5,785 research outputs found
Suppression of inflammation response by a novel A 3 adenosine receptor agonist thio-Cl-IB-MECA through inhibition of Akt and NF-κB signaling
No full textAdenosine, a purine nucleoside, is released from metabolically active cells into extracellular space and plays an important role in various pathophysiological processes. Adenosine regulates many biological responses including inflammation by the interaction with their receptors such as A 1, A 2A, A 2B, and A 3. Especially, A 3 adenosine receptor (A 3AR) is considered to be expressed in macrophage cells. To the end, A 3AR agonists have been reported to have an anti-inflammatory activity. In our continuous efforts to develop new anti-inflammatory agents, we found a novel adenosine analog, 2-chloro-N 6-(3-iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide (thio-Cl-IB-MECA), was a potent human A 3AR agonist. The study was designed to investigate whether thio-Cl-IB-MECA has an anti-inflammatory potential in mouse macrophage RAW 264.7 cells and mouse sepsis model in vivo. Thio-Cl-IB-MECA exhibited an effective anti-inflammatory activity. The expression of pro-inflammatory biomarkers including inducible nitric oxide synthase (iNOS), interleukin-1β (IL-1β), and tumor necrosis factor (TNF-α) was suppressed by the treatment of thio-Cl-IB-MECA in the protein and mRNA levels in lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells. Further examination revealed that thio-Cl-IB-MECA inhibited LPS-induced phosphatidylinositol 3-kinase (PI3 kinase)/Akt activation, NF-kB binding activity, and β-catenin expression. In addition, in in vivo LPS-induced mouse endotoxemia model, thio-Cl-IB-MECA exerted the increase of survival rate compared to vehicle-treated mouse. The analysis of the protein levels of iNOS, IL-1β, and TNF-α was also suppressed by the compound-treated groups in lung tissues. These results suggest that thio-Cl-IB-MECA might have an anti-inflammatory activity through the inhibition of pro-inflammatory cytokine expression by modulating PI3K/Akt and NF-κB signaling pathways. © 2011 Elsevier GmbH
A novel adenosine analog, thio-Cl-IB-MECA, induces G0/G 1 cell cycle arrest and apoptosis in human promyelocytic leukemia HL-60 cells
No full textHuman A3 adenosine receptor (A3AR) agonists have been shown to play important roles in several physiological and pathological processes, including growth inhibition of human cancer cells. On this line, we recently found that a novel adenosine analog, 2-chloro-N6-(3- iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide (thio-Cl-IB-MECA) was a potent human A3AR agonist, and is superior to a known agonist Cl-IB-MECA [Jeong LS, Jin DZ, Kim HO, Shin DH, Moon HR, Gunaga P, et al. J Med Chem 2003;46:3775]. Here, we report that a novel A3AR agonist, thio-Cl-IB-MECA inhibited the growth of human promyelocytic leukemia HL-60 cells by arresting cell cycle and induction of apoptosis. Thio-Cl-IB-MECA induced the cell cycle arrest of G0/G1 in the early time and at lower concentration (up to 25 μM). At higher concentration (50 μM), the apoptotic cell deaths were manifested by observation of the increase of sub-G0 phase of cell cycle distribution, DNA fragmentation and poly(ADP-ribose) polymerase (PARP) cleavage. In addition, the down-regulation of checkpoint protein cyclin D1 and c-myc by thio-Cl-IB-MECA was well correlated with the arrest of cell cycle transition of G1 to S phase. Further study revealed that the growth inhibitory activity of thio-Cl-IB-MECA is also related with the modulation of Wnt signaling pathway. The levels of β-catenin, phosphorylated forms of GSK-β and Akt were down-regulated by the treatment of thio-Cl-IB-MECA (10 nM) in a time-dependent manner, providing one of plausible mechanistic evidence for the involvement of the Wnt signaling pathway in the HL-60 cell growth inhibitory effects by thio-Cl-IB-MECA. These results suggest that a novel A3AR agonist, thio-Cl-IB-MECA can down-regulate Wnt signaling, inhibit proliferation and induce apoptosis in HL-60 leukemia cells, and thus provide the possibility of this compound in the potential therapeutic value of the treatment of leukemia. © 2005 Elsevier Inc. All rights reserved
Inhibition of cell proliferation through cell cycle arrest and apoptosis by thio-Cl-IB-MECA, a novel A3 adenosine receptor agonist, in human lung cancer cells
No full textHuman A3 adenosine receptor (A3AR) agonists showed the anti-tumor activity in various in vitro and in vivo studies. The present study investigates the anti-proliferative effect of a novel adenosine analog 2-chloro-N6-(3-iodobenzyl)-4′-thioadenosine-5′-N-methyluronamide (thio-Cl-IB-MECA) in A549 human lung cancer cells. Thio-Cl-IB-MECA induced arrest of cell cycle progression in G0/G1 phase at lower concentrations (up to 20 μM) and apoptotic cell death at a higher concentration (80 μM), which were manifested by down-regulation of cyclin D1, c-myc, and CDK4, activation of caspase-3 and -9, and cleavage of poly(ADP-ribose) polymerase (PARP). The activation of Akt-mediated signaling was also inhibited by treatment with thio-Cl-IB-MECA. These data might suggest the potential therapeutic value of an adenosine analog in the treatment of human lung cancer. © 2008 Elsevier Ireland Ltd. All rights reserved
Thio-Cl-IB-MECA, a novel A3 adenosine receptor agonist, suppresses angiogenesis by regulating PI3K/AKT/mTOR and ERK signaling in endothelial cells
No full textAlthough A3AR agonists exhibit a variety of biological activities including anticancer effects, their possible anti-angiogenic effects have not yet been investigated. In the present study, we assayed the anti-angiogenic activity of thio-Cl-IB-MECA, a novel A3AR agonist, in cultured HUVECs and mES/EB-derived endothelial cells. Thio-Cl-IB-MECA inhibited migration and tube formation by endothelial cells and dramatically decreased ex vivo microvessel sprouting in cultured mouse aortic rings. The anti-angiogenic activity of thio-Cl-IB-MECA was associated with suppression of the expression of the endothelial biomarker PECAM via regulation of PI3K/AKT/mTOR and ERK signaling in mES/EB-derived endothelial cells. © 2013 Elsevier Inc
A3 adenosine receptor antagonist, truncated thio-Cl-IB-MECA, induces apoptosis in T24 human bladder cancer cells
No full textBackground: Human A3 adenosine receptor (A3AR) plays an essential role in several physiopathological processes. Thus far, A 3AR-selective ligands have been evaluated as anti-inflammation and anticancer therapeutic agents. Among these ligands, truncated thio-Cl-IB-MECA is a newly reported antagonist, and its function has not been studied. Materials and Methods: Cell viability was measured by MTS assay. Cell cycle progression was analysed by propidium iodide (PI) flow cytometric assay. The apoptotic effects were investigated by Hoechst staining and annexin V-FITC/PI staining. The signal-transduction mechanism was explored by Western blot. Results: Truncated thio-Cl-IB-MECA induced the growth arrest of T24 cells at sub-G 1 phase and provoked apoptosis but not necrosis. Apoptotic death was mediated by the activation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). Conclusion: Since truncated thio-Cl-IB-MECA induces anti-proliferation and apoptotic effects via ERK and JNK activation, it may function as an anticancer agent in human bladder cancer cells
NGF-response of EGF-dependent progenitor cells obtained from human sympathetic ganglia
Get PDFSIGNALLING molecules are thought to play a significant role in determining the fate of neural crest progenitor cells. The human sympathetic chain was identified at 6.5, 7.5, 8.2, 10.2 and 11.4 postconception (PC) weeks demonstrating low affinity nerve growth factor (NGF) receptors, and was processed for tissue culture. In the presence of epidermal growth factor (EGF), floating spheres of proliferating progenitor cells were developed in vitro. In the absence of EGF progenitor cells differentiated into tyrosine hydroxylase (TH)-immunoreactive neuronal and TH-negative flat cells. NGF treatment significantly increased neurite outgrowth and survival of TH-immunoreactive cells. The multipotent cells we isolated differ from previously reported sympathoadrenal progenitors in that they give rise to TH immunoreactive neurones precociously sensitive to NGF
Thio- and selenosemicarbazones as antiprotozoal agents against <i>Trypanosoma cruzi</i> and <i>Trichomonas vaginalis</i>
No full textHerein, we report the preparation of a panel of Schiff bases analogues as antiprotozoal agents by modification of the stereoelectronic effects of the substituents on N-1 and N-4 and the nature of the chalcogen atom (S, Se). These compounds were evaluated towards Trypanosoma cruzi and Trichomonas vaginalis. Thiosemicarbazide 31 showed the best trypanocidal profile (epimastigotes), similar to benznidazole (BZ): IC50 (31)=28.72 μM (CL-B5 strain) and 33.65 μM (Y strain), IC50 (BZ)=25.31 μM (CL-B5) and 22.73 μM (Y); it lacked toxicity over mammalian cells (CC50 > 256 µM). Thiosemicarbazones 49, 51 and 63 showed remarkable trichomonacidal effects (IC50 =16.39, 14.84 and 14.89 µM) and no unspecific cytotoxicity towards Vero cells (CC50 ≥ 275 µM). Selenoisosters 74 and 75 presented a slightly enhanced activity (IC50=11.10 and 11.02 µM, respectively). Hydrogenosome membrane potential and structural changes were analysed to get more insight into the trichomonacidal mechanism.</p
Viral Hepatitis and Rapid Diagnostic Test Based Screening for HBsAg in HIV-infected Patients in Rural Tanzania.
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Co-infection with hepatitis B virus (HBV) is highly prevalent in people living with HIV in Sub-Saharan Africa. Screening for HBV surface antigen (HBsAg) before initiation of combination antiretroviral therapy (cART) is recommended. However, it is not part of diagnostic routines in HIV programs in many resource-limited countries although patients could benefit from optimized antiretroviral therapy covering both infections. Screening could be facilitated by rapid diagnostic tests for HBsAg. Operating experience with these point of care devices in HIV-positive patients in Sub-Saharan Africa is largely lacking. We determined the prevalence of HBV and Hepatitis C virus (HCV) infection as well as the diagnostic accuracy of the rapid test device Determine HBsAg in an HIV cohort in rural Tanzania. Prospectively collected blood samples from adult, HIV-1 positive and antiretroviral treatment-naïve patients in the Kilombero and Ulanga antiretroviral cohort (KIULARCO) in rural Tanzania were analyzed at the point of care with Determine HBsAg, a reference HBsAg EIA and an anti-HCV EIA. Samples of 272 patients were included. Median age was 38 years (interquartile range [IQR] 32-47), 169/272 (63%) subjects were females and median CD4+ count was 250 cells/µL (IQR 97-439). HBsAg was detected in 25/272 (9.2%, 95% confidence interval [CI] 6.2-13.0%) subjects. Of these, 7/25 (28%) were positive for HBeAg. Sensitivity of Determine HBsAg was rated at 96% (95% CI 82.8-99.6%) and specificity at 100% (95% CI, 98.9-100%). Antibodies to HCV (anti-HCV) were found in 10/272 (3.7%, 95% CI 2.0-6.4%) of patients. This study reports a high prevalence of HBV in HIV-positive patients in a rural Tanzanian setting. The rapid diagnostic test Determine HBsAg is an accurate assay for screening for HBsAg in HIV-1 infected patients at the point of care and may further help to guide cART in Sub-Saharan Africa
New reactions in diosphenols: a) Reactions of diosphenol thio carbamates with nucleophiles excluding Cl, Br, I b) Intramolecular radical cyclization reactions in branched diosphenol w-
No full textDoktoraDoktora TeziDiosfenollerde Yeni Reaksiyonlar: a) Diosfenol Tiyo Karbamatların -Cl, -Br, -IDışındaki Nükleofillerle Yer Değiştirme Reaksiyonları. b) Dallanmış Diosfenolω−Haloalkil Eterlerde Radikalik Halka Kapanma Reaksiyonları ve Bölge Seçiciliğinncelenmesi.Trakya ÜniversitesiFen Bilimleri EnstitüsüKimya Anabilim DalıÖZETAktive edici grup olarak dimetil tiyo karbomoil grubu kullanılarak,diosfenollerin enolik hidroksilinin -Cl ve -Br nükleofilleriyle yer değiştirmereaksiyonları bilinmektedir. Dimetil tiyo karbomoil oksi grubu asidik ortamda birmoleküliçi halka oluşumu ile nükleofilik yerdeğiştirmeye uygun bir yapı oluşturur. Buyöntem kullanılarak α-kloro ve α-bromo-α,β-doymamış ketonlar'ın sentezi daha önceyapılmıştır. Çalışmanın birinci kısmında üç farklı diosfenol ve dört farklı diosfenoldimetil tiyo karbamat'ın sentezi gerçekleştirilmiş, diosfenol dimetil tiyo karbamatlarındört farklı nükleofille (-N3, -SCN, -OCN, -CN) yer değiştirme reaksiyonlarıincelenmiştir. Bu nükleofillerle yapılan reaksiyonlar sonucunda α-azido ve α-tiyosiyanato-α,β-doymamış ketonların sentezi gerçekleştirilmiş, -CN ve -OCNnükleofilleriyle yerdeğiştirme gerçekleşmemiştir.Çalışmanın ikinci kısmında ise dallanmış diosfenol ω-haloalkil eterlerinradikalik halka kapanması ve reaksiyonun bölge seçiciliği incelenmiştir. Bu amaçlaöncelikle üç farklı dallanmış diosfenol ω-haloalkil eterin sentezi planlanmış, fakatbunlardan sadece ikisinin sentezi yapılabilmiştir. Daha sonra ise bu eterlerin halkakapanma reaksiyonları gerçekleştirilmiştir. Halka kapanma reaksiyonlarından spiroyapılı bileşikler ve bir indirgenme ürünü elde edilmiş, altı üyeli halka oluşumugözlenmemiştir.Anahtar Sözcükler: Diosfenol, diosfenol tiyo karbamat, nükleofilik yer değiştirme,diosfenol ω-haloalkil eter, moleküliçi radikalik halka kapanma, bölge seçicilik,heterosiklik bileşikler2005141 sayfaPh.D. ThesisNew Reactions in Diosphenols: a) Reaction of Diosphenol Thio Carbamates withNucleophiles Excluding -Cl, -Br, -I b) Intramolecular Radical Cyclization Reactions inBranched Diosphenol ω-Haloalkyl Ethers and Investigation of Regio Selectivity.Trakya UniversityGraduate School of Natural and Applied ScienceDepartment of ChemistrySUMMARYSubstitution reactions of enolic hydroxyl of diosphenols with chloride andbromide by using dimethyl thio carbomoyl group as an activating group is known.α−chloro and α−bromo-α,β-unsaturated ketones were synthesized by this method.Dimethyl thio carbomoyloxy group forms a suitable structure for nucleophilicsubstitution with intramolecular ring formation in acidic conditions. In the first part ofthe study, synthesis of three different diosphenols and four different diosphenol thiocarbamates have been realized, and then substitution reactions of diosphenol thiocarbamates with four different nucleophiles(-N3, -SCN, -CN, -OCN) have beeninvestigated. Consequently, α-azido and α-thiocyanato -α,β-unsaturated ketones havebeen synthesized. Replacement have not been occured with -CN and -OCNnucleophiles.In the second part of the study, intramolecular radical cyclization reactions ofbranched diosphenol ω-haloalkyl ethers and the regioselectivity of these reactions havebeen examined. At first, synthesis of three different branched diosphenol ω-haloalkylethers have been planned, but only synthesis of two branched diosphenol ω-haloalkylethers could have been synthesized. Then, intramolecular radical ring formationreactions of these ethers have been realized. Spiro oxabicyclo alkanones and a reductionproduct have been obtained, formation of fused oxabicyclo alkanones have not beenobserved.Keywords: Diosphenol, diosphenol thio carbamates, nucleophilic substitution,diosphenol ω-haloalkyl ethers, intramolecular radical cyclization, regioselectivity,heterocyclic compounds.2005141 page
Osmium(IV) thiocarbamide complexes. Synthesis and crystal and molecular structures of [Os(Thio)2Cl4]. 2H2O
No full textTetrachlorobis(thiocarbamide)osmium(IV) dehydrate, [Os(Thio) 2Cl4]. 2H2O, was synthesized by the reaction of K2[OsO2(OH)4] with thiocarbamide in 6 M HCl. The compound was characterized by chemical analysis and IR, UV, and X-ray photoelectron spectroscopies. The structure was determined by X-ray diffraction analysis. The coordination polyhedron of the osmium atom lying in the axis 2 is a distorted cis-octahedron formed by four chlorine atoms and two sulfur atoms of two monodentate thiocarbamide ligands: Os-S 2.3075(18) Å and Os-Cl 2.3625(18) Å (trans to Cl) and 2.4294(19) Å (trans to S). The conditions for the formation of the osmium(IV) thiocarbamide complexes in HCl solutions were determined using spectrophotometry, and the spectral characteristics of [Os(Thio)Cl5]-were obtained. © Pleiades Publishing, Ltd., 2010
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