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Biotransformation of Sesquiterpenoids, Ionones, Damascones, Adamantanes, and Aromatic Compounds by Green Algae, Fungi, and Mammals
Published in K. Hüsnü Can Başer, Gerhard Buchbauer, Handbook of Essential Oils, 2020
Yoshinori Asakawa, Yoshiaki Noma
Hinokitiol (589), which is easily obtained from cell suspension cultures of Thujopsis dolabrata and possesses potent antimicrobial activity, was incubated with cultured cells of E. perriniana for 7 days to give its monoglucosides (590, 591%, 32%) and gentiobiosides (592, 593) (Furuya et al., 1997; Hamada et al., 1998) (Figure 23.164).
Bioinformatic analysis of the clinicopathological and prognostic significance of oocyte-arresting BTG4 mRNA expression in gynecological cancers
Published in Journal of Obstetrics and Gynaecology, 2023
Hua-chuan Zheng, Hang Xue, Cong-yu Zhang, Rui Zhang
The development of mouse embryos lacking BTG4 is arrested at the one- to two-cell stage. Owing to this early developmental arrest, BTG4-null females produce morphologically normal oocytes but are infertile (Liu et al.2016, Zheng et al.2020). Mano et al. (2015) found that transient BTG4 expression induced alkaline phosphatase activity in human embryonic kidney cells. In addition, BTG4 mRNA was detected in pharynx, larynx, trachea, oviduct, ovary, caput epididymis, and testis, but not in lung, intestine, or liver. BTG4 protein is present in epithelial cells of the tongue, palate, pharynx, internal nose, and trachea. Findings also revealed that both protein and mRNA levels of BTG4 were reduced by aging when comparing 4- and 48-week-old mice. Moreover, Mori et al. (2011) found that BTG4 methylation could be used to distinguish colorectal cancer from age-matched control mucosa. Furthermore, Seo et al. (2017) demonstrated that hinokitiol induced DNA demethylation and mRNA restoration of BTG4 via DNMT1 in colon cancer cells. Dong et al. (2009) also reported that the BTG4 level was significantly reduced in gastric cancer compared with that in normal gastric tissues. BTG4 re-expression in gastric cancer then inhibited its growth, as confirmed by colony assays and a xenograft model.
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
Several small-molecule GPVI inhibitors have been reported which are shown in Figure 5A. The most thoroughly studied of these is the angiotensin II receptor antagonist, losartan [63], which was found in a drug-repurposing virtual screening assay. Several natural bioactive compounds, namely honokiol [64], hinokitiol [65] and caffeic acid phenethyl ester (CAPE) have also been identified [66]. Honokiol is the only one of the these for which direct binding has been studied using surface plasmon resonance [64]. As yet, molecular docking studies have not been reported with any of the compounds, and the value of these would be limited due to the low affinities of the compounds. S002-333 [67], a pyridoindole-based compound, and S007-867 [68], a chiral 3-aminomethylpiperidine analogue, have also been show to block GPVI and to have antithrombotic efficacy in animal models. All of the ligands (Figure 5A) display IC50 values in the micromolar range on platelet aggregation assays. Moreover, losartan has been shown to inhibit other platelet receptors, notably those for thromboxane A2 and CLEC-2 at similar or slightly higher concentrations [69], which suggests that it may be having a generalized effect on membrane organization rather than competing at the ligand-binding site.
Repurposing elesclomol, an investigational drug for the treatment of copper metabolism disorders
Published in Expert Opinion on Investigational Drugs, 2021
Treating Menkes patients by parenteral copper supplementation using hydrophilic complexes, such as copper histidinate, fails to ameliorate disease pathology in most cases [5]. This is because hydrophilic copper salts are unable to reach cuproenzymes present in different subcellular compartments of various tissues, especially the brain. Administration of supra-physiological levels of copper is toxic to cells, as copper has a strong tendency to generate reactive oxygen species (ROS) [6]. To counteract copper toxicity, organisms have evolved a highly regulated network of copper-transporting, copper-escorting, and copper-storing proteins that tightly control copper levels in cells [1]. Thus, site-specific delivery of copper to cuproenzymes has to overcome two major obstacles: First, it must cross multiple biological membranes, and, second, it must bypass the regulatory network of copper-trafficking/storing proteins. In this regard, a membrane-traversing drug capable of binding copper outside the cell and releasing it inside the cell might prove more effective in delivering copper to intracellular cuproenzymes. This ‘Trojan-horse’ fashion delivery of metals by other lipophilic carrier molecules, such as the iron-transporting hinokitiol, has shown promise in restoring iron levels in preclinical animal models [7]. Using this principle, Soma et al., performed a targeted screen with a number of copper-binding pharmacological agents for their ability to restore respiratory growth in a yeast mutant defective in copper delivery to cytochrome c oxidase (CcO), a mitochondrial cuproenzyme [8]. This screen identified elesclomol as the most potent copper-transporting molecule, which rescued CcO function in a number of in vitro and in vivo models of copper deficiency [8,9].