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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Epoxide functionalities are similar to aziridines in their ability to alkylate DNA. Although some carcinogens, such as the aflatoxins, are known to alkylate DNA via an epoxide moiety, there are currently no anticancer agents in clinical use that contain preformed epoxide moieties. However, treosulfan (L-threitol 1,4-bismethanesulfonate, OvastatTM, TrecondiTM) is a prodrug of a bifunctional epoxide alkylating agent that converts nonenzymatically under physiological conditions to L-diepoxybutane via the corresponding mono-epoxide intermediate (Figure 5.25). The mono-epoxide intermediate and L-diepoxybutane alkylate DNA at guanine residues, and the formation of DNA interstrand cross-links and guanine-adenine intrastrand cross-links have been reported, followed by DNA fragmentation and apoptosis. Treosulfan is available as a generic throughout most of the world, but in some parts of Europe it is marketed under its original trade name of OvastatTM. Conversion of treosulfan (OvastatTM) into the DNA-reactive L-diepoxybutane via the mono-epoxide intermediate.
Detection of Fungal Metabolites
Published in Johan A. Maertens, Kieren A. Marr, Diagnosis of Fungal Infections, 2007
Polyols are polyhydric alcohols derived from sugars and are present in almost all living organisms (4). Pathogenic yeasts and filamentous fungi produce acyclic polyols including D-mannitol, D-arabinitol, erythritol, and glycerol in culture. The relative abundance of each polyol depends on the fungal genus and growth conditions. For example, D-arabinitol is the predominant polyol produced by Candida albicans (5) and large amounts of D-mannitol are produced by Cryptococcus neoformans (6,7) and Aspergillus spp. (4,8). C. albicans is a net producer of D-arabinitol during the logarithmic phase of growth, with most being released into the medium, whereas synthesis and secretion of D-mannitol by C. neoformans is maximal in the stationary phase. In Aspergillus spp. most of the D-mannitol produced remains cell-associated. The serum and urine of human subjects also contains low concentrations of polyols that are produced by metabolism of endogenous or dietary substrates or ingested in food. L-arabinitol is the most abundant, followed by erythritol, D-mannitol, and threitol (9). Serum levels of the polyols arabinitol, mannitol, sorbitol, myoinositol, and anhydroglu-citol vary significantly between healthy individuals and the variation is greatest for mannitol. Polyol levels are also influenced by diet, renal dysfunction, and metabolic disorders such as diabetes mellitus, meningitis, sepsis, and cerebral atrophy (9,10). The L-enantiomer of arabinitol is the form produced by mammalian cells, whereas fungi produce the D-enantiomer; thus, quantitation of D-arabinitol will identify arabinitol of fungal origin (4,5,11).
Transforming Growth Factor-β: a Multifunctional Growth Regulator
Published in Velibor Krsmanović, James F. Whitfield, Malignant Cell Secretion, 2019
The first reports on specific cell surface receptors for TGF-β were essentially in agreement with each other in showing a dissociation constant of between 25 to 56 pM using NRK-49F, AKR-2B, or BALB/C 3T3 fibroblasts and the existence of some 10,500 to 19,000 receptors per cell.40-42 However, regarding the phenomenon of down-regulation, two of these reports found evidence for its existence,40,41 and one found none.42 In a subsequent report, it was shown that some cell types can downregulate their receptor, but often not extensively.43 Since partial receptor occupancy allows a full response, it was estimated that down-regulation of less than 50% of the total receptors might not affect the cellular response to the ligand.43 In the presence of the reducing reagent dithiothreitol, the major affinity-labeled receptor in mouse, rat, and chicken fibroblasts had an apparent molecular weight of about 280 kDa.44 Two other minor species of 65 kDa and 85 kDa were also found, with or without dithio-threitol.45 Molecular weight estimations of the major receptor type were found to vary, depending on the concentration of acrylamide used in the gel electrophoresis system.46 The 280-kDa (or 180-kDa, depending on experimental conditions) TGF-β binding subunit is part of a dimeric complex46 which contains glycosylated residues, since it binds to immobilized lectin columns.44 More recently, it was shown that the TGFβ-binding subunit of the major receptor type is a proteoglycan containing chains of heparin sulfate and chondroitin sulfate.47 These glycosaminoglycan (GAG) chains could be removed by specific degradative enzymes without preventing high affinity binding of TGF-β1 to the remaining core protein of 115 to 140 kDa.47 It is important to mention here that GAG chains can interact with proteins of both extracellular matrix and intracellular cytoskeletal components.48 This leads to the idea that the GAG chains associated with the major TGF-β receptor may be involved in mediating the cellular effects of the ligand. Several growth factor receptors undergo ligand-dependent clustering and tyrosine-specific autophosphorylation, but no evidence for either of these phenomena was found in regard to the (major) TGF-β receptor.46 Cheifetz et al.21 have shown that the 280-kDa receptor subunit recognizes both TGF-β1 and β2 isoforms equally well, whereas the 65-kDa and 85-kDa receptor types show a greater affinity for TGF-β1 than for TGF-β2. Although both of these two minor receptor types can discriminate between the two TGF-β isoforms, they can be distinguished from each other on the basis of structural45 and kinetic49 properties. All three receptor types are widely distributed in mammalian and avian cells.21
Effects of the application of general anesthesia with propofol during the early stage of pregnancy on brain development and function of SD rat offspring and the intervention of DHA
Published in Neurological Research, 2019
Xiangming Yu, Fei Ma, Xingnian Cao, Xiaodi Ma, Chenhu Hu
Five offspring rats in each group were sacrificed by decapitation, and the rat hippocampus was homogenized in lysis buffer containing complete protease inhibitor cocktail (1 M Tris-HCl (pH 8.0), 5 M NaCl, 10% Nonidet P-40 and 1 M 1,4-dithio-dl-threitol (DTT)). After quantitated with the bicinchoninic acid (BCA) protein assay kit (Beyotime Biotech, Shanghai, China), the protein was subjected to 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), followed by transmembrane to polyvinylidene difluoride (PVDF) membrane (Merck, Darmstadt, Germany). The membrane was incubated with Tris-buffered saline and Tween 20 (TBST) solution containing 5% skim milk for 1 h. Then, the primary antibodies of BDNF (1:200, Cat. no. H-117, Santa Cruz Biotechnology, Inc., CA, USA), TrkB (80E3) (1:1000, Cat. no. 4603, Cell Signaling Technology), Akt (1:1000, Cat. no. 9272, Cell Signaling Technology), p-Akt (Ser473), (1:1000, Cat. no. 4060, Cell Signaling Technology), CREB (1:1000; Cat. no. 9197, Cell Signaling Technology) and β-actin (1:5000, Cat. no. ab6276, Abcam, Cambridge, MA) were added and incubated overnight at 4°C. After washing with TBST, horseradish peroxidase-labeled secondary antibody was added and incubated for 1 h. chemiluminescence luminescent (ECL) substrate was added and the results were analyzed using a ChemiDoc XRSþ image analyzer (Bio-Rad, Hercules, CA).
pH and reduction dual-responsive micelles based on novel polyurethanes with detachable poly(2-ethyl-2-oxazoline) shell for controlled release of doxorubicin
Published in Drug Delivery, 2019
Leran Bu, Hena Zhang, Kang Xu, Baixiang Du, Caihong Zhu, Yuling Li
ε-caprolactone (ε-CL, 99%) and Stannous octoate [Sn (Oct)2] were obtained from Alfa Aesar (Shanghai, China). CDI and HDI were obtained from Energy-Chemical (Shanghai, China). 2-Ethyl-2-oxazoline (EtOz-OH, 99%) were purchased from Alfa Aesar (Shanghai, China), and distilled prior to use. N,N-dimethylformamide (DMF), dichloromethane, and toluene was purchased from Sinopharm Chemical Reagent Co. Ltd. (Shanghai, China). 1, 4-dithio-d, l-threitol (DTT) was obtained from Merck (Shanghai, China). Doxorubicin hydrochloride (DOX⋅HCl) was obtained from Beijing ZhongShuo Pharmaceutical Technology Development Co., Ltd. (Beijing, China). While the Roswell Park Memorial Institute medium (RPMI-1640, Thermo Fisher Scientific), fetal bovine serum (FBS, Gibco, Australia), and 96-well plates were obtained from Corning Costar (Shanghai, China). 3-(4, 5-dimethylthiazolyl-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) was purchased from Biosharp (Hefei, China). 4′, 6-diamidino-2-phenylindole (DAPI) was purchased from Roche (Shanghai, China). All other chemicals were used as received.
Computationally driven discovery of phenyl(piperazin-1-yl)methanone derivatives as reversible monoacylglycerol lipase (MAGL) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Giulio Poli, Margherita Lapillo, Vibhu Jha, Nayla Mouawad, Isabella Caligiuri, Marco Macchia, Filippo Minutolo, Flavio Rizzolio, Tiziano Tuccinardi, Carlotta Granchi
In order to verify whether the compounds could interact with cysteine residues of MAGL enzyme, the activity of the most potent inhibitor 4 was also tested in presence of the thiol-containing agent 1,4-dithio-dl-threitol (DTT). As shown in Figure 5(A), the IC50 value of compound 4 was only very slightly, but not significantly, influenced by the presence of DTT, shifting from 6.1 μM when assayed in the absence of DTT to 6.2 μM when assayed in the presence of 10 μM DTT, thus excluding any significant interaction with MAGL cysteine residues. Furthermore, with the aim of establishing whether the mechanism of inhibition was reversible or irreversible, the effects of preincubation on the inhibitory activity of compound 4 were evaluated. In this assay, the compound was preincubated with the enzyme for 0, 30, and 60 min before adding the substrate to start the enzymatic reaction. An irreversible inhibitor should show a higher potency after longer incubation times, whereas a reversible inhibitor should display a constant inhibition potency that is independent from the incubation time. As shown in Figure 5(B), this assay confirmed the reversible property of 4, as it did not show any significant increase in inhibitory potency at longer incubation times.