Karo Pharma (Sweden)

Abstract Three species of Aphanomyces, A. euteiches, A. cochlioides and A. cladogamus are devastating agricultural plant pathogens causing root rot disease on pea, sugar beet and spinach, respectively. Here we investigated the distribution of the three Aphanomyces species in parts of Sweden, Denmark and Lithuania using climate chamber soil bioassays, and tested for correlations with macronutrient levels in the soil. Aphanomyces euteiches was the most widespread pathogen found in 28% of the tested samples in Sweden and Denmark, while A. cochlioides had a more limited distribution, and was found in 22% of the samples. Aphanomyces cladogamus was only detected in Sweden and was present in 16% of the tested samples. Aphanomyces euteiches only infected pea plants, while A. cochlioides and A. cladogamus infected both sugar beet and spinach. There were significant (P < 0.001) differences in disease severity index (DSI) between regions, pathogens and for the interaction between regions and crops. Soil calcium (Ca) content ranged from 82 to 3600 mg/100 g dry soil. No species of Aphanomyces was detected in soils with Ca levels above 250 mg/100 g soil, indicating a pathogen-suppressive effect from calcium. Similar results were observed from 1350 soil samples collected from commercial pea growing fields, as DSI values on pea remained very low (below 20 on a 0–100 scale) in soil samples with confirmed presence of A. euteiches and a Ca value above 210 mg/100 g soil. High Ca levels was a significant (P < 0.05) predictor for low probability of presence of Aphanomyces spp. in soil.

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Amyloid beta peptide 42 (Ab 42) plays a pivotal role in Alzheimer's disease and is generated as the result of g -secretase mediated processing of APP. g -Secretase mediated processing of APP results in Ab peptides of different lengths (Ab 30 to Ab 42), according to a mechanism which is not fully understood. Recently, several different classes of molecules have been described which have been denoted gamma secretase modulators, GSMs, based on their ability to decrease Ab 40 and 42 production while they increase the production of shorter Ab peptides. The aim of this study was to understand the basic mechanism of g -secretase mediated processing of APP and to gain insights to the underpinning molecular mechanism of GSMs. A membrane assay, based on HEK293 cells stably transfected with the APPswedish mutant, was developed to study de novo g -secretase mediated processing of APP. Cells were grown to 80 % confluency and P2 membranes were then prepared during ice cold conditions. Aliquots of the membranes were subsequently heated to 37 C for 2 hours in the presence and absence of different compounds. The incubations were finally analyzed for APP metabolites using both ELISA and LC-MS. We could detect g -secretase dependent generation of Ab 37, 38, 40 and 42 in the de Novo assay. Moreover, LC-MS analysis revealed that g -secretase processing occurs at every 3 rd or 4 th amino acid of the APP trans-membrane domain (TMD), beginning at the epsilon site and ending at the outer leaflet of the membrane, which cleavage event would liberate Ab 30. Finally, the Ab 40 and 42 lowering effects of GSMs were shown to be the result of increased processing of Ab 40 and 42 into Ab 37 and Ab 39/38, respectively. We conclude that g -Secretase mediated processing of APP TMD generates Ab peptides of different lengths as the result of the sequential cleavage of the APP TMD at every 3rd or 4th amino acid, and that two major pathway exists (ie Ab 40 and Ab 42 product lines). We also provide evidence that GSM activity does not result in novel cleavage reactions but rather increase the g -secretase mediated processing of Ab 40 and 42 into shorter Ab peptides.

Thyroid hormone receptorβ (TRβ) increases metabolic rate (MR) with a shallow dose‐response slope without tachycardia (HR), unlike T 3 . The TRβ selective agonist KB‐141, has a 10‐fold window in lean rats with 5–10% increases in MR with no HR effect. We determined if KB‐141 causes loss of body weight (BW), adiposity, glucose and lipids in obese Zucker fa/fa rats and ob/ob mice. In cholesterol (C)‐fed Zucker rats, KB‐141 given p.o. at 0.005– 0.50 mg/kg/day for 21 days and. BW was reduced by 6 and 8% compared for the 0.167 and 0.50 mg/kg/day doses with no HR effect. At 0.167 mg/kg/day KB‐141, adiposity (DEXA) and BW were reduced 6%. In Zucker rats, serum C was slightly reduced (14% for high dose), while triglycerides were significantly reduced at 0.05–0.5 mg/kg/day KB‐141. In ob/ob mice treated for 7 days with KB‐141 0.5 mg/kg/day KB‐141), significant serum C lowering (35% vs vehicle) in addition to reduction of triglycerides was seen. Also, KB‐141 significantly reduced BW in ob/ob mice by 6–7% without tachycardia. In ob/ob mice, 2 week treatment with 0.5 and 0.3 mg/kg/day KB‐141 significantly obtunded the glucose excursion after an i.p. glucose challenge and increased insulin sensitivity using i.p insulin tolerance test. Therefore, the selective MR profile for the TRβ selective agonist KB‐141 correlates with its anti‐obesity effects. Lipid‐lowering and anti‐diabetic effects show the exciting possibility of treating metabolic syndrome.

A new high-affinity thyroid hormone antagonist 6 with druglike properties was designed and synthesized. The compound behaved as an antagonist in a cell transactivation assay, and in a first in vivo experiment in rats.

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