The subunit structure of islet-activating protein (IAP), pertussis toxin, has been analyzed to study a possibility that this protein is one of the A-B toxins [Gill, D. M. (1978) in Bacterial Toxins and Cell Membranes (Jeljaszewicz, J., & Wadstrom, T., Eds.) pp 291-332, Academic Press, New York]. Heating IAP with 1% sodium dodecyl sulfate caused its dissociation into five dissimilar subunits named S-1 (with a molecular weight of 28 000), S-2 (23 000), S-3 (22 000), S-4 (11 700), and S-5 (9300), as revealed by polyacrylamide gel electrophoresis; their molar ratio in the native IAP was 1:1:1:2:1. The molecular weight of IAP estimated by equilibrium ultracentrifugation was 117 000 which was not at variance with the value obtained by summing up molecular weights of the constituent subunits. The preparative separation of these IAP subunits was next undertaken; exposure of IAP to 5 M ice-cold urea for 4 days followed by column chromatography with carboxymethyl-Sepharose caused sharp separation of S-1 and S-5, leaving the other subunits as two dimers. These dimers were then dissociated into their constituent subunits, i.e., S-2 and S-4 for one dimer and S-3 and S-4 for the other, after 16-h exposure to 8 M urea; these subunits were obtained individually upon further chromatography on a diethylaminoethyl-Sepharose column. Subunits other than S-1 were adsorbed as a pentamer by a column using haptoglobin as an affinity adsorbent. The same pentamer was obtained by adding S-5 to the mixture of two dimers. Neither this pentamer nor other oligomers (or protomers) exhibited biological activity in vivo. Recombination of S-1 with the pentamer at the 1:1 molar ratio yielded a hexamer which was identical with the native IAP in electrophoretic mobility and biological activity to enhance glucose-induced insulin secretion when injected into rats. In the broken-cell preparation, S-1 was biologically as effective as the native IAP; both catalyzed ADP-ribosylation of a protein in membrane preparations from rat C6 glioma cells. In conclusion, IAP is an oligomeric protein consisting of an A (active) protomer (the biggest subunit) and a B (binding) oligomer which is produced by connecting two dimers by the smallest subunit in a noncovalent manner. Rationale for this terminology is discussed based on the A-B model.

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Thiazolidinediones (TZDs) constitute an exciting new class of antidiabetic compounds, which function as activating ligands for peroxisome proliferator-activated receptor ␥ (PPAR␥). Until now, there has been an excellent correlation between in vivo hypoglycemic potency and in vitro binding and activation of PPAR␥ by TZDs. We have characterized MCC-555, a novel thiazolidinedione ligand for PPAR␥ with unique functional properties. The antidiabetic potency of this compound is greater than that of other TZDs, including BRL49653, yet its binding affinity for PPAR␥ is less than 1 ⁄10 that of BRL49653. The effect of MCC-555 binding on PPAR␥ transcriptional activity is highly context-specific such that it can function as a full agonist, partial agonist, or antagonist depending on the cell type or DNA binding site. These transcriptional properties are partly explained by unique partial agonism of coactivator recruitment to PPAR␥. The properties of MCC-555 are mechanistically distinct from those of the estrogen receptor partial agonist and antagonist tamoxifen because the N terminus of PPAR␥ is not required for activation by MCC-555, and MCC-555 does not stimulate corepressor recruitment to PPAR␥. The context selectivity of MCC-555 may contribute to its enhanced hypoglycemic potency in vivo despite reduced affinity for PPAR␥ relative to other TZDs. Nuclear hormone receptors (NHRs)1 constitute a class of transcription factors with activity that is regulated by natural or synthetic lipophilic ligands (1). A number of NHRs are involved in developmental and/or metabolic processes, and modulation of NHR activity is an effective strategy in the treatment of a variety of cancers, such as breast cancer (2), prostate cancer (3), and acute promyleocytic leukemia (4), as well as metabolic diseases including thyroid disease (5) and diabetes. Non-insulin-dependent diabetes mellitus is a major cause of morbidity and mortality in industrialized nations and is characterized by a post-insulin receptor defect that has been difficult to target therapeutically until the recent discovery that thiazolidinediones (TZDs) enhance the actions of insulin at a level distal to the insulin receptor (6).The mechanism of TZD action is not completely understood, but a number of lines of evidence point to their function as ligands for a member of the NHR superfamily called peroxisome proliferator-activated receptor ␥ (PPAR␥), the natural ligand of which may be derived from or related to prostaglandin J2 (7-9). One of the most potent TZDs, BRL49653, binds to PPAR␥ with an affinity in the nanomolar range (10), and the rank order of TZD potency for in vivo plasma glucose lowering correlates well with their rank order potency for PPAR␥ activation (11, 12). Nevertheless, a number of questions remain with regard to the mechanism of TZD potentiation of insulin action. The main problem is that PPAR␥ is primarily expressed in adipose tissue (13, 14), whereas muscle is ordinarily the main site of insulin-dependent glucose disposal in mammals. This apparent paradox h...

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Two novel antimicrobial tetrapeptide-like substances, halocyamine A and B, were isolated from the solitary ascidian Halocynthia roretzi by a procedure including extraction steps, chromatographies on coarse and fine HP-20 columns, and preparative reversed-phase high-performance liquid chromatography. The structures of halocyamine A and B were determined to be L-histidyl-L-6,7-dihydroxyphenylalanylglycyl-6-bromo-8,9-didehy drotryptamine and L-threonyl-L-6,7-dihydroxyphenylalanyl-L-histidyl-6-bromo-8,9- didehydrotryptamine, respectively, by spectral analyses and degradation studies. Besides antimicrobial activities against several kinds of bacteria and yeasts, both of them showed cytotoxic activities against neuronal cells cultured from rat fetal brain, mouse neuroblastoma N-18 cells, and human hepatoma Hep-G2 cells. They were only detected in the "morula"-like cells, which are of the most abundant cell type among the hemocytes of H. roretzi.

Sarcopenia is common in patients before allo-HSCT and related to low muscle strength, fatigue, and health-related QOL. Male patients may be more susceptible to sarcopenia than female patients before allo-HSCT. Further study of rehabilitation with gender insight is warranted for patients receiving allo-HSCT.