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Molecular Targets for 17α-Ethynyl-5-Androstene-3β,7β,17β-Triol, an Anti-Inflammatory Agent Derived from the Human Metabolome  [PDF]
Christopher L. Reading, James M. Frincke, Steven K. White
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0032147
Abstract: HE3286, 17α-ethynyl-5-androstene-3β, 7β, 17β-triol, is a novel synthetic compound related to the endogenous sterol 5-androstene-3β, 7β, 17β-triol (β-AET), a metabolite of the abundant adrenal steroid dehydroepiandrosterone (DHEA). HE3286 has shown efficacy in clinical studies in impaired glucose tolerance and type 2 diabetes, and in vivo models of types 1 and 2 diabetes, autoimmunity, and inflammation. Proteomic analysis of solid-phase HE3286-bound bead affinity experiments, using extracts from RAW 264.7 mouse macrophage cells, identified 26 binding partners. Network analysis revealed associations of these HE3286 target proteins with nodes in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for type 2 diabetes, insulin, adipokine, and adipocyte signaling. Binding partners included low density lipoprotein receptor-related protein (Lrp1), an endocytic receptor; mitogen activated protein kinases 1 and 3 (Mapk1, Mapk3), protein kinases involved in inflammation signaling pathways; ribosomal protein S6 kinase alpha-3 (Rsp6ka3), an intracellular regulatory protein; sirtuin-2 (Sirt2); and 17β-hydroxysteroid dehydrogenase 1 (Hsd17β4), a sterol metabolizing enzyme.
17α-Ethynyl-5α-androstane-3α, 17β-diol Treatment of MNU-Induced Mammary Cancer in Rats  [PDF]
Clarence N. Ahlem,James M. Frincke,Steven K. White,Christopher L. Reading,Richard J. Trauger,Rajkumar Lakshmanaswamy
International Journal of Breast Cancer , 2011, DOI: 10.4061/2011/618757
Abstract: N-methyl-N-nitrosourea (MNU) induces estrogen-dependent mammary tumors in female Lewis rats. We explored the antineoplastic activity of a synthetic androstane derivative, 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235), as a single agent or in combination with docetaxel compared to tamoxifen, anastrazole, and docetaxel monotherapies against MNU-induced mammary tumors in female Lewis rats. Treatment with HE3235 alone rapidly reduced tumor burden, similar in effect to tamoxifen and anastrozole. The combination of HE3235 with docetaxel was more effective than any single agent, although without apparent toxicity. Only HE3235 or HE3235 plus docetaxel continued to suppress tumor growth after cessation of treatment. HE3235 treatment increased immunohistochemical markers of apoptosis and expression of proapoptotic genes and estrogen receptor beta and decreased expression of antiapoptotic genes, androgen receptor, and estrogen receptor alpha. These data warrant clinical investigation of HE3235 for breast cancer treatment. 1. Introduction Breast cancer is one of the most common cancers among women, and the incidence of breast cancer is increasing worldwide [1]. Approximately 200,000 women are diagnosed with breast cancer annually, with an associated mortality of 40,000 in the United States [2]. Currently, there are few treatments for hormone-dependent breast cancer, with tamoxifen and anastrazole being the most widely used therapies [3]. Although generally well tolerated, these treatments can be associated with significant morbidity [4], and development of resistance is common [5, 6]. The carcinogen N-methyl-N-nitrosourea (MNU) induc-es hormone-dependent mammary tumors in rats. This model has previously been used to develop tamoxifen therapy in women with breast cancer [7], and is considered to be appropriate for studies of novel compounds potentially useful for the treatment of breast cancer. Substantial evidence suggests that this rodent model system mimics human breast cancer: the initiation of cancer occurs primarily at the same site in both humans and rats, the majority of the tumors express estrogen and progesterone receptors, and tumor development is dependent on the reproductive history, diet, and hormonal milieu [8]. Thus the model provides an opportunity to examine cause-and-effect relationships of the in situ environment fully impacted by systemic factors [9]. 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235) is a synthetic androstane derivative that inhibits 5-androstene-diol [10], testosterone, and estrogen (unpublished) stimulated prostate cancer cell
14α-Hydroxylation of Androst-4-en-3, 17-dione by the Whole Cells of Cyanobacterium Nostoc piscinale  [PDF]
A. Kalbasi,M.A. Faramarzi,M.S. Hejazi,H. Jahandar
Biotechnology , 2009,
Abstract: The potential of microalga Nostoc piscinale was evaluated in bioconversion of androst-4-en-3, 17-dione (I). Bio-reaction was performed in BG-11 liquid medium supplemented with 0.05% steroid substrate under continuous light photo-regime of 3000 lux at 25°C for 5 days. Three major metabolites were purified chromatographically and identified on the bases of their spectral data and physical constants as 17β-hydroxyandrost-4-en-3-one (II), 14α-hydroxyandrost-4-en-3,17-dione (III) and 14α,17β-dihydroxyandrost-4-en-3-one (IV). Bioconversion characteristics observed were 14α-hydroxylation and 17-keto reduction. Present results showed that the green biocatalyst is suitable for some specific alterations on androst-4-en-3,17-dione including 14α-hydroxylation.
5-Androstene-3β,7β,17β-triol (β-AET) Slows Thermal Injury Induced Osteopenia in Mice: Relation to Aging and Osteoporosis  [PDF]
Ajay K. Malik,Sophia Khaldoyanidi,Dominick L. Auci,Scott C. Miller,Clarence N. Ahlem,Christopher L. Reading,Theodore Page,James M. Frincke
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0013566
Abstract: 5-androstene-3β,7β,17β-triol (β-AET), an active metabolite of dehydroepiandrosterone (DHEA), reversed glucocorticoid (GC)-induced suppression of IL-6, IL-8 and osteoprotegerin production by human osteoblast-like MG-63 cells and promoted osteoblast differentiation of human mesenchymal stem cells (MSCs). In a murine thermal injury model that includes glucocorticoid-induced osteopenia, β-AET significantly (p<0.05) preserved bone mineral content, restored whole body bone mineral content and endochondral growth, suggesting reversal of GC-mediated decreases in chondrocyte proliferation, maturation and osteogenesis in the growth plate. In men and women, levels of β-AET decline with age, consistent with a role for β-AET relevant to diseases associated with aging. β-AET, related compounds or synthetic derivatives may be part of effective therapeutic strategies to accelerate tissue regeneration and prevent or treat diseases associated with aging such as osteoporosis.
Advance in Degrading Side Chain of Sterols of Getting Androst-4-Ene-3, 17-Dione by Microorganism
微生物降解甾醇侧链转化雄甾-4-烯-3,17-二酮的研究进展

YANG Ying,JIANG Shao-Tong,
杨英
,姜绍通

微生物学通报 , 2006,
Abstract: Sterols hormones plays an indispensable role in clinic. Androst-4-ene-3,17-dione is a middling product of sterol hormones for which can not be substituted and have an very important regulative effect in organism. We can say that almost of hormonal medicines are made of androst -4-ene-3,17-dione .Recently, many researches showed that some microorganisms have the capacity to carry out the selective side chain degradation of sterols and get androst-4-ene-3,17-dione . This paper described the recent advance of the technique in this area. There still some question in this area should be taken into consideration in industry production.
HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression
Douglas Conrad, Angela Wang, Raymond Pieters, Ferdinando Nicoletti, Katia Mangano, Anna M van Heeckeren, Steven K White, James M Frincke, Christopher L Reading, Dwight Stickney, Dominick L Auci
Journal of Inflammation , 2010, DOI: 10.1186/1476-9255-7-52
Abstract: In mice, oral treatment with HE3286 (40 mg/kg) significantly (p < 0.05) decreased neutrophil counts and exudate volumes (~50%) in carrageenan-induced pleurisy, and myeloperoxidase in lipopolysaccharide-induced lung injury. HE3286 (40 mg/kg) was not found to be profoundly immune suppressive in any of the classical animal models of immune function, including those used to evaluate antigen specific immune responses in vivo (ovalbumin immunization). When mice treated for two weeks with HE3286 were challenged with K. pneumoniae, nearly identical survival kinetics were observed in vehicle-treated, HE3286-treated and untreated groups.HE3286 represents a novel, first-in-class anti-inflammatory agent that may translate certain benefits of β-AET observed in rodents into treatments for chronic inflammatory pulmonary disease.Chronic obstructive pulmonary disease (COPD), a term most often used to describe chronic bronchitis and emphysema [1,2] is an inflammatory disease of the lungs marked by a loss of elastic recoil, an increased resistance to airflow and decreased expiratory flow rate leading to dyspnea [3]. Chronic bronchitis, emphysema and cystic fibrosis (CF), all forms of COPD, share many features including a progressive airway remodeling driven by chronic inflammation [4-7]. COPD is a major cause of morbidity and mortality in industrialized countries and novel treatments are urgently needed because many patients respond poorly to conventional therapies [8-10]. Even in responders, narrow therapeutic windows and a myriad of unwanted side effects, including immune suppression are treatment limiting [9-12]. We have suggested that suitable agents may be found within the adrenal metabolome [13].Dehydroepiandrosterone (DHEA) is an abundant adrenal steroid and a precursor in the biosynthesis of androgens, estrogens and other anti-inflammatory immune regulating steroids [14,15]. From studies reporting aberrant metabolism of adrenal steroids in CF patients [16,17] we surmised that
4-(Dimethylamino)phenyl ethynyl telluride  [cached]
Joan Farran,Angel Alvarez-Larena,Joan F. Piniella,Mario V. Capparelli
Acta Crystallographica Section E , 2009, DOI: 10.1107/s1600536809009404
Abstract: The title compound, C10H11NTe, is the first organyl ethynyl telluride, R—Te—C[triple-bond]C—H, to be structurally characterized. In the L-shaped molecule, the aryl moiety, viz. Me2NC6H4Te, is almost perpendicular to the Te—C[triple-bond]C—H fragment. The Te—Csp2 bond [2.115 (3) ] is significantly longer than the Te—Csp bond [2.041 (4) ]. The Te—C[triple-bond]C group is approximately linear [Te—C—C = 178.5 (4)° and C[triple-bond]C = 1.161 (5) ], while the coordination at the Te atom is angular [C—Te—C = 95.92 (14)°]. In the crystal structure, there are Csp—H...N hydrogen bonds which are perpendicular to the CNMe2 group; the N atom displays some degree of pyramidalization. Centrosymmetrically related pairs of molecules are linked by Te...π(aryl) interactions, with Te...Cg = 3.683 (4) and Csp—Te...Cg = 159.1 (2)° (Cg is the centroid of the benzene ring). These interactions lead to the formation of zigzag ribbons which run along c and are approximately parallel to (110).
Bis[(4-methylphenyl)ethynyl] telluride
Ignez Caracelli,Julio Zukerman-Schpector,Jesus M. Pena,Hélio A. Stefani
Acta Crystallographica Section E , 2010, DOI: 10.1107/s1600536810006264
Abstract: The tellurium atom in the title bis-ethynyl telluride, Te(C9H7)2 or C18H14Te, is located on a crystallographic twofold axis, the C—Te—C angle being 92.23 (15)°. The dihedral angle between the rings is 87.27 (7)°. In the crystal structure, molecules are connected in chains parallel to the b axis and mediated by C—H...π interactions.
Cholestane-3β, 5α, 6β-triol Suppresses Proliferation, Migration, and Invasion of Human Prostate Cancer Cells  [PDF]
Ching-Yu Lin, Chieh Huo, Li-Kuo Kuo, Richard A. Hiipakka, Richard Baker Jones, Hui-Ping Lin, Yuwen Hung, Liang-Cheng Su, Jen-Chih Tseng, Ying-Yu Kuo, Yu-Ling Wang, Yasuhisa Fukui, Yung-Hsi Kao, John M. Kokontis, Chien-Chih Yeh, Linyi Chen, Shiaw-Der Yang, Hsiao-Hui Fu, Ya-Wen Chen, Kelvin K. C. Tsai, Jang-Yang Chang, Chih-Pin Chuu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0065734
Abstract: Oxysterols are oxidation products of cholesterol. Cholestane-3β, 5α, 6β-triol (abbreviated as triol) is one of the most abundant and active oxysterols. Here, we report that triol exhibits anti-cancer activity against human prostate cancer cells. Treatment of cells with triol dose-dependently suppressed proliferation of LNCaP CDXR-3, DU-145, and PC-3 human prostate cancer cells and reduced colony formation in soft agar. Oral administration of triol at 20 mg/kg daily for three weeks significantly retarded the growth of PC-3 xenografts in nude mice. Flow cytometric analysis revealed that triol treatment at 10–40 μM caused G1 cell cycle arrest while the TUNEL assay indicated that triol treatment at 20–40 μM induced apoptosis in all three cell lines. Micro-Western Arrays and traditional Western blotting methods indicated that triol treatment resulted in reduced expression of Akt1, phospho-Akt Ser473, phospho-Akt Thr308, PDK1, c-Myc, and Skp2 protein levels as well as accumulation of the cell cycle inhibitor p27Kip. Triol treatment also resulted in reduced Akt1 protein expression in PC-3 xenografts. Overexpression of Skp2 in PC-3 cells partially rescued the growth inhibition caused by triol. Triol treatment suppressed migration and invasion of DU-145, PC-3, and CDXR-3 cells. The expression levels of proteins associated with epithelial-mesenchymal transition as well as focal adhesion kinase were affected by triol treatment in these cells. Triol treatment caused increased expression of E-cadherin protein levels but decreased expression of N-cadherin, vimentin, Slug, FAK, phospho-FAK Ser722, and phospho-FAK Tyr861 protein levels. Confocal laser microscopy revealed redistribution of β-actin and α-tubulin at the periphery of the CDXR-3 and DU-145 cells. Our observations suggest that triol may represent a promising therapeutic agent for advanced metastatic prostate cancer.
Dissociative photoionization of polycyclic aromatic hydrocarbon molecules carrying an ethynyl group  [PDF]
Ga?l Rouillé,Serge A. Krasnokutski,Daniele Fulvio,Cornelia J?ger,Thomas Henning,Gustavo A. Garcia,Xiao-Feng Tang,Laurent Nahon
Physics , 2015, DOI: 10.1088/0004-637X/810/2/114
Abstract: The life cycle of the population of interstellar polycyclic aromatic hydrocarbon (PAH) molecules depends partly on the photostability of the individual species. We have studied the dissociative photoionization of two ethynyl-substituted PAH species, namely, 9-ethynylphenanthrene and 1-ethynylpyrene. Their adiabatic ionization energy and the appearance energy of fragment ions have been measured with the photoelectron photoion coincidence (PEPICO) spectroscopy technique. The adiabatic ionization energy has been found at 7.84 +/- 0.02 eV for 9-ethynylphenanthrene and at 7.41 +/- 0.02 eV for 1-ethynylpyrene. These values are similar to those determined for the corresponding non-substituted PAH molecules phenanthrene and pyrene. The appearance energy of the fragment ion indicative of the loss of a H atom following photoionization is also similar for either ethynyl-substituted PAH molecule and its non-substituted counterpart. The measurements are used to estimate the critical energy for the loss of a H atom by the PAH cations and the stability of ethynyl-substituted PAH molecules upon photoionization. We conclude that these PAH derivatives are as photostable as the non-substituted species in HI regions. If present in the interstellar medium, they may play an important role in the growth of interstellar PAH molecules.
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