5 research outputs found
An Invertebrate Hyperglycemic Model for the Identification of Anti-Diabetic Drugs
The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover, AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the hyperglycemic silkworms and restored growth, suggesting that the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals
細胞形態変化に基づく天然物ライブラリーのプロファイリングによるアクチン線維安定化化合物ビセブロモアミドおよびミウラエナミドAの同定
京都大学0048新制・課程博士博士(医科学)甲第16277号医科博第26号新制||医科||2(附属図書館)28886京都大学大学院医学研究科医科学専攻(主査)教授 萩原 正敏, 教授 成宮 周, 教授 楠見 明弘学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDA
Inhibition of Microtubule Assembly by a Complex of Actin and Antitumor Macrolide Aplyronine A
Aplyronine A (ApA) is a marine natural
product that shows potent
antitumor activity. While both ApA and ApC, a derivative of ApA that
lacks a trimethylserine ester moiety, inhibit actin polymerization
in vitro to the same extent, only ApA shows potent cytotoxicity. Therefore,
the molecular targets and mechanisms of action of ApA in cells have
remained unclear. We report that ApA inhibits tubulin polymerization
in a hitherto unprecedented way. ApA forms a 1:1:1 heterotrimeric
complex with actin and tubulin, in association with actin synergistically
binding to tubulin, and inhibits tubulin polymerization. Tubulin-targeting
agents have been widely used in cancer chemotherapy, but there are
no previous descriptions of microtubule inhibitors that also bind
to actin and affect microtubule assembly. ApA inhibits spindle formation
and mitosis in HeLa S3 cells at 100 pM, a much lower concentration
than is needed for the disassembly of the actin cytoskeleton. The
results of the present study indicate that ApA represents a rare type
of natural product, which binds to two different cytoplasmic proteins
to exert highly potent biological activities