Summary Californian populations of Echinochloa phyllopogon have evolved multiple‐herbicide resistance (MHR), posing a threat to rice production in California. Previously, we identified two CYP81A cytochrome P450 genes whose overexpression is associated with resistance to acetolactate synthase (ALS) inhibitors from two chemical groups. Resistance mechanisms to other herbicides remain unknown. We analyzed the sensitivity of an MHR line to acetyl‐CoA carboxylase (ACCase) inhibitors from three chemical groups, followed by an analysis of herbicide metabolism and segregation of resistance of the progenies in sensitive (S) and MHR lines. ACCase herbicide metabolizing function was investigated in the two previously identified P450s. MHR plants exhibited resistance to all the ACCase inhibitors by enhanced herbicide metabolism. Resistance to the ACCase inhibitors segregated in a 3 : 1 ratio in the F2 generation and completely co‐segregated with ALS inhibitor resistance in F6 lines. Expression of the respective P450 genes conferred resistance to the three herbicides in rice, which is in line with the detection of hydroxylated herbicide metabolites in vivo in transformed yeast. CYP81As are super P450s that metabolize multiple herbicides from five chemical classes, and concurrent overexpression of the P450s induces metabolism‐based resistance to the three ACCase inhibitors in MHR E. phyllopogon, as it does to ALS inhibitors.
Listeria monocytogenes evades the antimicrobial mechanisms of macrophages by escaping from the phagosome into the cytosolic space via a unique cytolysin that targets the phagosomal membrane, listeriolysin O (LLO), encoded by hly. Gamma interferon (IFN-␥), which is known to play a pivotal role in the induction of Th1-dependent protective immunity in mice, appears to be produced, depending on the bacterial virulence factor. To determine whether the LLO molecule (the major virulence factor of L. monocytogenes) is indispensable or the escape of bacteria from the phagosome is sufficient to induce IFN-␥ production, we first constructed an hly-deleted mutant of L. monocytogenes and then established isogenic L. monocytogenes mutants expressing LLO or ivanolysin O (ILO), encoded by ilo from Listeria ivanovii. LLO-expressing L. monocytogenes was highly capable of inducing IFN-␥ production and Listeria-specific protective immunity, while the hly-deleted mutant was not. In contrast, the level of IFN-␥ induced by ILO-expressing L. monocytogenes was significantly lower both in vitro and in vivo, despite the ability of this strain to escape the phagosome and the intracellular multiplication at a level equivalent to that of LLO-expressing L. monocytogenes. Only a negligible level of protective immunity was induced in mice against challenge with LLO-and ILO-expressing L. monocytogenes. These results clearly show that escape of the bacterium from the phagosome is a prerequisite but is not sufficient for the IFN-␥-dependent Th1 response against L. monocytogenes, and some distinct molecular nature of LLO is indispensable for the final induction of IFN-␥ that is essentially required to generate a Th1-dependent immune response.
Severe infestations of Alopecurus aequalis (shortawn foxtail), a noxious weed in wheat and barley cropping systems in Japan, can occur even after application of thifensulfuron-methyl, a sulfonylurea (SU) herbicide. In the present study, nine accessions of A. aequalis growing in a single wheat field were tested for sensitivity to thifensulfuron-methyl. Seven of the nine accessions survived application of standard field rates of thifensulfuron-methyl, indicating that severe infestations likely result from herbicide resistance. Acetolactate synthase (ALS) is the target enzyme of SU herbicides. Full-length genes encoding ALS were therefore isolated to determine the mechanism of SU resistance. As a result, differences in ALS gene copy numbers among accessions were revealed. Two copies, ALS1 and ALS2, were conserved in all accessions, while some carried two additional copies, ALS3 and ALS4. A single-base deletion in ALS3 and ALS4 further indicated that they represent pseudogenes. No differences in ploidy level were observed between accessions with two or four copies of the ALS gene, suggesting that copy number varies. Resistant plants were found to carry a mutation in either the ALS1 or ALS2 gene, with all mutations causing an amino acid substitution at the Pro197 residue, which is known to confer SU resistance. Transcription of each ALS gene copy was confirmed by reverse transcription PCR, supporting involvement of these mutations in SU resistance. The information on the copy number and full-length sequences of ALS genes in A. aequalis will aid future analysis of the mechanism of resistance.
We have previously reported that agaro-oligosaccharides (AGOs) suppressed the elevated levels of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), and pro-inflammatory cytokines in activated monocytes/macrophages, via heme oxygenase-1 induction. In this report, we initially demonstrated that AGOs intake inhibited NO production in activated peritoneal macrophages. Then, we tested for the ability of AGOs to prevent tumor promotion on the two-stage mouse skin carcinogenesis model. As a result, AGOs feeding led to delayed tumor appearance and decreased tumor number. It is known that PGE 2 is one of key players in carcinogenesis. Thus, we confirmed that PGE 2 production was suppressed by AGOs intake in TPA-induced ear edema model. We also demonstrated that cyclooxygenase-2 and microsomal PGE synthase-1, rate-limiting enzymes in PGE 2 production, were down-regulated by AGOs in human monocytes. Consequently, AGOs are expected to prevent tumor promotion by inhibiting PGE 2 elevation in chronic inflammation site.Key words agaro-oligosaccharide; anti-inflammation; cancer chemoprevention Agarose, the main component of polysaccharide in agar, is composed of the alternating residues of 3-O-linked β-Dgalactopyranose (Gal) and 4-O-linked 3,6-anhydro-α-Lgalactopyranose (Ah-Gal).1) When agarose is treated by mild acidic conditions, the α1 3 linkage is hydrolyzed, and then yielding agaro-oligosaccharides (AGOs) that have repeating agarobiose (AB) units, with Gal at the non-reducing end and Ah-Gal at the reducing end (Fig. 1). We previously reported that AGOs suppress the elevated levels of nitric oxide (NO), prostaglandin E 2 (PGE 2 ), and pro-inflammatory cytokines such as tumor necrosis factor-α, interleukin-1β and interleukin-6 in lipopolysaccharide (LPS)-stimulated monocytes and macrophages.2) These pro-inflammatory mediators have been implicated in the pathogenesis of inflammatory diseases such as rheumatoid arthritis (RA) and carcinogenesis.3-5) Elevated levels of NO and PGE 2 have been observed in the synovial fluid of RA patients, and excessive NO or PGE 2 contribute to inflammation-related carcinogenesis. [6][7][8][9][10] The activated macrophages at the sites of inflammation persistently express inducible NO synthase (iNOS), resulting in the production of a large amount of NO which interacts with other free radicals (superoxide anions) to form the highly toxic peroxynitrite. 11)Also, overproduced PGE 2 increases the blood flow and potentiates edema and hyperalgesia. 12) It has been shown that AGOs can suppress the excess NO and PGE 2 production via heme oxygenase-1 induction.2) Further, with respect to NO suppression, we confirmed that iNOS expression is inhibited by AGOs treatment, and showed the inhibition of pro-inflammatory mediators release in activated macrophages in vitro. Thus, AGOs were expected to elicit their beneficial effects on subjects having chronic inflammation state such as carcinogenesis.The aim of this study is to demonstrate whether AGOs exert the anti-tumor-promoting activity on well-established mouse...
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