Aggregation of physiologically produced soluble amyloid ␤ protein (A␤) to insoluble, neurotoxic fibrils is a crucial step in the pathogenesis of Alzheimer's disease. Aggregation studies with synthetic A␤1-40 peptide by the thioflavin T fluorescence assay and electron microscopy and cytotoxicity assays using rat pheochromocytoma PC12 cells showed that an antibiotic, rifampicin, and its derivatives, which possess a naphthohydroquinone or naphthoquinone structure, inhibited A␤1-40 aggregation and neurotoxicity in a concentration-dependent manner. Hydroquinone, p-benzoquinone, and 1,4-dihydroxynaphthalene, which represent partial structures of the aromatic chromophore of rifampicin derivatives, also inhibited A␤1-40 aggregation and neurotoxicity at comparable molar concentrations to rifampicin. Electron spin resonance spectrometric analysis revealed that the inhibitory activities of those agents correlated with their radical-scavenging ability on hydroxyl free radical, which was shown to be generated in cell-free incubation of A␤1-40 peptide. These results suggest that at least one mechanism of rifampicin-mediated inhibition of A␤ aggregation and neurotoxicity involves scavenging of free radicals and that rifampicin and/or appropriate hydroxyl radical scavengers may have therapeutic potential for Alzheimer's disease.Amyloid ␤ protein (A␤), 1 a 39 -43 amino acid peptide, is a primary component of the amyloid that is deposited in the brains of patients with Alzheimer's disease (AD). A␤ is physiologically produced as a soluble form by enzymatic cleavage of the larger precursor, termed amyloid precursor protein (1-3). Soluble A␤ is not toxic and its physiological function is not known; however, it has been shown that aggregation of A␤ to insoluble fibrils causes neurotoxic change of the peptide (4 -6). Therefore, inhibition of this process would seem to be an effective therapeutic strategy for AD.The mechanisms of A␤ aggregation and neurotoxicity are not completely known. Recently, it was suggested that free radical generation may be involved in the processes of A␤ aggregation and/or neurotoxicity (7-9). Those hypotheses imply that appropriate radical scavengers could inhibit A␤ aggregation and/or neurotoxicity.It was previously reported that non-demented elderly leprosy patients showed an unusual absence of senile plaques in their brains compared with age-matched controls (10). Although that finding itself is still a matter of controversy (11), we surmised that some drug being used for leprosy might be preventing A␤ aggregation, resulting in the absence of amyloid deposition. Thus, we tested two well known anti-leprosy drugs, dapsone and rifampicin, and found that rifampicin inhibited A␤1-40 aggregation and neurotoxicity in vitro (12). Rifampicin is a semisynthetic derivative of the rifamycins, a class of antibiotics that are fermentation products of Nocardia mediterranei (for a review, see Ref. 13). The common structure of rifamycins is a naphthohydroquinone or naphthoquinone chromophore spanned by an aliphatic ansa c...

The present study was conducted to examine the effect of activin A on growth of rat hepatocytes. EGF induced a 10-fold increase in DNA synthesis as assessed by [3HI thymidine mRNA for iBA subunit of activin was detected only slightly in unstimulated hepatocytes, but markedly increased at 48 h after the addition of EGF. To determine whether endogenously produced activin A affects DNA synthesis, we examined the effect of follistatin, an activin-binding protein that blocks the action of activin A. An addition of follistatin significantly enhanced EGF-induced DNA synthesis. Finally, in partial hepatectomized rat, expression of mRNA for #A subunit in liver was markedly increased 24 h after the partial hepatectomy. These results indicate that activin A inhibits initiation ofDNA synthesis in hepatocytes by acting on its own receptor and that activin A acts as an autocrine inhibitor of DNA synthesis in rat hepatocytes. (J.

In eukaryotes, cyclin B-bound cyclin-dependent protein kinase 1 promotes mitotic entry but is held in check, in part, by Wee1 protein kinase. Timely mitotic entry in budding yeast requires inactivation of Swe1 (Wee1 ortholog). Perturbations of the septin collar at the bud neck lead to Swe1 stabilization, delaying the G2͞M transition. Swe1 is recruited to the neck and hyperphosphorylated before ubiquitin-mediated degradation. Hsl1 kinase (Nim1 ortholog), a negative regulator of Wee1, is required for efficient Swe1 localization at the neck but seems not to phosphorylate Swe1. Here, we show that two other kinases targeted sequentially to the neck, Cla4͞PAK and Cdc5͞Polo, are responsible for stepwise phosphorylation and down-regulation of Swe1. This mechanism links assembly of a cellular structure to passage into mitosis.Cdk1 regulation ͉ mitotic progression ͉ G2͞M transition ͉ Saccharomyces cerevisiae