Dual modulation by thrombin of the motility of rat oesophageal muscularis mucosae via two distinct protease-activated receptors (PARs): a novel role for PAR-4 as opposed to PAR-1 1 Since protease-activated receptors (PARs) are distributed throughout the gastrointestinal tract, we investigated the role of PARs in modulation of the motility of the rat oesophageal muscularis mucosae. 2 Thrombin produced contraction of segments of the upper and lower part of the smooth muscle. Trypsin contracted both the muscle preparations only at high concentrations. SFLLR-NH 2 and TFLLR-NH 2 (PAR-1-activating peptides), but not the PAR-1-inactive peptide FSLLR-NH 2 , evoked a marked contraction. In contrast, the PAR-2 agonist SLIGRL-NH 2 and the PAR-4 agonist GYPGKF-NH 2 caused no or only a negligible contraction. 3 In oesophageal preparations precontracted with carbachol, thrombin produced a dual action i.e. relaxation followed by contraction. TFLLR-NH 2 further contracted the precontracted preparations with no preceding relaxation. GYPGKF-NH 2 , but not the inactive peptide GAPGKF-NH 2 , produced marked relaxation. Trypsin or SLIGRL-NH 2 caused no relaxation. 4 The PAR-1-mediated contraction was completely abolished in Ca 2+-free medium and considerably attenuated by nifedipine (1 mM) and in a low Na + medium. The PAR-4-mediated relaxation was resistant to tetrodotoxin (10 mM), apamin (0.1 mM), charybdotoxin (0.1 mM), L-N G -nitroarginine methyl ester (100 mM), indomethacin (3 mM), propranolol (5 mM) or adenosine 3',5'-cyclic monophosphorothioate, 8-bromo, Rp-isomer (30 mM). 5 Thus, thrombin plays a dual role in modulating the motility of the oesophageal muscularis mucosae, producing contraction via PAR-1 and relaxation via PAR-4. The PAR-1-mediated eect appears to occur largely through increased Na + permeability followed by activation of L-type Ca 2+ channels and subsequent in¯ux of extracellular Ca 2+. Our data could provide evidence for a novel role of PAR-4 as opposed to PAR-1, although the underlying mechanisms are still open to question.

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Mental stress and immunological abnormality have recently been listed as causes of alopecia universalis. This disease is difficult to treat with only ordinary pharmacotherapy. Thus, from the standpoint of psychoneuroimmunology, stress was relieved by relaxation and image therapy, and administration of small doses of a strong immunosuppressant was effective, leading to clinically favorable results. In addition, changes were recognized in the subpopulation of peripheral lymphocytes and in Β-endorphin before and after relaxation and image therapy. The treatment of alopecia universalis favorably changed the subpopulations of T cells. A patient suffering from alopecia is always under stress. Alleviating this stress facilitates recovery of immunological competence. Our method was effective in 5 of 6 cases with refractory alopecia universalis.

The DOT5 gene was originally cloned as one of the DOT (disrupter of telomeric silencing) genes; and later it was re-discovered as a nuclear thioredoxin peroxidase in Saccharomyces cerevisiae. Here, we demonstrate that the telomeric-silencing disruption activity of Dot5 is independent of thioredoxin peroxidase activity. In addition, Dot5 cannot suppress the increased susceptibility to peroxides of mutants defected in cytosolic thioredoxin peroxidase, even when Dot5 is expressed in the cytoplasm. Furthermore, Dot5 does not affect redox regulation of the Yap1 transcription factor. These results suggest that Dot5 is less important as an antioxidant in yeast cells.

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