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Synthesis, Enzyme Localization, and Regulation of Neurosteroids
Published in Sheryl S. Smith, Neurosteroid Effects in the Central Nervous System, 2003
reply, Lancet, 351, 1512, 1998). Rapkin, A.J., Morgan, M., Goldman, L., Brann, D.W., Simone, D., and Mahesh, V.B., Progesterone metabolite allopregnanolone in women with premenstrual syndrome, Obstet. Gynecol., 90, 709-714, 1997.Schmidt, P.J., Purdy, R.H., Moore, P.H., Jr., Paul, S.M., and Rubinow, D.R., Circulating levels of anxiolytic steroids in the luteal phase in women with premenstrual syndrome and in control subjects, J. Clin. Endocrinol. Metab., 79, 1256-1260, 1994.Monteleone, P., Luisi, S., Tonetti, A., Bernardi, F., Genazzani, A.D., Luisi, M., Petraglia, F., and Genazzani, A.R., Allopregnanolone concentrations and premenstrual syndrome, Eur. J. Endocrinol., 142, 269-273, 2000.Wang, M., Seippel, L., Purdy, R.H., and Backstrom, T., Relationship between symptom severity and steroid variation in women with premenstrual syndrome: study on serum pregnenolone, pregnenolone sulfate, 5 alpha-pregnane-3,20-dione and 3 alpha-hydroxγ-5 alpha-pregnan-20-one, J. Clin. Endocrinol. Metab., 81, 1076-1082, 1996.Griffin, L.D., Conrad, S.C., and Mellon, S.H., Current perspectives on the role of neurosteroids in PMS and depression, Int. Rev. Neurobiol., 46, 479-492, 2001.Dimmock, P.W., Wyatt, K.M., Jones, P.W., and O’Brien, P.M., Efficacy of selective serotonin-reuptake inhibitors in premenstrual syndrome: a systematic review, Lancet, 356, 1131-1136, 2000.Uzunov, D.P., Cooper, T.B., Costa, E., and Guidotti, A., Fluoxetine-elicited changes in brain neurosteroid content measured by negative ion mass fragmentography, Proc. Natl. Acad. Sci. U.S.A., 93, 12599-12604, 1996.Trauger, J.W., Jiang, A., Stearns, B.A., and LoGrasso, P.V., Kinetics of allopregnanolone formation catalyzed by human 3 alpha-hydroxysteroid dehydrogenase type III (AKR1C2), Biochemistry, 41, 13451-13459, 2002.Hara, A., Matsuura, K., Tamada, Y., Sato, K., Miyabe, Y., Deyashiki, Y., and Ishida, N., Relationship of human liver dihydrodiol dehydrogenases to hepatic bile-acid-binding protein and an oxidoreductase of human colon cells, Biochem. J., 313 (Pt.
Synthesis and evaluation of AKR1C inhibitory properties of A-ring halogenated oestrone derivatives
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2021
Maša Sinreih, Rebeka Jójárt, Zoltán Kele, Tomaž Büdefeld, Gábor Paragi, Erzsébet Mernyák, Tea Lanišnik Rižner
To further evaluate these oestrone derivatives as inhibitors of the AKR1C enzymes, we conducted detailed kinetic studies on three different compounds, which were chosen as they were the most potent inhibitors of AKR1C1, AKR1C2, and AKR1C3. The first was compound 1_2Cl,4Cl, or bis-chloro-13β-methyl-17-keto-oestrone, which inhibited both AKR1C1 and AKR1C3 potently, but showed low inhibition of AKR1C2. These inhibition studies revealed a mixed type of inhibition of 1_2Cl,4Cl for AKR1C1 (Ki = 0.69 μM), which was instead competitive for inhibition of AKR1C3 (Ki = 1.43 μM) (Table S1). The second compound chosen here was 2_2I,4Br, a 3-hydroxy disubstituted 13α-methyl-17-keto-oestrone, which at 10 μM showed 90.7% inhibition of AKR1C1, 59.5% inhibition of AKR1C2 and 40.0% of AKR1C3. Its IC50 for AKR1C1 was 0.7 μM, with Ki of 0.57 μM. Here, 2_2I,4Br showed a mixed type of inhibition of AKR1C1. Finally, the third compound chosen was 3_2Br,4Br, a 13α-methyl-17-deoxy bis-bromo oestrone, which showed selectivity for AKR1C2, with IC50 of 0.9 μM. 3_2Br,4Br also showed mixed type of inhibition, with Ki of 1.98 μM.
Non-animal methods to predict skin sensitization (I): the Cosmetics Europe database*
Published in Critical Reviews in Toxicology, 2018
Sebastian Hoffmann, Nicole Kleinstreuer, Nathalie Alépée, David Allen, Anne Marie Api, Takao Ashikaga, Elodie Clouet, Magalie Cluzel, Bertrand Desprez, Nichola Gellatly, Carsten Goebel, Petra S. Kern, Martina Klaric, Jochen Kühnl, Jon F. Lalko, Silvia Martinozzi-Teissier, Karsten Mewes, Masaaki Miyazawa, Rahul Parakhia, Erwin van Vliet, Qingda Zang, Dirk Petersohn
The KeratinoSensTM assay evaluates the activation of the Keap1-Nrf2-ARE-pathway by a test substance as published by Emter et al. (2010), using an immortalized adherent cell line derived from HaCaT human keratinocytes, stably transfected with a luciferase gene under the control of the ARE-element of the human gene AKR1C2. Twelve concentrations of a DMSO or cell culture media-dissolved test substance (ranging from 0.98 to 2000 µM) were applied to the cells for 48 h in at least two independent repetitions. Mixtures or test substances lacking a defined molecular weight (MW) were diluted considering a pro forma molecular weight of 200 g/mol, resulting in 12 test concentrations ranging from 0.195 µg/mL to 400 µg/ml. Luciferase induction is summarized as EC1.5, EC2 and EC3, i.e. the interpolated concentration inducing a 1.5-, 2- and 3-fold response as compared to vehicle control, respectively. In addition, the test concentration with the highest induction is defined as the lmax. Cytotoxicity was determined by the MTT assay and expressed as IC50, i.e. the concentration inducing 50% of the maximum cytotoxicity. KeratinoSensTM data were available for all 128 substances and were produced and interpreted according to procedure described in the OECD test guideline 442 D (OECD 2015 b). Data for 27 of these substances were newly generated, while data on 99 substances were obtained from the literature, mainly Natsch et al. (2015). In addition, the test developer provided data on two substances through personal communication.
Prognostic significance of ferroptosis-related genes and their methylation in AML
Published in Hematology, 2021
Aldo-keto reductases family 1 member C2 (AKR1C2), a member of the aldo/keto reductase superfamily. Previous studies have shown that its expression is selectively deleted in prostate and breast cancer and leads to clonal expansion of tumor cells. In addition, some studies have shown that its expression is negatively correlated with apoptosis-inducing factor (AIF), and is involved in the metastasis of liver cancer and the occurrence of NSCLC drug resistance [18–20]. Suppressor of cytokine signaling 1 (SOCS1) is identified as a tumor suppressor gene. Silencing of SOCS1 expression due to promoter methylation has been found in several malignancies such as pancreatic cancer, breast cancer, lymphoma, and leukemia [21–25]. There is a study mentioned that SOCS1 methylation leads to SOCS1 gene silencing, which promotes AML cell growth and proliferation by inhibiting the downstream JAK2/STAT signaling pathway [26]. However, in our study, low expression of SOCS1 suggested a better prognosis. The specific role of SOCS1 methylation in AML still needs to be further investigated. Besides, no studies have been conducted on the prognostic effect of AKR1C2 and SOCS1 on AML. In this study, we systematically investigated the relationship between AKR1C2 and SOCS1 expression and survival using the TCGA database and found that low AKR1C2 and SOCS1 expression was highly correlated with more favorable OS and DFS in AML patients. Multivariate Cox regression further confirmed this conclusion, suggesting that low expression of AKR1C2 and SOCS1 is a strong prognostic factor for OS and DFS in AML patients. Finally, we further evaluated the overall prognostic value of ARK1C2 and SOCS1 in patients with a molecular and cytogenetic risk status of intermediate risk in the NCCN AML classification, proving that decreased expressions of ARK1C2 and SOCS1 are indeed associated with better OS and DFS in AML patients. Moreover, the expressions of ARK1C2 and SOCS1 are possible to further refine the risk stratification in clinic and to help accurately stratify patients with intermediate-risk. In conclusion, our analysis highlights that ARK1C2 and SOCS1 are promising biomarkers for predicting prognosis in patients with AML.