķproduktu 7 iegūšanas paņēmiens, izstrādājot vienreaktora sintēzes metodi. 6-Etilsulfanil-, 6-ciklopropilmetilsulfanil- un 6-izobutilsulfanil-1,4-dihidropiridīn-3-karbonskābes metilesteri 7b, e, f uzrāda L-tipa kalcija kanālu bloķējošo aktivitāti in vitro modeļos - šūnu līnijās SH-SY5Y.
