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Fan Yang - One of the best experts on this subject based on the ideXlab platform.
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AsperSecosteroids A and B, Two 11(9 → 10)-abeo-5,10-Secosteroids with a Dioxatetraheterocyclic Ring System from Aspergillus flocculosus 16D-1
Organic Letters, 2018Co-Authors: Bin-bin Gu, Fu-rong Jiao, Wei-hua Jiao, Shu-ping Wang, Wei Wu, Lei Li, Fan YangAbstract:Two 11(9 → 10)-abeo-5,10-Secosteroids possessing an unprecedented dioxatetraheterocyclic ring system, asperSecosteroids A (1) and B (2), and a new ergosteroid, asperflosterol (3), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. Their structures were determined by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 1–3 demonstrated inhibitory effects on key pro-inflammatory cytokine production in THP-1 cells. A biogenetic pathway with oxidative cleavage, Wagner–Meerwein rearrangement, and sequential acetalization as key steps is proposed for 1 and 2.
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asperSecosteroids a and b two 11 9 10 abeo 5 10 Secosteroids with a dioxatetraheterocyclic ring system from aspergillus flocculosus 16d 1
Organic Letters, 2018Co-Authors: Fu-rong Jiao, Wei-hua Jiao, Shu-ping Wang, Fan Yang, Fan Sun, Houwen LinAbstract:Two 11(9 → 10)- abeo-5,10-Secosteroids possessing an unprecedented dioxatetraheterocyclic ring system, asperSecosteroids A (1) and B (2), and a new ergosteroid, asperflosterol (3), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. Their structures were determined by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 1-3 demonstrated inhibitory effects on key pro-inflammatory cytokine production in THP-1 cells. A biogenetic pathway with oxidative cleavage, Wagner-Meerwein rearrangement, and sequential acetalization as key steps is proposed for 1 and 2.
Robert C Tuckey - One of the best experts on this subject based on the ideXlab platform.
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differential and overlapping effects of 20 23 oh d3 and 1 25 oh d3 on gene expression in human epidermal keratinocytes identification of ahr as an alternative receptor for 20 23 oh d3
International Journal of Molecular Sciences, 2018Co-Authors: Andrzej Slominski, Zorica Janjetovic, Robert C Tuckey, Tae Kang Kim, Anna A Brozyna, Michal A żmijewski, Thomas R Sutter, Anton M Jetten, David K CrossmanAbstract:A novel pathway of vitamin D activation by CYP11A has previously been elucidated. To define the mechanism of action of its major dihydroxy-products, we tested the divergence and overlap between the gene expression profiles of human epidermal keratinocytes treated with either CYP11A1-derived 20,23(OH)₂D3 or classical 1,25(OH)₂D3. Both Secosteroids have significant chemical similarity with the only differences being the positions of the hydroxyl groups. mRNA was isolated and examined by microarray analysis using Illumina's HumanWG-6 chip/arrays and subsequent bioinformatics analyses. Marked differences in the up- and downregulated genes were observed between 1,25(OH)₂D3- and 20,23(OH)₂D3-treated cells. Hierarchical clustering identified both distinct, opposite and common (overlapping) gene expression patterns. CYP24A1 was a common gene strongly activated by both compounds, a finding confirmed by qPCR. Ingenuity pathway analysis identified VDR/RXR signaling as the top canonical pathway induced by 1,25(OH)₂D3. In contrast, the top canonical pathway induced by 20,23(OH)₂D3 was AhR, with VDR/RXR being the second nuclear receptor signaling pathway identified. QPCR analyses validated the former finding by revealing that 20,23(OH)₂D3 stimulated CYP1A1 and CYP1B1 gene expression, effects located downstream of AhR. Similar stimulation was observed with 20(OH)D3, the precursor to 20,23(OH)₂D3, as well as with its downstream metabolite, 17,20,23(OH)₃D3. Using a Human AhR Reporter Assay System we showed marked activation of AhR activity by 20,23(OH)₂D3, with weaker stimulation by 20(OH)D3. Finally, molecular modeling using an AhR LBD model predicted vitamin D3 hydroxyderivatives to be good ligands for this receptor. Thus, our microarray, qPCR, functional studies and molecular modeling indicate that AhR is the major receptor target for 20,23(OH)₂D3, opening an exciting area of investigation on the interaction of different vitamin D3-hydroxyderivatives with AhR and the subsequent downstream activation of signal transduction pathways in a cell-type-dependent manner.
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detection of novel cyp11a1 derived Secosteroids in the human epidermis and serum and pig adrenal gland
Scientific Reports, 2015Co-Authors: Andrzej Slominski, Edith K Y Tang, Elaine W Tieu, Arnold E. Postlethwaite, Wei Li, Robert C TuckeyAbstract:To investigate whether novel pathways of vitamin D3 (D3) and 7-dehydrocholesterol (7DHC) metabolism initiated by CYP11A1 and previously characterized in vitro, occur in vivo, we analyzed samples of human serum and epidermis, and pig adrenals for the presence of intermediates and products of these pathways. We extracted human epidermis from 13 individuals and sera from 13 individuals and analyzed them by LC/qTOF-MS alongside the corresponding standards. Pig adrenal glands were also analyzed for these steroids and Secosteroids. Epidermal, serum and adrenal samples showed the presence of D3 hydroxy-derivatives corresponding to 20(OH)D3, 22(OH)D3, 25(OH)D3, 1,25(OH)2D3, 20,22(OH)2D3, 20,23(OH)2D3, 20,24(OH)2D3, 20,25(OH)2D3, 20,26(OH)2D3, 1,20,23(OH)3D3 and 17,20,23(OH)3D3, plus 1,20(OH)2D3 which was detectable only in the epidermis. Serum concentrations of 20(OH)D3 and 22(OH)D3 were only 30- and 15-fold lower than 25(OH)D3, respectively, and at levels above those required for biological activity as measured in vitro. We also detected 1,20,24(OH)3D3, 1,20,25(OH)3D3 and 1,20,26(OH)3D3 in the adrenals. Products of CYP11A1 action on 7DHC, namely 22(OH)7DHC, 20,22(OH)27DHC and 7-dehydropregnenolone were also detected in serum, epidermis and the adrenal. Thus, we have detected novel CYP11A1-derived Secosteroids in the skin, serum and adrenal gland and based on their concentrations and biological activity suggest that they act as hormones in vivo.
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Novel non-calcemic Secosteroids that are produced by human epidermal keratinocytes protect against solar radiation.
The Journal of Steroid Biochemistry and Molecular Biology, 2015Co-Authors: Andrzej Slominski, Zorica Janjetovic, Sofia Rosas, Sherie Hanna, Robert M Sayre, John C Dowdy, Piotr Wasilewski, Wei Li, Robert C TuckeyAbstract:Abstract CYP11A1 hydroxylates the side chain of vitamin D3 (D3) in a sequential fashion [D3 → 20 S (OH)D3 → 20,23(OH) 2 D3 → 17,20,23(OH) 3 D3], in an alternative to the classical pathway of activation [D3 → 25(OH)D3 → 1,25(OH) 2 D3]. The products/intermediates of the pathway can be further modified by the action of CYP27B1. The CYP11A1-derived products are biologically active with functions determined by the lineage of the target cells. This pathway can operate in epidermal keratinocytes. To further define the role of these novel Secosteroids we tested them for protective effects against UVB-induced damage in human epidermal keratinocytes, melanocytes and HaCaT keratinocytes, cultured in vitro . The Secosteroids attenuated ROS, H 2 O 2 and NO production by UVB-irradiated keratinocytes and melanocytes, with an efficacy similar to 1,25(OH) 2 D3, while 25(OH)D3 had lower efficacy. These attenuations were also seen to some extent for the 20(OH)D3 precursor, 20 S -hydroxy-7-dehydrocholesterol. These effects were accompanied by upregulation of genes encoding enzymes responsible for defense against oxidative stress. Using immunofluorescent staining we observed that the Secosteroids reduced the generation cyclobutane pyrimidine dimers in response to UVB and enhanced expression of p53 phosphorylated at Ser-15, but not at Ser-46. Additional evidence for protection against DNA damage in cells exposed to UVB and treated with Secosteroids was provided by the Comet assay where DNA fragmentation was markedly reduced by 20(OH)D3 and 20,23(OH) 2 D3. In conclusion, novel Secosteroids that can be produced by the action of CYP11A1 in epidermal keratinocytes have protective effects against UVB radiation. This article is part of a special issue entitled ‘17th Vitamin D Workshop’.
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correlation between secosteroid induced vitamin d receptor activity in melanoma cells and computer modeled receptor binding strength
Molecular and Cellular Endocrinology, 2012Co-Authors: Jin Wang, Zorica Janjetovic, Edith K Y Tang, Robert C Tuckey, Duane D. Miller, Jianjun Chen, Wei Li, Minh Nguyen, Andrzej SlominskiAbstract:To define the interaction of novel Secosteroids produced by the action of cytochrome P450scc with vitamin D receptor (VDR), we used a human melanoma line overexpressing VDR fused with enhanced green fluorescent protein (EGFP) and tested the ligand induced translocation of VDR from the cytoplasm to the nucleus. Hydroxyderivatives of vitamin D3 with a full length (D3) side chain and hydroxy-Secosteroids with a shortened side chain (pD) stimulated VDR translocation and inhibited proliferation, however, with different potencies. In general the D3 were more potent than pD analogues. Molecular modeling of the binding of the Secosteroids to the VDR genomic binding pocket (G-pocket) correlated well with the experimental data for VDR translocation. In contrast, docking scores for the non-genomic binding site of the VDR were poor. In conclusion, both the length of the side chain and the number and position of hydroxyl groups affect the activation of VDR by novel Secosteroids.
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Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity.
Public Library of Science (PLoS), 2010Co-Authors: Andrzej T. Slominski, Zorica Janjetovic, Robert C Tuckey, Michal A. Zmijewski, Jordan K. Zjawiony, Brian E. Fuller, Minh N. Nguyen, Trevor Sweatman, Duane MillerAbstract:Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH)(2)D3, as well as 1-hydroxyvitamin D3 to 1alpha,20-dihydroxyvitamin D3 (1,20(OH)(2)D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL).To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1alpha,25-dihydroxyvitamin D3 (1,25(OH)(2)D3). These Secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH)(2)D3 being either equipotent or slightly less potent than 1,25(OH)(2)D3, while 1,20(OH)(2)D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH)(2)D3 was the most potent, 20(OH)D3, 20,23(OH)(2)D3 and 1,20(OH)(2)D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that Secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 microg/kg, whereas, 1,20(OH)(2)D3 was slightly to moderately calcemic and 1,25(OH)(2)D3 had strong calcemic activity.We identified novel Secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity
Fu-rong Jiao - One of the best experts on this subject based on the ideXlab platform.
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AsperSecosteroids A and B, Two 11(9 → 10)-abeo-5,10-Secosteroids with a Dioxatetraheterocyclic Ring System from Aspergillus flocculosus 16D-1
Organic Letters, 2018Co-Authors: Bin-bin Gu, Fu-rong Jiao, Wei-hua Jiao, Shu-ping Wang, Wei Wu, Lei Li, Fan YangAbstract:Two 11(9 → 10)-abeo-5,10-Secosteroids possessing an unprecedented dioxatetraheterocyclic ring system, asperSecosteroids A (1) and B (2), and a new ergosteroid, asperflosterol (3), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. Their structures were determined by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 1–3 demonstrated inhibitory effects on key pro-inflammatory cytokine production in THP-1 cells. A biogenetic pathway with oxidative cleavage, Wagner–Meerwein rearrangement, and sequential acetalization as key steps is proposed for 1 and 2.
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asperSecosteroids a and b two 11 9 10 abeo 5 10 Secosteroids with a dioxatetraheterocyclic ring system from aspergillus flocculosus 16d 1
Organic Letters, 2018Co-Authors: Fu-rong Jiao, Wei-hua Jiao, Shu-ping Wang, Fan Yang, Fan Sun, Houwen LinAbstract:Two 11(9 → 10)- abeo-5,10-Secosteroids possessing an unprecedented dioxatetraheterocyclic ring system, asperSecosteroids A (1) and B (2), and a new ergosteroid, asperflosterol (3), were isolated from the sponge-derived fungus Aspergillus flocculosus 16D-1. Their structures were determined by spectroscopic analysis, X-ray diffraction, and computational methods. Compounds 1-3 demonstrated inhibitory effects on key pro-inflammatory cytokine production in THP-1 cells. A biogenetic pathway with oxidative cleavage, Wagner-Meerwein rearrangement, and sequential acetalization as key steps is proposed for 1 and 2.
Hideo Kigoshi - One of the best experts on this subject based on the ideXlab platform.
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Aplysiasecosterols B and C: two new 9,11-Secosteroids with a cis-fused 1,4-quinone structure from the sea hare Aplysia kurodai
Tetrahedron Letters, 2016Co-Authors: Masaki Kita, Atsushi Kawamura, Hideo KigoshiAbstract:Abstract Two new 9,11-Secosteroids with a cis -fused 3β,5β-dihydroxy-1,4-quinone structure, aplysiasecosterols B and C, were isolated from the sea hare Aplysia kurodai . Their structures were determined by 1D- and 2D-NMR spectroscopic analysis, molecular modeling studies, and a modified Mosher’s method. Aplysiasecosterol B might be the biosynthetic precursor of aplysiasecosterol A, another 9,11-secosteroid with a tricyclic γ-diketone structure from A. kurodai , via two α-ketol rearrangements and intramolecular acetalization.
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aplysiasecosterol a a 9 11 secosteroid with an unprecedented tricyclic γ diketone structure from the sea hare aplysia kurodai
ChemInform, 2015Co-Authors: Atsushi Kawamura, Masaki Kita, Hideo KigoshiAbstract:The title compound shows moderate cytotoxicity against human myelomonocytic leukemia cell line HL-60.
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aplysiasecosterol a a 9 11 secosteroid with an unprecedented tricyclic γ diketone structure from the sea hare aplysia kurodai
Angewandte Chemie, 2015Co-Authors: Atsushi Kawamura, Masaki Kita, Hideo KigoshiAbstract:A new 9,11-secosteroid having an unprecedented tricyclic γ-diketone structure, aplysiasecosterol A (1), was isolated from the sea hare Aplysia kurodai. The structure was determined by one- and two-dimensional NMR spectroscopic analysis, molecular modeling studies, a comparison of experimental and calculated ECD spectra, and a modified Mosher′s method. Aplysiasecosterol A (1) exhibited cytotoxicity against human myelocytic leukemia HL-60 cells. A biosynthetic pathway for 1 from a known cholesterol was proposed and includes twice α-ketol rearrangements and an intramolecular acetalization.
Chang-yun Wang - One of the best experts on this subject based on the ideXlab platform.
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bioactive 9 11 Secosteroids from gorgonian subergorgia suberosa collected from the south china sea
ChemInform, 2015Co-Authors: Min Liu, Chang-lun Shao, Min Chen, Yu Wang, Yuchun Fang, Chang-yun WangAbstract:isolation, structure and cytotoxicity of five new Secosteroids (I) and seven known analogues
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Subergorgiaols A-L, 9,10-Secosteroids from the South China Sea gorgonian Subergorgia rubra.
Steroids, 2014Co-Authors: Chang-lun Shao, Cai-juan Zheng, Min Chen, Chang-yun WangAbstract:Abstract Twelve new 9,10-Secosteroids designated as subergorgiaols A–L ( 1 – 12 ), along with four known analogues ( 13 – 16 ), were isolated from the gorgonian Subergorgia rubra collected from the South China Sea . Their planar structures and the relative configurations were elucidated by comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of 1 was established by a dimolybdenum tetraacetate [Mo 2 (AcO) 4 ] induced circular dichroism (ICD) procedure and the modified Mosher’s method. Compounds 1 – 12 represent the first series of 9,10-Secosteroids characterized with a hydroxy group at C-8, which are 8-OH derivatives of astrogorgiadiols/calicoferols. Compound 4 exhibited cytotoxicity against the cervical carcinoma cell line (CaSki) with an IC 50 value of 2.4 μM, and 6 showed toxicity toward brine shrimp Artemia salina with an LC 50 value of 2.0 μM.
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bioactive 9 11 Secosteroids from gorgonian subergorgia suberosa collected from the south china sea
Chemistry & Biodiversity, 2014Co-Authors: Min Liu, Chang-lun Shao, Min Chen, Yu Wang, Yuchun Fang, Chang-yun WangAbstract:Five new 9,11-Secosteroids 1, 2, and 4–6, and seven known analogs, 3 and 7–12, with the same steroid skeleton, (5αH)-3β,6α,11-trihydroxy-9,11-secocholest-7-en-9-one, were isolated from the South China Sea gorgonian Subergorgia suberosa. Among them, 2/3 and 4/5 are C(24)-epimeric mixtures, and 6/7 is an (E)/(Z) mixture of (C(24)C(28)). Their structures and relative configurations were elucidated by using comprehensive spectroscopic methods including NOESY spectra. The absolute configuration of the steroidal nucleus was established by the modified Mosher method applied to 10 and on the basis of a common biogenesis for all of these compounds. All isolated compounds, 1–12, and five synthetic acetylated derivatives, 12a–12e, were evaluated for their cytotoxicities in vitro. Compounds 4/5, 11, 12, and 12b–12d showed cytotoxic activities against K562 cell line with the IC50 values ranging from 1.09 to 8.12 μM.