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111.
Gazivoda T Raić-Malić S Kristafor V Makuc D Plavec J Bratulić S Kraljević-Pavelić S Pavelić K Naesens L Andrei G Snoeck R Balzarini J Mintas M 《Bioorganic & medicinal chemistry》2008,16(10):5624-5634
A series of the novel C-5 alkynyl pyrimidine nucleoside analogues (1-14) in which the sugar moiety was replaced by the conformationally restricted Z- and E-2-butenyl spacer between the phthalimido and pyrimidine ring were synthesized by using Sonogashira cross-coupling reaction. Cytostatic activity evaluation of the novel compounds showed that E-isomers exhibited, in general, better cytostatic activities than the corresponding Z-isomers. E-isomer 14 exhibited the best cytostatic effect against all evaluated malignant cell lines, particularly against hepatocellular carcinoma (Hep G2, IC(50)=4.3microM). However, this compound was also cytotoxic to human normal fibroblasts (WI 38). Its Z-isomer 7 showed highly specific antiproliferative activity against Hep G2 (IC(50)=18microM) and no cytotoxicity to WI 38. Moreover, compounds 3, 4 and 14 expressed some marginal inhibitory activity against HIV-1 and HIV-2. 相似文献
112.
Wittine K Stipković Babić M Makuc D Plavec J Kraljević Pavelić S Sedić M Pavelić K Leyssen P Neyts J Balzarini J Mintas M 《Bioorganic & medicinal chemistry》2012,20(11):3675-3685
Several novel 1,2,4-triazole and imidazole L-ascorbic acid (1, 2, 3, 5, 6 and 9) and imino-ascorbic acid (4, 7 and 8) derivatives were prepared and evaluated for their inhibitory activity against hepatitis C virus (HCV) replication and human tumour cell proliferation. Compounds 6 and 9 exerted the most pronounced cytostatic effects in all tumour cell lines tested, and were highly selective for human T-cell acute lymphoblastic leukaemia cells (CEM/0) with IC(50)s of 10 ± 4 and 7.3 ± 0.1 μM, respectively. Unlike compound 9, compound 6 showed no toxicity in human diploid fibroblasts. One of the possible mechanisms of action of compound 6 accounting for observed cytostatic activity towards haematological malignancies might be inhibition of inosine monophosphate dehydrogenase (IMPDH) activity, a key enzyme of de novo purine nucleotide biosynthesis providing the cells with precursors for DNA and RNA synthesis indispensable for cell growth and division, which has emerged as an important target for antileukemic therapy. In addition, this compound proved to be the most potent inhibitor of the hepatitis C virus replication as well. However, observed antiviral effect was most likely associated with the effect that the compound exerted on the host cell rather than with selective effect on the replication of the virus itself. In conclusion, results of this study put forward compound 6 as a potential novel antitumor agent (IMPDH inhibitor) for treating leukaemia. Its significant biological activity and low toxicity in human diploid fibroblasts encourage further development of this compound as a lead. 相似文献
113.
Kenji Dohi Brian C. Kraemer Michelle A. Erickson Pamela J. McMillan Andrej Kovac Zuzana Flachbartova Kim M. Hansen Gul N. Shah Nader Sheibani Therese Salameh William A. Banks 《PloS one》2014,9(9)
Traumatic brain injury (TBI) in its various forms has emerged as a major problem for modern society. Acute TBI can transform into a chronic condition and be a risk factor for neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases, probably through induction of oxidative stress and neuroinflammation. Here, we examined the ability of the antioxidant molecular hydrogen given in drinking water (molecular hydrogen water; mHW) to alter the acute changes induced by controlled cortical impact (CCI), a commonly used experimental model of TBI. We found that mHW reversed CCI-induced edema by about half, completely blocked pathological tau expression, accentuated an early increase seen in several cytokines but attenuated that increase by day 7, reversed changes seen in the protein levels of aquaporin-4, HIF-1, MMP-2, and MMP-9, but not for amyloid beta peptide 1–40 or 1–42. Treatment with mHW also reversed the increase seen 4 h after CCI in gene expression related to oxidation/carbohydrate metabolism, cytokine release, leukocyte or cell migration, cytokine transport, ATP and nucleotide binding. Finally, we found that mHW preserved or increased ATP levels and propose a new mechanism for mHW, that of ATP production through the Jagendorf reaction. These results show that molecular hydrogen given in drinking water reverses many of the sequelae of CCI and suggests that it could be an easily administered, highly effective treatment for TBI. 相似文献
114.
115.
Dendritic cells (DC) are crucial components of the early events of HIV infection. Dendritic cells capture and internalize HIV at mucosal surfaces and efficiently transfer the virus to CD4+ T cells in trans through infectious synapses (trans-infection pathway). Alternatively, HIV-1 replicates in DC (R5-HIV-1) (cis-infection pathway). Here, we analyzed HIV trafficking in DC during the trans-infection pathway as well as the cis-infection pathway. Confocal immunofluorescence microscopy demonstrated that after capture by DC, R5-HIV-1 and HIV-1 pseudotyped with vesicular stomatitis virus protein G colocalized in a viral compartment enriched in tetraspanins including CD81, CD82 and CD9, although at different levels, indicating a role of the viral envelope in targeting to the tetraspanin-rich compartment. Replication of R5-HIV-1 in DC (cis-infection pathway) also led to the accumulation, in an envelope-independent manner, of mature viral particles in a tetraspanin-rich compartment. A fraction of the HIV-1-containing compartments appeared directly accessible from the cell surface. In sharp contrast with the trans-infection pathway, the delta-subunit of the adaptor protein 3 (AP-3) complex was enriched on the HIV-1-containing compartment during R5-HIV-1 replication in DC (cis-infection pathway). Downregulation of AP-3 delta-adaptin reduced significantly viral particle release from HIV-1-infected DC. Together, these studies demonstrate a role for AP-3 in HIV replication in a tetraspanin-rich compartment in DC and contribute to the elucidation of the trafficking pathways required for DC-T cell transfer of HIV-1 infection, a critical step during the early events of HIV infection. 相似文献
116.
Damjan Janeš Irena Klun Blanka Vidan-Jeras Matjaž Jeras Samo Kreft 《Central European Journal of Biology》2010,5(3):324-330
The Major Histocompatibility Complex (MHC) is a large gene family that is found in most vertebrates and has an important influence on body odour preference and mate selection in animals. In this research we found, that human leukocyte antigen (HLA) phenotype is strongly connected with the strength and pleasantness of perceived odour of selected chemical compounds found in sweat. Among different chemical classes of compounds tested, the esters of fatty acids such as methyl undecanoate, methyl decanoate, methyl nonanoate, methyl octanoate and methyl hexanoate show strongest connection to HLA. On the other hand, our experiment did not confirm the connection of MHC to the perceived strength and pleasantness of body odour. 相似文献
117.
Kovac JR Preiksaitis HG Sims SM 《American journal of physiology. Gastrointestinal and liver physiology》2005,289(6):G998-1006
Excitation of human esophageal smooth muscle involves the release of Ca(2+) from intracellular stores and influx. The lower esophageal sphincter (LES) shows the distinctive property of tonic contraction; however, the mechanisms by which this is maintained are incompletely understood. We examined Ca(2+) channels in human esophageal muscle and investigated their contribution to LES tone. Functional effects were examined with tension recordings, currents were recorded with patch-clamp electrophysiology, channel expression was explored by RT-PCR, and intracellular Ca(2+) concentration was monitored by fura-2 fluorescence. LES muscle strips developed tone that was abolished by the removal of extracellular Ca(2+) and reduced by the application of the L-type Ca(2+) channel blocker nifedipine (to 13 +/- 6% of control) but was unaffected by the inhibition of sarco(endo)plasmic reticulum Ca(2+)-ATPase by cyclopiazonic acid (CPA). Carbachol increased tension above basal tone, and this effect was attenuated by treatment with CPA and nifedipine. Voltage-dependent inward currents were studied using patch-clamp techniques and dissociated cells. Similar inward currents were observed in esophageal body (EB) and LES smooth muscle cells. The inward currents in both tissues were blocked by nifedipine, enhanced by Bay K8644, and transiently suppressed by acetylcholine. The molecular form of the Ca(2+) channel was explored using RT-PCR, and similar splice variant combinations of the pore-forming alpha(1C)-subunit were identified in EB and LES. This is the first characterization of Ca(2+) channels in human esophageal smooth muscle, and we establish that L-type Ca(2+) channels play a critical role in maintaining LES tone. 相似文献
118.
Kraus I Rubinić M Uravić M Kovac D Brncić N Kraus D Vojniković B 《Collegium antropologicum》2003,27(2):677-683
We report a case of 35-yr-old woman with early cancer in congenital choledochal cyst. She had a five-year history of intermittent right upper abdominal pain and intermittent jaundice. In this period she had a few abdominal ultrasonographies, but the cholelithiasis had not been found. Now, she was admitted to our hospital because she felt right upper abdominal pain with slight jaundice and subfebrile temperature four weeks ago. Abdominal ultrasonography showed enormous dilatation of the common bile duct, which was suspected as choledochal cyst. Computed tomography and endoscopic retrograde cholangiopancreatography revealed cystic dilatation of extrahepatic bile duct. An anomalous pancreaticobiliary junction was not found. The patient with congenital choledochal cyst was operated on. The excision of choledochal cyst was done with hepaticojejunostomy Roux-en-Y. There were no lymph nodes metastases. On the central part of choledochal cysts mucosa, it was shown a white plain area of thickness 0.3 cm and 0.8 cm in diameter. Histologically it was well-differentiated tubular adenocarcinoma, which was limited to the mucosa and which did not penetrate to other parts of the bile duct wall. From our knowledge, only small number cases of early cholangiocarcinoma in choledochal cyst were until now reported. Nearly eight years after the operation the patient feels very well, and has optimal working ability (Karnofsky 100%). 相似文献
119.
Molecular mechanics and dynamics calculations were carried out on the disaccharides α-L-Rhap-(1 → 2)-α-L-Rhap-(1 → OMe) (1) and α-L-Rhap-(1 → 3)-α-L-Rhap-(1 OMe) (2), and the trisaccharide α-L-Rhap-(1 → 2)-α-L-Rhap-(1 → 3)-α-L-Rhap-(1 → OMe) (3). The semiflexible conformational behavior of these molecules was characterized by the occupation of a combination of different glycosidic linkage and side-chain conformational positions whose relative occupations were sensitive to dielectric screening. Molecular dynamics simulations of the trisaccharide 3 showed little difference between the linkage conformations in the trisaccharide and the component disaccharides 1 and 2. Experimental optical rotation data of 1 and 2 were obtained as a function of temperature in varying solvents. The molecular models were combined with the semiempirical theory of Stevens and Sathyanarayana to yield calculated optical rotations. Interpretation of the data of both 1 and 2 implied that a combination of conformations, both in glycosidic and side-chain positions, could explain the experimental data. Solvents effects were important in influencing the conformational mix and averaged optical rotation. Three-bond heteronuclear coupling constants 3JC, H were obtained for the glycosidic linkages of 1 and 2 in D2O and DMSO. Analysis of the coupling constants with a Karplus curve showed that small reductions in the glycosidic torsion angles of the conformations of the models used here of ca. 10°–15° in ϕ and 5°–10° in ψ were required to give better agreement with experiment; a combination of conformations for both 1 and 2 was consistent with the data. There was a negligible influence on the coupling constants of 1 on changing the solvent from D2O to DMSO. © 1997 John Wiley & Sons, Inc. 相似文献
120.