Yihe Wang

Seoul National University, Sŏul, Seoul, South Korea

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Publications (5)24.81 Total impact

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    ABSTRACT: Previous reports on Selective Androgen Receptor Modulators (SARMs) have described their activity primarily by their tissue selectivity in animal models. A few SARMs have been described with tissue selectivity ascribed to their diminished activity in promoting the intramolecular interaction between the androgen receptor (AR) carboxyl and amino termini. In the current study we characterized an AR ligand PF-05314882 that has an unusual in vitro selectivity profile in AR cell based assays. This SARM was previously reported to have tissue selective AR activity in rats. In the current study PF-05314882 bound to the AR ligand binding domain with good affinity and activated AR-mediated transcription in vitro. However, unlike naturally occurring androgens and other SARMs, PF-05314882 does not stimulate interaction between AR and β-catenin. Consistent with this observation, PF-05314882 had only weak activity on androgen-AR dependent inhibition of Wnt reporter activity. In castrated rats, the daily administration of PF-05314882 had anabolic activity on increasing levator ani muscle weight and elevating RNA expression of androgen regulated metabolic genes in the liver. Similar to previously described tissue selective SARMs, PF-05314882 has very little activity in the prostate, seminal vesicles and in repressing circulating luteinizing hormone (LH) levels. More importantly, since AR and β-catenin have been shown to play important roles in overlapping tissues including adipose, bone, hair and in diseases such as prostate cancer, PF-05314882 may be an important pharmacologic tool to elucidate the role and extent of cross-talk between AR and β-catenin.
    Medicinal Chemistry Communication 02/2013; 4(3):582-589. DOI:10.1039/C3MD20341G · 2.63 Impact Factor
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    ABSTRACT: One of the many harmful factors faced by the skin is solar UV radiation, which damages skin by inducing chronic low-grade inflammation through increased expression of proinflammatory cytokines, metalloproteinases (MMPs) and cyclooxygenase-2 (COX-2). Estrogen receptors (ERs) alpha and beta are ligand-dependent transcription factors that are expressed in skin, and an ERbeta agonist has previously shown efficacy in vivo in models of pain and inflammation. Because ERbeta does not carry the breast and uterine proliferation liabilities of ERalpha, we decided to explore the possibility of using ERbeta as a target for photoaging. We show that ERbeta-selective compounds suppressed the expression of cytokines and MMPs in activated keratinocytes and fibroblast-based in vitro models of photoaging. Furthermore, in activated dermal fibroblasts, ERbeta-selective compounds also inhibited COX-2. These activities of ERbeta ligands in skin cells correlated with the expression levels of ERbeta and showed reversal by treatment with a potent synthetic ER antagonist. Furthermore, the pharmacology of ERbeta-selective compound was observed in wild-type but not in skin cells obtained from ERbeta knockout mice. Finally, we demonstrate that a synthetic ERbeta agonist inhibited UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the potential of an ERbeta ligand to regulate multiple pathways underlying the cause of photoaging suggests ERbeta to be a novel therapeutic target for the prevention and treatment of photoaging.
    Molecular pharmacology 05/2010; 77(5):744-50. DOI:10.1124/mol.109.062877 · 4.12 Impact Factor
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    ABSTRACT: Osteoarthritis (OA), the most common arthritic condition in humans, is characterized by the progressive degeneration of articular cartilage accompanied by chronic joint pain. Inflammatory mediators, such as cytokines and prostaglandin E(2) (PGE(2)) that are elevated in OA joints, play important roles in the progression of cartilage degradation and pain-associated nociceptor sensitivity. We have found that the nuclear receptor family transcription factors Liver X Receptors (LXRalpha and -beta) are expressed in cartilage, with LXRbeta being the predominant isoform. Here we show that genetic disruption of Lxrbeta gene expression in mice results in significantly increased proteoglycan (aggrecan) degradation and PGE(2) production in articular cartilage treated with IL-1beta, indicating a protective role of LXRbeta in cartilage. Using human cartilage explants, we found that activation of LXRs by the synthetic ligand GW3965 significantly reduced cytokine-induced degradation and loss of aggrecan from the tissue. Furthermore, LXR activation dramatically inhibited cytokine-induced PGE(2) production by human osteoarthritic cartilage as well as by a synovial sarcoma cell line. These effects were achieved at least partly by repression of the expression of ADAMTS4, a physiological cartilage aggrecanase, and of cyclooxygenase-2 and microsomal prostaglandin E synthase-1, key enzymes in the PGE(2) synthesis pathway. Consistent with our in vitro observations, oral administration of GW3965 potently alleviated joint pain in a rat meniscal tear model of osteoarthritis.
    Proceedings of the National Academy of Sciences 02/2010; 107(8):3734-9. DOI:10.1073/pnas.0911377107 · 9.81 Impact Factor
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    ABSTRACT: Bazedoxifene (BZA), a new selective estrogen receptor modulator (SERM) was recently approved in Europe for the prevention and treatment of postmenopausal osteoporosis. Combination therapy using BZA and conjugated estrogens (CE) is currently in late stage development representing a new paradigm for the treatment of menopausal symptoms and prevention of osteoporosis. A GeneChip microarray study was designed to compare gene expression profiles of BZA to that of other SERMs, raloxifene (RAL) and lasofoxifene (LAS). In addition, we compared the gene expression profiles of the three SERMs in combination with CE, a mixture of 10 most abundant estrogens present in Premarin. According to the hierarchical clustering heat map analysis, gene clusters that specifically responded to CE treatments or SERM treatments were identified and gene lists sorted based on a set of cutoff filters. A group of genes differentially regulated by CE were also identified to be antagonized by BZA when comparing CE with the BZA+CE treatment. All three SERMs showed significant antagonistic effect against CE-stimulated cell proliferation, based on the MCF-7 cell proliferation assay and GeneChip data, with the order of antagonist activity being BZA>RAL>LAS. These results indicate that SERMs in combination with CE exhibit differential pharmacology, and therefore, combinations of other SERMs and estrogen preparations may not yield the same effects that are observed in clinic by pairing BZA with CE.
    The Journal of steroid biochemistry and molecular biology 11/2009; 118(1-2):117-24. DOI:10.1016/j.jsbmb.2009.11.003 · 4.05 Impact Factor
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    ABSTRACT: Liver X receptors (LXRalpha and -beta) are liposensors that exert their metabolic effects by orchestrating the expression of macrophage genes involved in lipid metabolism and inflammation. LXRs are also expressed in other tissues, including skin, where their natural oxysterol ligands induce keratinocyte differentiation and improve epidermal barrier function. To extend the potential use of LXR ligands to dermatological indications, we explored the possibility of using LXR as a target for skin aging. We demonstrate that LXR signaling is down-regulated in cell-based models of photoaging, i.e. UV-activated keratinocytes and TNFalpha-activated dermal fibroblasts. We show that a synthetic LXR ligand inhibits the expression of cytokines and metalloproteinases in these in vitro models, thus indicating its potential in decreasing cutaneous inflammation associated with the etiology of photoaging. Furthermore, a synthetic LXR ligand induces the expression of differentiation markers, ceramide biosynthesis enzymes, and lipid synthesis and transport genes in keratinocytes. Remarkably, LXRbeta-null mouse skin showed some of the molecular defects that are observed in chronologically aged human skin. Finally, we demonstrate that a synthetic LXR agonist inhibits UV-induced photodamage and skin wrinkle formation in a murine model of photoaging. Therefore, the ability of an LXR ligand to modulate multiple pathways underlying the etiology of skin aging suggests that LXR is a novel target for developing potential therapeutics for photoaging and chronological skin aging indications.
    Molecular Endocrinology 10/2008; 22(11):2407-19. DOI:10.1210/me.2008-0232 · 4.20 Impact Factor