10 research outputs found

    Structure/activity corrrelations for auxins

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    Structure-activity correlations for the endogenous phytohonnone, indole- -3-acetic acid (1AA), and its ring-alkylated and -halogenated derivatives are based on geometric and electronic molecular characteristics, and the resulting physical and chemical attributes. Plant growth-regulating properties are discussed with particular emphasis on molecular (bio)conformation and on substituent effects and their influence on properties such as lipophilicity

    Conformational Studies in Solid State and Solution of Protected C-terminal Dipeptide Fragment (Boc-Phe-Pro-NH2) of Morphiceptin

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    The crystal structure of the protected C-terminal dipeptide fragment (Boc-Phe-Pro-NH2) of the μ-opioid receptor highly selective agonist, morphiceptin (Tyr-Pro-Phe-Pro-NH2), was determined; the crystals are monoclinic with space group P21 and unit cell dimensions: a = 11.5731(5), b = 6.4490(3), c = 15.4082(5) ƅ, β = 100.359(5)Ā° and Z = 2. To examine the influence of proline on the conformation of peptide bond, the molecular conformation was studied in solid state and solution (using 1H and 13C NMR data). The X-ray analysis revealed the following conformations of peptide backbone: φ1 = -63.2(5)Ā°, ψ1 = 156.1(4)Ā°, ω1 =-174.3(4)Ā°, φ2 =-66.0(5)Ā° and ψ2 = 152.0(4)Ā°. The conformation of the Boc group is trans-trans. Experimental data revealed the trans conformation about the Phe-Pro amide bond, both in solid state and solution (DMSO). The possibility of cis/trans isomerization about the peptide bond (ω1) was examined by theoretical calculations using BIOSYM software. Molecular modelling, including molecular dynamics simulations of the title dipeptide, is in favour of trans peptide bond

    Retrospektivna procjena učinka nintedaniba u miÅ”jem modelu plućne fibroze - usporedba učinkovitosti s kliničkim ishodom idiopatske plućne fibroze

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    Pulmonary function tests (PFTs) routinely implemented in clinics are the first step in the diagnosis of idiopathic pulmonary fibrosis. Evaluation of PFTs in the mouse model of pulmonary fibrosis accompanied by histological readouts may improve the clinical predictability of new therapeutic candidates. Forced vital capacity (FVC) is considered the most predictive of restrictive pulmonary disorders. This study aimed to test the improvement of PFT in mice lung fibrosis induced by treatment with an approved substance nintedanib, considered the gold standard. The hypothesis that treatment in animal models will demonstrate similar effects as in humans in the most relevant clinical outcomes was tested. Two experimental designs were enrolled in this study, a preventive regimen, with treatment initiation from the day of the challenge; and a therapeutic regimen, starting on day 7 postchallenge when fibrotic changes are present in the lungs. Experiments were terminated at two different time points, at 14 and 21 days postchallenge. C57BL/6 mice were administered with bleomycin (BLM) intranasally and treated with nintedanib from day 0 to day 14 or from day 7 until day 21. Fourteen or 21 days after the BLM challenge, PFTs were assessed using the in vivo invasive lung function measurement system BuxcoĀ® Pulmonary Function Test (PFT) (DSIā„¢, New Brighton, USA). Histological evaluation was performed as a modified Ashcroft score. The bleomycin challenge induced a significant decrease of FVC in both experiments. However, nintedanib treatment given in both regimens significantly improved lung functionality. These findings were confirmed with histological analysis of the Ashcroft scoring system, modified by Matsuse. In conclusion, a good correlation between functional test parameters and the clinical effect of nintedanib was shown in both experiments: the preventive regimen was sampled 14 days post-challenge and the therapeutic regimen 21 days post-challenge. Based on these findings, the implementation of PFTs could be a good platform to increase the translational value of the model and potential new treatments.Testovi funkcije pluća prvi su klinički postupak u dijagnostici respiratornih bolesti kao Å”to je idiopatska plućna fibroza (IPF). MiÅ”ji modeli plućne fibroze su vrlo važni u razvoju novih terapija. Uvođenje testova u životinjski model, zajedno s histoloÅ”kom procjenom omogućit će bolji probir novih molekula i njihovo daljnje kliničko istraživanje. Cilj je ovog istraživanja bio odrediti precizne vrijednosti parametara plućnih funkcija koriÅ”tenjem standardne humane terapije za IPF, nintedaniba na miÅ”jim modelima u svrhu postavljanja platforme za učinkovitiji razvoj novih potencijalnih terapija. Testiranje je vrÅ”eno pod pretpostavkom da će odabrani tretman u miÅ”jem modelu dati sličan efekt kao i kod ljudi u odabranoj dijagnostičkoj metodi. Testirana su dva eksperimentalna protokola: preventivnouvođenje terapije prije razvoja fibrotičnih promjena i terapijski protokol aplikacije terapije u vrijeme nastanka plućne fibroze. C57Bl/6 miÅ”evima je bleomicin apliciran intranazalno prvog dana studije, a terapija nintedanibom primijenjena je od prvog dana do 14. u preventivnom te od sedmog dana do 21. u terapijskom protokolu. Četrnaestog ili Retrospektivna procjena učinka nintedaniba u miÅ”jem modelu plućne fibroze - usporedba učinkovitosti s kliničkim ishodom idiopatske plućne fibroze 21. dana nakon početka pokusa nakon bleomicinske primjene, testovi funkcije pluća su provedeni koristeći BuxcoĀ® Pulmonary Function Test (PFT) (DSIā„¢, New Brighton, SAD) u in vivo invazivni sustav. HistoloÅ”ka procjena je provedena koristeći modificirani Ashcroft sustav ocjenjivanja količine patoloÅ”kih promjena u plućima. Primjena bleomicina u plućima miÅ”eva je utjecala na značajno smanjenje parametra forsiranog vitalnog kapaciteta (FVC) u oba ispitana protokola, dok je terapija nintedanibom značajno poboljÅ”ala nastale promjene. Ovi rezultati su potvrđeni i ocjenom histoloÅ”kih promjena u tkivu pluća. Testovi funkcionalnosti pluća u miÅ”jem modelu značajno koreliraju s kliničkim efektom istraživane terapije u obje studije. U preventivnom protokolu istraženom 14. dana te u terapijskom 21. dana eksperimenta. Na temelju ovih saznanja, možemo zaključiti kako uvođenje ovog testa, kao relevantne kliničke dijagnostike, možemo poboljÅ”ati translacijsku vrijednost životinjskih modela u razvoju nove terapije

    Synthesis, Structure Elucidation and Reactivity of Novel Azetidinone-oxiranes

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    Oxidation of 2,3-cis-2-sulfonamide-N-butenoate-azetidinone 3 and 2,3-trans-2-acetoxy-N-butenoate-azetidinone 6 led to the formation of azetidinone-oxiranes 5 and 7. Molecular structure of 5, including its absolute configuration, was unambiguously determined by X-ray structure analysis. Cleavage of the benzyl ester group using AlCl3 / anisole as well as H2Pd/C procedures failed. Instead, new methods for the removal of the substituent from the azetidinone nitrogen of compounds 5 and 7 were found. Azetidinone 8 was isolated in the reaction of azetidinone-oxiranes 5 with AlCl3/anisole. During hydrogenation of azetidinone-oxirane 5, afforded azetidinone p-hydroxy acid sodium salt 9, which was transformed into azetidinone 8 in acidic media. Compounds 5 and 7 gave the azetidinone-halohydrines 10 and 11 by the oxirane ring opening with HCl

    Claudins: Beyond Tight Junctions in Human IBD and Murine Models

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    Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activityā€“dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodiumā€“induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well ; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations ; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study

    A peptide deformylase-ribosome complex reveals mechanism of nascent chain processing

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    Messenger- RNA- directed protein synthesis is accomplished by the ribosome(1-3). In eubacteria, this complex process is initiated by a specialized transfer RNA charged with formylmethionine ( tRNA(fMet))(4-6). The amino- terminal formylated methionine of all bacterial nascent polypeptides blocks the reactive amino group to prevent unfavourable side- reactions and to enhance the efficiency of translation initiation(7,8). The first enzymatic factor that processes nascent chains is peptide deformylase ( PDF)(5,9-11); it removes this formyl group as polypeptides emerge from the ribosomal tunnel(12,13) and before the newly synthesized proteins can adopt their native fold, which may bury the N terminus. Next, the N-terminal methionine is excised by methionine aminopeptidase(14). Bacterial PDFs are metalloproteases sharing a conserved N- terminal catalytic domain. All Gram- negative bacteria, including Escherichia coli, possess class- 1 PDFs characterized by a carboxy- terminal alpha- helical extension(15). Studies focusing on PDF as a target for antibacterial drugs(14,16) have not revealed the mechanism of its co- translational mode of action despite indications in early work that it co- purifies with ribosomes(17). Here we provide biochemical evidence that E. coli PDF interacts directly with the ribosome via its C- terminal extension. Crystallographic analysis of the complex between the ribosome- interacting helix of PDF and the ribosome at 3.7 angstrom resolution reveals that the enzyme orients its active site towards the ribosomal tunnel exit for efficient co- translational processing of emerging nascent chains. Furthermore, we have found that the interaction of PDF with the ribosome enhances cell viability. These results provide the structural basis for understanding the coupling between protein synthesis and enzymatic processing of nascent chains, and offer insights into the interplay of PDF with the ribosome- associated chaperone trigger factor
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