[신간의 별자리x] 우리/미술, 그리고 ‘슬픔의 박물관’

Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.

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Biological Roles of Glycans

The peer-reviewed marine pharmacology literature in 2007-8 is covered in this review, which follows a similar format to the previous 1998-2006 reviews of this series. The preclinical pharmacology of structurally characterized marine compounds isolated from marine animals, algae, fungi and bacteria is discussed in a comprehensive manner. Antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 74 marine natural products. Additionally, 59 marine compounds were reported to affect the cardiovascular, immune and nervous systems as well as to possess anti-inflammatory effects. Finally, 65 marine metabolites were shown to bind to a variety of receptors and miscellaneous molecular targets, and thus upon further completion of mechanism of action studies, will contribute to several pharmacological classes. Marine pharmacology research during 2007-8 remained a global enterprise, with researchers from 26 countries, and the United States, contributing to the preclinical pharmacology of 197 marine compounds which are part of the preclinical marine pharmaceuticals pipeline. Sustained preclinical research with marine natural products demonstrating novel pharmacological activities, will probably result in the expansion of the current marine pharmaceutical clinical pipeline, which currently consists of 13 marine natural products, analogs or derivatives targeting a limited number of disease categories.

Marine pharmacology in 2007-8: Marine compounds with antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous system, and other miscellaneous mechanisms of action.

Purpose: Combretastatin A4 (CA4) phosphate (CA4P) inhibits microtubule polymerization and is toxic to proliferating endothelial cells in vitro. It causes reversible vascular shutdown in established tumors in vivo, consistent with an antivascular mechanism of action. The present study investigated escalating doses of CA4P administered intravenously to patients with advanced cancer. Patients and Methods: Patients with solid malignancies and good performance status received CA4P as a 10-minute infusion daily for 5 days repeated every 3 weeks. Pharmacokinetic sampling was performed during cycle 1. Patients receiving ≥ 52 mg/m 2 /d had serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) studies to measure changes in tumor perfusion with CA4P treatment. Results: Thirty-seven patients received 133 treatment cycles. CA4P dose levels ranged from 6 mg/m 2 to 75 mg/m 2 daily. Severe pain at sites of known tumor was dose limiting at 75 mg/m 2 . Dose-limiting cardiopulmonary toxicity (syncope and dyspnea or hypoxia) was noted as well in two patients treated at 75 mg/m 2 . Other toxicities included hypotension, ataxia, dyspnea, nausea or vomiting, headache, and transient sensory neuropathy. Plasma CA4P and CA4 area under the concentration-time curve and maximal concentration values increased linearly with dose. Tumor perfusion, as measured by the first-order rate constant of gadolinium plasma to tissue transfer during DCE-MRI studies, was found to decrease in eight of 10 patients. Relationships were also demonstrated between perfusion changes and pharmacokinetic indices. A partial response was observed in a patient with metastatic soft tissue sarcoma, and 14 patients exhibited disease stability for a minimum of two cycles. Conclusion: Doses of CA4P on a daily times five schedule of 52 to 65 mg/m 2 were reasonably well-tolerated. The 52 mg/m 2 dose is recommended for further study based on cumulative phase I experience with CA4P. Antitumor efficacy was observed, and the use of DCE-MRI provided a valuable noninvasive measure of the vascular effects of CA4P treatment.

Phase I trial of the antivascular agent Combretastatin A4 phosphate on a 5-day schedule to patients with cancer: Magnetic resonance imaging evidence for altered tumor blood flow

This book provides an introduction to the important methods of chiroptical spectroscopy in general, and circular dichroism (CD) in particular, which are increasingly important in all areas of chemistry, biochemistry, and structural biology. The book can be used as a text for undergraduate and graduate students and as a reference for researchers in academia and industry. Experimental methods and instrumentation are described with topics ranging from the most widely used methods (electronic and vibrational CD) to frontier areas such as nonlinear spectroscopy and photoelectron CD, as well as the theory of chiroptical methods and techniques for simulating chiroptical properties. Applications of chiroptical spectroscopy to problems in organic stereochemistry, inorganic stereochemistry, and biochemistry and structural biology are also discussed, and each chapter is written by one or more leading authorities with extensive experience in the field.

Applications in stereochemical analysis of synthetic compounds, natural products, and biomolecules

Hybrid isoprenoids from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64.

Fifteen meroterpenoids (1-15) with diverse ring systems including an unprecedented oxaspiro[5.5]nonane-fused cyclohexenone (1), hydrogenated benzofurans (2-5), hydrogenated chromans (6, 7), hydrogenated cyclopenta[b]chromans (8-11), and four monocyclic structures (12-15) were isolated from the sponge-associated fungus Alternaria sp. JJY-32. The structures were elucidated by detailed spectroscopic analysis, including 2D NMR and electronic circular dichroism (ECD) calculations, and assisted by chemical derivatizations. On the basis of supplementation experiments with specific enzyme inhibitors and putative precursors, a shikimate-isoprenoid hybrid biosynthetic pathway is proposed. The NF-κB inhibitory activities of 1-15 were tested, and all of them, except 6 and 7 (IC50 > 100 μM), showed activities with IC50 values ranging from 39 to 85 μM in RAW264.7 cells.

Meroterpenoids with diverse ring systems from the sponge-associated fungus alternaria sp. JJY-32

Polysialic acid (PSA), a carbohydrate polymer mainly present in the neural cell adhesion molecule (NCAM), promotes neural plasticity; however, its mode of action in tumor malignancy remains largely unknown. In this study, we investigated the influence of polysialylation on cell migration. PSA consistently promoted cell migration on different extracellular matrices (ECMs) but differentially affected cell adhesion. All of these actions were reversed by endo-N-acetylneuraminidase treatment, and PSA-driven migration was inhibited by the specific fibroblast growth factor receptor (FGFR) inhibitor Su5402. Consistent with this latter observation, PSA-stimulated migration on different ECMs was paralleled by activation of the FGFR and its downstream signaling components, PLC-γ, focal adhesion kinase and extracellular signal-regulated kinase 1/2. In contrast, the pattern of p59(fyn) activation correlated with differential adhesion to different ECMs. Collectively, these results indicate that PSA-conjugated NCAM potentiates signal transduction by the FGFR pathway and thereby enhances cell migration independent of adhesion capability, providing additional insights into the role of PSA in cancer development.

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Polysialylation promotes neural cell adhesion molecule-mediated cell migration in a fibroblast growth factor receptor-dependent manner, but independent of adhesion capability.

// Xiaoping Song 1 , Zhimin Zhao 1 , Xin Qi 1 , Shuai Tang 2 , Qiang Wang 3 , Tianjiao Zhu 1 , Qianqun Gu 1 , Ming Liu 1 , Jing Li 1 1 Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, P. R. China 2 Division of Antitumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, P. R. China 3 Department of Pharmacy, School of Pharmaceutical Sciences, South-Central University for Nationalities, Wuhan, P. R. China Correspondence to: Ming Liu, e-mail: lmouc@hotmail.com Jing Li, e-mail: ljlilac@163.com Keywords: pipolythiodioxopiperazines, HDN-1, chaetocin, inhibitor, Hsp90 Received: September 28, 2014      Accepted: January 01, 2015      Published: January 24, 2015 ABSTRACT The molecular chaperone heat shock protein 90 (Hsp90) has emerged as an important target for cancer treatment. HDN-1, an epipolythiopiperazine-2, 5-diones (ETPs) compound, was here identified as a new Hsp90 inhibitor. HDN-1 bound directly to C-terminus of Hsp90α, resulting in a potential conformational change that interfered with the binding of 17-AAG and novobiocin to Hsp90α. In contrast, association of 17-AAG, novobiocin or ATP with Hsp90α did not prevent the binding HDN-1 to Hsp90α. HDN-1 in combination with 17-AAG exhibited an enhanced inhibitory effect on non-small lung cancer cell proliferation. Molecular docking analyses revealed that HDN-1 bound to Hsp90α at C-terminal 526–570 region. In addition, HDN-1 degraded multiple oncoproteins and promoted EGF-induced wild type and mutated EGFR downregulation. Notably, chaetocin, used as a SUV39H1 inhibitor with similar structure to HDN-1, bound to Hsp90 and degraded Hsp90 client proteins and SUV39H1 as did HDN-1. These results indicate that HDN-1 and chaetocin are inhibitors of Hsp90 and that SUV39H1 is a novel client protein of Hsp90.

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Xin Qi

Papers

Hybrid isoprenoids from a reeds rhizosphere soil derived actinomycete Streptomyces sp. CHQ-64.

Meroterpenoids with diverse ring systems from the sponge-associated fungus alternaria sp. JJY-32

Polysialylation promotes neural cell adhesion molecule-mediated cell migration in a fibroblast growth factor receptor-dependent manner, but independent of adhesion capability.

Identification of epipolythiodioxopiperazines HDN-1 and chaetocin as novel inhibitor of heat shock protein 90.

Penicisulfuranol A, a novel C-terminal inhibitor disrupting molecular chaperone function of Hsp90 independent of ATP binding domain.