In Vitro Inhibition of Human Placental Glutathione S-Transferase by 3-Arylcoumarin Derivatives

PubMedID: 26205366Glutathione S-transferases (EC: 2.5.1.18, GSTs) are phase II detoxification enzymes that catalyze the conjugation of various electrophilic compounds to glutathione (GSH), thus usually producing less reactive and more water soluble compounds. However, there is evidence that elevated expression of GSTs, especially GSTP1, is involved in the resistance of tumor cells against chemotherapeutic agents. In this study, we synthesized and investigated the inhibitory effects of differently substituted 3-arylcoumarin derivatives on human placental GST, identified as GSTP1-1, using 1-chloro-2,4-dinitrobenzene as a substrate. A known potent inhibitor of GST, ethacrynic acid was used as a positive control. Among the tested compounds, 6,7-dihydroxy substituted coumarin derivatives exhibited the highest inhibitory activity (IC50=13.50-20.83µM). These results suggest that 6,7-dihydroxy-3-arylcoumarins may represent a new promising scaffold to discover potent GST inhibitors. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Synthesis of selected 3- and 4-arylcoumarin derivatives and evaluation as potent antioxidants

A series of hydroxyl-, methoxy-, and acetoxy-substituted 3- and 4-arylcoumarins were synthesized. All title compounds were screened for their antioxidant capacity, ability to scavenge the 1,1-diphenyl-1-picrylhydrazyl (DPPH) radical, and ability to chelate iron ions. Furthermore, all derivatives were assessed using molecular properties prediction and drug likeness using Molinspiration. It was found that all studied derivatives were potential candidates for further research, as they complied with Lipinski’s rule of five for drug likeness. 3- or 4-arylcoumarins that possess two hydroxyl groups in ortho position, such as 4h, 5b, h, and 6a, had remarkable half-maximal effective concentration (EC50) for radical scavenging, with better performance than known antioxidants in DPPH and metal-chelating assays. In addition, the cupric-reducing antioxidant capacity and ferric-reducing antioxidant power of the synthesized compounds were investigated for antioxidant activity. Among them, 5g, h and 6a, b showed significantly better Trolox equivalent antioxidant capacity (TEAC) than standard compounds. The results demonstrate that the compounds with dihydroxyl groups at 6- and 7-positions of the benzopyrone ring of the arylcoumarin structure are the most active of the series as antioxidants. On the basis of these findings, these new coumarin derivatives are potential therapeutic candidates for pathogenesis of many diseases characterized by free-radical overproduction. © 2016, Springer Science+Business Media Dordrecht

Therapeutic Potential of Pterostilbene and Resveratrol on Biomechanic, Biochemical, and Histological Parameters in Streptozotocin-Induced Diabetic Rats

Aims. The aim of this study was to investigate the effects of pterostilbene (PTS) (trans-3,5-dimethoxy-4'-hydroxystilbene) and resveratrol (RSV) (trans-3,5,4' trihydroxystilbene) applied at different doses for the treatment of streptozotocin- (STZ-) induced diabetic rats. Materials and Methods. At the end of the 5-week experimental period, the right gastrocnemius muscles of the rats were examined biomechanically, while the left ones were examined histologically. In addition, blood glucose, serum insulin, and malondialdehyde (MDA) levels were analyzed in blood samples taken from the rats. Results. The skeletal muscle isometric contraction forces, which showed a decrease with diabetes, were observed to increase with antioxidant applications. Blood glucose, serum insulin, and MDA levels in diabetic rats approached normal levels after applying PTS. When the electron microscopic images of the rat skeletal muscle were examined, those in the combination treatment group were observed to show a better enhancement in the skeletal muscle morphological structure compared to the other diabetic and treatment groups. Conclusion. According to the findings, we suggest that these antioxidant treatments might have good therapeutic nutraceutical potential for some muscle diseases that coexist with diabetes. These treatments should be comprehensively investigated in the future. © 2018 Bora Tastekin et al.The research was supported by the C¸ ukurova University Scientific Research Foundation (Project no. TSA-2016-4958). Thanks are due to the Sabinsa Corporation for the supply of antioxidants

Effects of osteocalcin on synthesis of testosterone and INSL3 during adult leydig cell differentiation

Proliferation and differentiation of adult Leydig cells are mainly completed in puberty. In many studies, apart from normal postnatal development process, it is widely indicated that, through administrating EDS, Leydig cell population is eliminated and regenerated. It is believed that osteocalcin released from osteoblasts, which is responsible for modulating bone metabolism, induces testosterone production in Leydig cells, independent of the HPG axis. In addition, INSL3 produced by Leydig cells, such as testosterone, plays a critical role in bone metabolism and is known to reflect the development process and functional capacities of Leydig cells. This study is aimed at investigating OC-mediated testosterone regulation and INSL3 synthesis during differentiation of adult Leydig cells that are independent of LH. For this purpose, male rats were divided into 2 groups: Prepubertal normal rats and adult EDS-injected rats. Each group was divided into 4 subgroups in which GnRH antagonist or OC was applied. After adult Leydig cells completed their development, testicular tissue samples obtained from the sacrificed rats were examined by light-electron microscopic, immunohistochemical, and biochemical methods. Slight upregulation in 3ßHSD, INSL3, and GPRC6A expressions along with the increase in serum testosterone levels was observed in groups treated with osteocalcin against GnRH antagonist. In addition, biochemical and microscopic findings in osteocalcin treated groups were similar to those in control groups. While there was no significant difference in the number of Leydig cells reported, the presence of a significant upregulation in INSL3 and GPRC6A expressions and the increase in serum testosterone and ucOC levels were observed. After evaluation of findings altogether, it is put forward that, for the first time in this study, although osteocalcin treatment made no significant difference in the number of Leydig cells, it increased the level of testosterone through improving the function of existing adult Leydig cells during normal postnatal development process and post-EDS regeneration. This positive correlation between osteocalcin-testosterone and osteocalcin-INSL3 is concluded to be independent of LH at in vivo conditions. © 2019 Gulfidan Coskun et al