Double-Stranded DNA-Graphene Hybrid: Preparation and Anti-Proliferative Activity

Joseph, Dickson,Seo, Shinae,Williams, Darren R.,Geckeler, Kurt E. American Chemical Society 2014 ACS APPLIED MATERIALS & INTERFACES Vol.6 No.5

<P>Herein, we demonstrate a simple method to prepare graphene dispersions in an aqueous solution of DNA by the sonication of bulk graphite. The use of a commercial double-stranded DNA as a stabilizer for graphite exfoliation without any chemical modification is presented. The high energy sound waves cleave a double-stranded DNA into two single-stranded DNAs. UV–vis spectral studies show that the nucleobases in the product are intact. Atomic force microscopy studies reveal that the size of the obtained nanosheets can be enriched into smaller lateral dimensions using centrifugation. Raman spectroscopy suggests that the defects found in the nanosheets induced by the sonication are edge defects, whereas the bodies of the sheets remain relatively defect free. The graphene dispersions are extremely stable over a wide range of pH values, possessing high negative zeta potential values. The anti-proliferative effect observed through in vitro cytotoxicity studies is supported by in vivo studies using the zebrafish human tumor xenograft model. The migration of cancer cells in zebrafish embryos are inhibited by the graphene nanosheet dispersion. The negatively charged nanosheet serves as a platform for the adsorption of gold nanoparticles with positively charged surfaces.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/aamick/2014/aamick.2014.6.issue-5/am405378x/production/images/medium/am-2013-05378x_0010.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/am405378x'>ACS Electronic Supporting Info</A></P>

Potent Suppressive Effects of 1-Piperidinylimidazole Based Novel P2X7 Receptor Antagonists on Cancer Cell Migration and Invasion

Park, Jin-Hee,Williams, Darren R.,Lee, Ji-Hyung,Lee, So-Deok,Lee, Je-Heon,Ko, Hyojin,Lee, Ga-Eun,Kim, Sujin,Lee, Jeong-Min,Abdelrahman, Aliaa,Mü,ller, Christa E.,Jung, Da-Woon,Kim, Yong-Chul American Chemical Society 2016 Journal of medicinal chemistry Vol.59 No.16

<P>The P2X7 receptor (P2X7R) has been reported as a key mediator in inflammatory processes and cancer invasion/metastasis. In this study, we report the discovery of novel P2X7R antagonists and their functional activities as potential antimetastatic agents. Modifications of the hydantoin core-skeleton and the side chain substituents of the P2X7R antagonist 7 were performed. The structure activity relationships (SAR) and optimization demonstrated the importance of the sulfonyl group at the R-1 position and the substituted position and overall size of R-2 for P2X7R antagonism. The optimized novel analogues displayed potent P2X7 receptor antagonism (IC50 = 0.11-112 nM) along with significant suppressive effects on IL-1 beta release (IC50 = 0.32-210 nM). Moreover, representative antagonists (12g, 13k, and 17d) with imidazole and uracil core skeletons significantly inhibited the invasion of MDA-MB-231 triple negative breast cancer cells and cancer cell migration in a zebrafish xenograft model, suggesting the potential therapeutic application of these novel P2X7 antagonists to block metastatic cancer.</P>

Novel Chemically Defined Approach To Produce Multipotent Cells from Terminally Differentiated Tissue Syncytia

Jung, Da-Woon,Williams, Darren R. American Chemical Society 2011 ACS chemical biology Vol.6 No.6

<P>In urodele amphibians, a critical step in limb regeneration is the cellularization and dedifferentiation of skeletal muscle. In contrast, mammalian skeletal muscle does not undergo this response to injury. We have developed a novel simple, stepwise chemical method to induce dedifferentiation and multipotency in mammalian skeletal muscle. Optimal muscle fiber cellularization was induced by the trisubstituted purine small molecule, myoseverin, compared to colchicine, nocodazole, or myoseverin B. The induction of a proliferative response in the cellulate was found to be a crucial step in the dedifferentiation process. This was achieved by down-regulation of the cyclin-dependent kinase inhibitor, p21 (CDKN 1A, CIP1). p21 was found to be a key regulator of this process, because down-regulation of the cyclin-dependent kinase inhibitors p27 (CDKN1B/KIP1) or p57 (CDKN1C/KIP2) or the tumor suppressor p53 (TP53/LFS1) failed to induce proliferation and subsequent dedifferentiation. Treatment with the small molecule reversine (2-(4-morpholinoanilino)-6-cyclohexylaminopurine) during this proliferative “window” induced the muscle cellulate to differentiate into non-muscle cell types. This lineage switching was assessed using a relatively stringent approach, based on comparative functional and phenotypic assays of cell-type specific properties. This showed that our chemical method allowed the derivation of adipogenic and osteogenic cells that possessed a degree of functionality. This is the first demonstration that mammalian muscle culture can be induced to undergo cellularization, proliferation, and dedifferentiation, which is grossly similar to the key early steps in urodele limb regeneration. These results, based solely on the use of simple chemical approaches, have implications for both regenerative medicine and stem cell biology.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/acbcct/2011/acbcct.2011.6.issue-6/cb2000154/production/images/medium/cb-2011-000154_0002.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/cb2000154'>ACS Electronic Supporting Info</A></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/cb2000154'>ACS Electronic Supporting Info</A></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/cb2000154'>ACS Electronic Supporting Info</A></P>

Magnesium Lithospermate B Blocks four Major Pathways of Hyperglycemic Damage and Prevents Diabetes-Accelerated Atherosclerosis

Kyu Yeon Hur,Soo Hyun Kim,Darren R. Williams,Sang Won Kang,Jee Rhan Kim,Ki Chul Hwang,Jin Won Cho,Man Kil Jung,Sung Wan Chun,Seung Jin Han,Eun Seok Kang,Bong Soo Cha,Hyun Chul Lee 한국지질동맥경화학회(구 한국지질학회) 2007 한국지질동맥경화학회 추계학술발표논문집 Vol.2007 No.-

Chemical genetics and its application to moonlighting in glycolytic enzymes.

Jung, Da-Woon,Kim, Woong-Hee,Williams, Darren R Biochemical Society 2014 Biochemical Society transactions Vol.42 No.6

<P>Glycolysis is an ancient biochemical pathway that breaks down glucose into pyruvate to produce ATP. The structural and catalytic properties of glycolytic enzymes are well-characterized. However, there is growing appreciation that these enzymes participate in numerous moonlighting functions that are unrelated to glycolysis. Recently, chemical genetics has been used to discover novel moonlighting functions in glycolytic enzymes. In the present mini-review, we introduce chemical genetics and discuss how it can be applied to the discovery of protein moonlighting. Specifically, we describe the application of chemical genetics to uncover moonlighting in two glycolytic enzymes, enolase and glyceraldehyde dehydrogenase. This led to the discovery of moonlighting roles in glucose homoeostasis, cancer progression and diabetes-related complications. Finally, we also provide a brief overview of the latest progress in unravelling the myriad moonlighting roles for these enzymes.</P>

ZebIAT, an image analysis tool for registering zebrafish embryos and quantifying cancer metastasis

Annila, Teppo,Lihavainen, Eero,Marques, Ines J,Williams, Darren R,Yli-Harja, Olli,Ribeiro, Andre BioMed Central 2013 BMC bioinformatics Vol.14 No.suppl10

<P><B>Background</B></P><P>Zebrafish embryos have recently been established as a xenotransplantation model of the metastatic behaviour of primary human tumours. Current tools for automated data extraction from the microscope images are restrictive concerning the developmental stage of the embryos, usually require laborious manual image preprocessing, and, in general, cannot characterize the metastasis as a function of the internal organs.</P><P><B>Methods</B></P><P>We present a tool, ZebIAT, that allows both automatic or semi-automatic registration of the outer contour and inner organs of zebrafish embryos. ZebIAT provides a registration at different stages of development and an automatic analysis of cancer metastasis per organ, thus allowing to study cancer progression. The semi-automation relies on a graphical user interface.</P><P><B>Results</B></P><P>We quantified the performance of the registration method, and found it to be accurate, except in some of the smallest organs. Our results show that the accuracy of registering small organs can be improved by introducing few manual corrections. We also demonstrate the applicability of the tool to studies of cancer progression.</P><P><B>Conclusions</B></P><P>ZebIAT offers major improvement relative to previous tools by allowing for an analysis on a per-organ or region basis. It should be of use in high-throughput studies of cancer metastasis in zebrafish embryos.</P>

Fishing for Nature's Hits: Establishment of the Zebrafish as a Model for Screening Antidiabetic Natural Products

Tabassum, Nadia,Tai, Hongmei,Jung, Da-Woon,Williams, Darren R. Hindawi Publishing Corporation 2015 Evidence-based Complementary and Alternative Medic Vol.2015 No.-

<P>Diabetes mellitus affects millions of people worldwide and significantly impacts their quality of life. Moreover, life threatening diseases, such as myocardial infarction, blindness, and renal disorders, increase the morbidity rate associated with diabetes. Various natural products from medicinal plants have shown potential as antidiabetes agents in cell-based screening systems. However, many of these potential “hits” fail in mammalian tests, due to issues such as poor pharmacokinetics and/or toxic side effects. To address this problem, the zebrafish (<I>Danio rerio</I>) model has been developed as a “bridge” to provide an experimentally convenient animal-based screening system to identify drug candidates that are active<I> in vivo</I>. In this review, we discuss the application of zebrafish to drug screening technologies for diabetes research. Specifically, the discovery of natural product-based antidiabetes compounds using zebrafish will be described. For example, it has recently been demonstrated that antidiabetic natural compounds can be identified in zebrafish using activity guided fractionation of crude plant extracts. Moreover, the development of fluorescent-tagged glucose bioprobes has allowed the screening of natural product-based modulators of glucose homeostasis in zebrafish. We hope that the discussion of these advances will illustrate the value and simplicity of establishing zebrafish-based assays for antidiabetic compounds in natural products-based laboratories.</P>

Reprogram or Reboot: Small Molecule Approaches for the Production of Induced Pluripotent Stem Cells and Direct Cell Reprogramming

Jung, Da-Woon,Kim, Woong-Hee,Williams, Darren Reece American Chemical Society 2014 ACS CHEMICAL BIOLOGY Vol.9 No.1

<P>Stem cell transplantation is a potential therapy for regenerative medicine, which aims to restore tissues damaged by trauma, aging, and diseases. Since its conception in the late 1990s, chemical biology has provided powerful and diverse small molecule tools for modulating stem cell function. Embryonic stem cells could be an ideal source for transplantation, but ethical concerns restrict their development for cell therapy. The seminal advance of induced pluripotent stem cell (iPSC) technology provided an attractive alternative to human embryonic stem cells. However, iPSCs are not yet considered an ideal stem cell source, due to limitations associated with the reprogramming process and their potential tumorigenic behavior. This is an area of research where chemical biology has made a significant contribution to facilitate the efficient production of high quality iPSCs and elucidate the biological mechanisms governing their phenotype. In this review, we summarize these advances and discuss the latest progress in developing small molecule modulators. Moreover, we also review a new trend in stem cell research, which is the direct reprogramming of readily accessible cell types into clinically useful cells, such as neurons and cardiac cells. This is a research area where chemical biology is making a pivotal contribution and illustrates the many advantages of using small molecules in stem cell research.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/acbcct/2014/acbcct.2014.9.issue-1/cb400754f/production/images/medium/cb-2013-00754f_0016.gif'></P>

Phenolic Constituents from the Flowers of Hamamelis japonica Sieb. et Zucc.

임순호,이영주,박기덕,이익수,신부안,정다운,Darren R. Williams,김현정 한국생약학회 2015 Natural Product Sciences Vol.21 No.3

Hamamelis japonica (Hamamelidaceae), widely known as Japanese witch hazel, is a deciduous flowering shrub that produces compact clumps of yellow or orange-red flowers with long and thin petals. As a part of our ongoing search for phenolic constituents from this plant, eleven phenolic constituents including six flavonol glycosides, a chalcone glycoside, two coumaroyl flavonol glycosides and two galloylated compounds were isolated from the flowers. Their structures were elucidated as methyl gallate (1), myricitrin (2), hyperoside (3), isoquercitrin (4), quercitrin (5), spiraeoside (6), kaempferol 4'-O-b-glucopyranoside (7), chalcononaringenin 2'-O-b-glucopyranoside (8), trans-tiliroside (9), cis-tiliroside (10), and pentagalloyl-O-b-D-glucose (11), respectively. These structures of the compounds were identified on the basis of spectroscopic studies including the on-line LC-NMR-MS and conventional NMR techniques. Particularly, directly coupled LC-NMR-MS afforded sufficient structural information rapidly to identify three flavonol glycosides (2 - 4) with the same molecular weight in an extract of Hamamelis japonica flowers without laborious fractionation and purification step. Cytotoxic effects of all the isolated phenolic compounds were evaluated on HCT116 human colon cancer cells, and pentagalloyl-O-b-D-glucose (11) was found to be significantly potent in inhibiting cancer cell growth.

Targeting the Tumor Microenvironment for Cancer Therapy: Novel Cellular and Molecular Targets

JUNG Da-Woon,KIM Jinmi,KIM Jin,WILLIAMS Darren 大韓藥學會 2011 大韓藥學會 總會 및 學術大會 Vol.2011 No.1