Hydrogen peroxide (H(2)O(2)), which is contained in industrial products, is also generated within cells. H(2)O(2) causes pain but it has not been elucidated how it activates sensory neurons in the pain pathway. Here we show that transient receptor potential ankyrin 1 (TRPA1), expressed by sensory neurons in the pain pathway, is a receptor for H(2)O(2). H(2)O(2) activated mouse TRPA1 to induce Ca(2+) influx and elicit non-selective cation currents. These effects of H(2)O(2) were mimicked by both reactive oxygen species and reactive nitrogen species. Cysteine-reducing agents suppressed H(2)O(2)-induced TRPA1 activation, whereas cysteine-oxidizing agents activated TRPA1. H(2)O(2) caused Ca(2+) influx in a subset of dorsal root ganglia neurons, which responded to allyl isothiocyanate, a TRPA1 ligand. These results suggest that TRPA1 might be involved in the sensation of pain caused by H(2)O(2).

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Streptomyces amphibiosporus R310-104 (ATCC53964) produced a novel antibiotic lactimidomycin which showed inhibitory activity against fungi and prolonged the survival time of mice transplanted with experimental tumors. Structural studies clarified that lactimidomycin is a new glutarimide antibiotic having a unique unsaturated 12-memberedlactone ring.In the course of screening for new antibiotics effective against experimental tumors, we have isolated a novel antibiotic designated lactimidomycin from the culture broth of Streptomyces amphibiosporus R310-104 collected in Akita city1'2*. The antibiotic exhibited strong cytotoxicity against various tumor cells and inhibitory activity against fungi but no antibacterial activity. It demonstrated prolongation of life span in mice bearing P388 leukemia and B l 6 melanoma. The structure oflactimidomycin was determined by spectroscopic analyses and 13C-enriched biosynthetic studies to be a novel glutarimide group antibiotic having a unique 12-memberedlactone ring as a side chain.In this paper, we describe the production, isolation, physico-chemical properties, structure determination and biological activity of lactimidomycin. Antibiotic Production A loopful mature slant culture of S. amphibiosporus R3 10-104 was inoculated into 100 ml of vegetative mediumconsisting of soluble starch (Nichiden Kagaku) 2%, Pharmamedia(Traders Protein) 1%, ZnSO4-7H2O0.003% and CaCO3 0.4% in a 500-ml Erlenmeyer flask (pH 7.0 before sterilization).The flask was incubated at 32°C for 7 days on a rotary shaker (200rpm) and 5 ml of vegetative inoculum was added to 100ml of sterile production medium containing Protein-S (Ajinomoto Co.) 3%, glucose 3%, Pharmamedia 0.5%, yeast extract (Oriental Yeast Co.) 0.1% and CaCO3 0.3%, pH 7.0 in a 500-ml Erlenmeyer flask. The flask was incubated at 28°C on a rotary shaker (200rpm). Antibiotic production was monitored by the in vitro cytotoxicity against B16 melanomacells and it reached maximumafter 4 days incubation. Isolation and PurificationThe fermentation broth (18 liters, pH 7.4) was stirred with 1-butanol for one hour. The solvent layer was separated from the aqueous layer and mycelial cake by use ofa Sharpies type centrifuge and concentrated under reduced pressure. The residue (30 g) was suspended in water (1 liter) and extracted three times with Lactimidomycin was originally called as BU-4146T or BMY-28886.