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The Influence of Pituitary-Adrenal Axis on the Immune System
Published in Istvan Berczi, Pituitary Function and Immunity, 2019
Treatment of rats for 3 weeks with aminoglutethimide, which inhibits adrenal steroidogenesis, led to a marked increase in the number of circulating lymphocytes.56 Adrx, or treatment with aminoglutethimide, enhanced the delayed-hypersensitivity response of mice to SRBC.51 Similarly, Adrx and the glucocorticoid synthesis inhibitor, metyrapone, abolished the suppression caused by immobilization stress of delayed-type hypersensitivity reaction to SRBC in mice. In contrast, the immobilization induced increase in contact sensitivity to 2,4-dinitro-1-fluorobenzene was still observed after hormonal modification. Similar results were observed whether the mice were given metyrapone or adrenalectomized before or after sensitization.57
Affinity Modification — Organic Chemistry
Published in Dmitri G. Knorre, Valentin V. Vlassov, Affinity Modification of Biopolymers, 1989
Dmitri G. Knorre, Valentin V. Vlassov
Arylating groups, although being less reactive than alkylating groups, show similar broad specificity toward nucleophiles. These groups are represented in affinity reagents mainly by derivatives of fluorobenzene. A typical example is α-N-fluorodinitrophenyl-β-N-phospho-pyridoxyl-diaminopropionate which was used for the modification of aspartate aminotransferase (EC 2.6.1.1).102
Xenobiotic Biotransformation
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Halobenzenes, such as bromobenzene, are similarly bioactivated by P450 to epoxides (arene oxides) [reviewed by Jollow and Smith (1977)]. Chlorobenzene, bromobenzene, iodobenzene, and o-dichlorobenzene are biotransformed to arene oxides. All induce hepatotoxicity, whereas fluorobenzene and p-chlorobenzene are not biotransformed to arene oxides and do not cause hepatic necrosis. Arene oxides are detoxified by spontaneous rearrangement to a phenol or by biotransformation by epoxide hydratase and/or glutathione transferases. Bromobenzene is biotransformed by two P450 pathways: a 3,4-bromobenzene oxide synthetase (CYP2B) and a 2,3-bromobenzene oxide synthetase (CYP1A). Although both arene oxides are electrophilic, the former is believed to be primarily responsible for hepatotoxicity. This compound illustrates how both dose and induction modify toxicity resulting from xenobiotic biotransformation. As the dose of administered bromobenzene increases, arene oxide formation increases as does the severity of necrosis due to P450 induction exceeding epoxide hydrolase induction and limited availability of glutathione. Although the CYP2B subfamily is predominant for bioactivation of halobenzenes, activation by the P450 family can reduce toxicity due to coordinate induction of epoxide hydrolase and glutathione transferase. In the case of bromobenzene, PB pretreatment at low doses results in reduced hepatic necrosis due to the induction of epoxide hydrolase and glutathione transferase; but at higher doses, PB pretreatment results in increased hepatic necrosis because the induction of P450 activity exceeds the increased epoxide hydrolase and glutathione transferase activities. If P450s are induced with 3-MC, bromobenzene hepatic necrosis is reduced because the pattern of epoxide formation is altered (increased proportion of 2,3-bromobenzene epoxide relative to 3,4-bromobenzene epoxide) and epoxide hydrolase is induced.
A patent review of selective CDK9 inhibitors in treating cancer
Published in Expert Opinion on Therapeutic Patents, 2023
Tizhi Wu, Xiaowei Wu, Yifan Xu, Rui Chen, Jubo Wang, Zhiyu Li, Jinlei Bian
In view of the great potential of compound 23 in cancer therapy, many pharmaceutical companies have made structural optimization based on this compound in recent years (Figure 4). In patent WO2021115335 A1, researchers identified a series of CDK9 inhibitors by collocating the superior groups of compounds 23 and 2 [80]. The modification of the methyl portion of N-cyclohexane acetamide resulted in two superior compounds, 24 and 25. Both compounds were shown to be highly specific for CDK9 (about 100-fold), and could kill MV4–11 cells at low nano molar concentrations (Both IC50<35 nM). In addition, the introduction of F-atoms at the 5`position of methoxy fluorobenzene resulted in compounds 26 and 27. Compared to compound 24, they displayed similar enzymatic activity but slightly reduced selectivity and cellular activity. Interestingly, both F-atom based compounds 26 and 27 (5 mg/kg, po, TGI (tumor growth inhibition) = 67.8%, 78.1% in MV4–11 ×enograft tumor model, respectively) exhibited higher in vivo antitumor effects relative to compounds 24 and 25 (5 mg/kg, po, TGI = 56.9%, 62.9% in MV4–11 ×enograft tumor model, respectively). Compound 27 also exhibited marked in vivo antitumor activity in HL-60 ×enograft tumor model with TGI = 90.2%. Moreover, a better safety profile of compound 25 than that of 2 was observed in toxicity evaluation [80].
Chronic exposure to dim light at night disrupts cell-mediated immune response and decreases longevity in aged female mice
Published in Chronobiology International, 2022
Jennifer A. Liu, James C. Walton, Jacob R. Bumgarner, William H. Walker, O. Hecmarie Meléndez-Fernández, A. Courtney DeVries, Randy J. Nelson
To assess cell-mediated immune response, mice were sensitized to a chemical antigenic challenge as previously described (Bilbo and Nelson 2003). Briefly, under light anesthesia 25 μl of 2–4 dinitro-1-fluorobenzene (DNFB; Sigma, St. Louis, MO; 0.5% volume in a 4:1 acetone/olive oil vehicle) was applied to a 2 × 3 cm shaved region of the dorsum for 2 consecutive days starting at week 22. Prior to manipulation, mice acclimated to the experimental room for 30 min and the thickness of the right and left pinna was measured using a constant-loaded thickness gauge (Mitutoyo #7309, Kawasaki, Kanagawa, Japan) at the same time point each day (zeitgeber time; ZT 8–10, 1200 h to 1400 h). Mice were lightly anesthetized with isoflurane vapors during DNFB challenge and pinnae thickness measurements. Seven days post sensitization, mice were re-challenged with 20 μl DNFB (0.2% volume DNFB in vehicle) to the external right pinna, the left pinna received the vehicle solution. Pinnae thickness was measured for the following 6 days. All experiments were approved by West Virginia University Institutional Animal Care and Use Committee and animals were maintained in accordance with NIH Animal Welfare guidelines.
Fluorinated vectors for gene delivery
Published in Expert Opinion on Drug Delivery, 2022
Yu Wan, Yuhan Yang, Mingyu Wu, Shun Feng
In addition, there are several micro-environmentally responsive fluorinated polymers for application in gene editing and gene therapy. An acid-labile polycation decorated with fluorinated alkyl chains was used to deliver the CRISPR/Cas9 system (pCas9-surv) for gene editing [38]. In Zhang’s work, the fluorobenzene substituted and ROS responsive moieties contained polycations(tris(2-aminoethyl)amine-S-xF) were synthesized to obtain good transfection efficiency and serum tolerance [52]. Jiang et al., recently reported ROS responsive gene delivery polymers constituted with a thioketal cross-linker, histamine and undecafluorohexylamine, which could enhance the penetrating ability across the membranes of mitochondria. It exhibited an excellent curative effect on Leber’s hereditary optic neuropathy when this fluorinated vector was loaded with idebenone and NADH ubiquinone oxidoreductase subunit-4 gene [89]. Hence, there are many proofs that the fluorination modification of polymers is an effective strategy to improve the gene transfection efficiency of nonviral gene carriers, which has broad application prospects.