The Induction of Phagocytic Activation by Mixtures of the Water Chlorination By‐Products,Dichloroacetate‐ and Trichloroacetate,in Mice after Subchronic Exposure

In this study, groups of B6C3F1 male mice were treated with dichloroacetate (DCA), trichloroacetate (TCA), and mixtures of the compounds (Mix I, II, and III) daily by gavage, for 13 weeks. The tested doses were 7.5, 15, and 30 mg DCA/kg/day and 12.5, 25, and 50 mg TCA/kg/day. The DCA: TCA ratios in Mix I, II, and III were 7.5:12.5, 15:25, and 30:50 mg/kg/day, respectively. Peritoneal lavage cells were collected at the end of the treatment period and assayed for the biomarkers of phagocytic activation, including superoxide anion and tumor necrosis factor‐alpha production, and myeloperoxidase activity. The mixtures produced nonlinear effects on the biomarkers of phagocytic activation, with Mix I and II effects were found to be additive, but Mix III effects were found to be less than additive. © 2013 Wiley Periodicals, Inc. J BiochemMol Toxicol 27:237‐242, 2013; View this article online at wileyonlinelibrary.com . DOI 10.1002/jbt.21476     

Changes in antioxidants and kinetics of glutathione-S-transferase of maize in response to isoproturon treatment

Abstract

Isoproturon at the recommended field dose (RFD) significantly reduced fresh and dry weights of shoots and roots as well as chlorophyll and carotenoid contents of 10-day-old maize seedlings during the following 20 days. The higher the herbicide dose, the greater the reduction. Meanwhile, ascorbate (AsA) and reduced glutathione (GSH) increased in leaves for only the first few days. Similar increases in activities of superoxide dismutase (SOD), catalase (CAT), guaiacol peroxidase (GPX) and ascorbate peroxidase (APX) were detected. Low doses caused general increases while high doses induced diminutions; however, CAT and APX activities were inhibited by all doses. Nevertheless, H₂O₂ was significantly accumulated throughout the experiment; the magnitude of accumulation increased with time and herbicide dose. On the contrary, there were significant inhibitions in activities of the glutathione S-transferase (GST) isoforms (GST_(CDNB), GST_(ALA), or GST_(MET)) with no variation in GST_(ATR); the inhibition was greater with increasing isoproturon doses. These findings suggest the occurrence of an oxidative stress induced by isoproturon, a state that prolonged with increasing herbicide dose and/or treatment time. Moreover, V _max of GST was lowered by isoproturon, whereas K _m was unchanged, indicating that the herbicide is a competitive inhibitor of GST.     

Establishment of rat brain endothelial cells susceptible to rat cytomegalovirus ALL-03 infection

Endothelial cells have been implicated as key cells in promoting the pathogenesis and spread of cytomegalovirus (CMV) infection. This study describes the isolation and culture of rat brain endothelial cells (RBEC) and further evaluates the infectious potential of a Malaysian rat CMV (RCMV ALL-03) in these cultured cells. Brain tissues were mechanically fragmented, exposed to enzymatic digestion, purified by gradient density centrifugation, and cultured in vitro. Morphological characteristics and expression of von Willebrand factor (factor VIII-related antigen) verified the cells were of endothelial origin. RBEC were found to be permissive to the virus by cytopathic effects with detectable plaques formed within 7 d of infection. This was confirmed by electron microscopy examination which proved the existence of the viral particles in the infected cells. The susceptibility of the virus to these target cells under the experimental conditions described in this report provides a platform for developing a cell-culture-based experimental model for studies of RCMV pathogenesis and allows stimulation of further studies on host cell responses imposed by congenital viral infections.     

Reprofiling of pyrimidine-based DAPK1/CSF1R dual inhibitors: identification of 2,5-diamino-4-pyrimidinol derivatives as novel potential anticancer lead compounds

Abstract

Hybridization of reported weakly active antiproliferative hit 5-amino-4-pyrimidinol derivative with 2-anilino-4-phenoxypyrimidines suggests a series of 2,5-diamino-4-pyrimidinol derivatives as potential antiproliferative agents. Few compounds belonging to the proposed series were reported as CSF1R/DAPK1 inhibitors as anti-tauopathies. However, the correlation between CSF1R/DAPK1 signalling pathways and cancer progression provides motives to reprofile them against cancer therapy. The compounds were synthesised, characterized, and evaluated against M-NFS-60 cells and a kinase panel which bolstered predictions of their antiproliferative activity and suggested the involvement of diverse molecular targets. Compound 6e, the most potent in the series, showed prominent broad-spectrum antiproliferative activity inhibiting the growth of hematological, NSCLC, colon, CNS, melanoma, ovarian, renal, prostate and breast cancers by 84.1, 52.79, 72.15, 66.34, 66.48, 51.55, 55.95, 61.85, and 60.87%, respectively. Additionally, it elicited an IC₅₀ value of 1.97?µM against M-NFS-60 cells and good GIT absorption with P_e value of 19.0?±?1.1?×?10^?6?cm/s (PAMPA-GIT). Molecular docking study for 6e with CSF1R and DAPK1 was done to help to understand the binding mode with both kinases. Collectively, compound 6e could be a potential lead compound for further development of anticancer therapies.     

CD154: the atherosclerotic risk factor in rheumatoid arthritis?

Atherosclerosis, now regarded as a chronic inflammatory disease of the arterial wall, and its clinical manifestations have increasingly been associated with rheumatoid arthritis (RA), supporting the notion that autoimmune diseases and vascular disorders share common etiological features. Indeed, evidence pertaining to this matter indicates that inflammation and its multiple components are the driving force behind the pathogenesis of these disorders. Interestingly, CD154 and its receptors have emerged as major players in the development of RA and atherosclerosis, which raises the possibility that this axis may represent an important biological link between both complications. Indeed, CD154 signaling elicits critical inflammatory responses that are common to the pathogenesis of both diseases. Here, we provide an overview of the traditional and disease-related interrelations between RA and vascular abnormalities, while focusing on CD154 as a potential mediator in the development of atherosclerotic events in RA patients.     

Optimization and validation of spectrofluorimetric method for determination of cefadroxile and cefuroxime sodium in pharmaceutical formulations

A simple, accurate, precise and validated spectrofluorimetric method is proposed for the determination of two cephalosporins, namely, cefadroxile (cefa) and cefuroxime sodium (cefu) in pharmaceutical formulations. The method is based on a reaction between cephalosporins with 1,2‐naphthoquinone‐4‐sulfonate in alkaline medium, to form fluorescent derivatives that are extracted with chloroform and subsequently measured at 610 and 605 nm after excitation at 470 and 460 nm for cefa and cefu respectively. The optimum experimental conditions have been studied. Beer's law is obeyed over the concentrations of 20–70 ng/mL and 15–40 ng/mL for cefa and cefu, respectively. The detection limits were 4.46 ng/mL and 3.02 ng/mL with a linear regression correlation coefficient of 0.9984 and 0.998, and recoveries ranging 97.50–109.96% and 95.73–98.89% for cefa and cefu, respectively. The effects of pH, temperature, reaction time, 1,2‐naphthoquinone‐4‐sulfonic concentration and extraction solvent on the determination of cefa and cefu, have been examined. The proposed method can be applied for the determination of cefa and cefu in pharmaceutical formulations in quality control laboratories. Copyright © 2013 John Wiley & Sons, Ltd.     

Synthesis of Acyclovir and HBG Analogues Having Nicotinonitrile and Its 2-methyloxy 1,2,3-triazole

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide (12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Furthermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding 2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate (16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18 and 19, respectively. The structures of the new synthesized compounds were characterized by using IR, ¹H, ¹³C NMR spectra, and microanalysis. Selected members of these compounds were screened for antibacterial activity.     

Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

Abstract

Reaction of 2′-deoxy-2′-methylidene-5′-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH₂Cl₂ resulted in the formation of a mixture of (3′R)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivative 3 and 2′,3′-didehydro-2′,3′-dideoxy-2′-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-β-D-threo-pentofuranosyl)uracil (19) with DAST in CH₂Cl₂ afforded (3′S)-2′,3′-dideoxy-3′-fluoro-2′-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.