Phosphodiesterase inhibitors. Part 6: Design,synthesis, and structure–activity relationships of PDE4-inhibitory pyrazolo[1,5-a]pyridines with anti-inflammatory activity

We previously identified KCA-1490 [(?)-6-(7-methoxy-2-trifluoromethyl-pyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone], a dual PDE3/4 inhibitor. In the present study, we found highly potent selective PDE4 inhibitors derived from the structure of KCA-1490. Among them, N-(3,5-dichloropyridin-4-yl)-7-methoxy-2-(trifluoromethyl)pyrazolo[1,5-a]pyridine-4-carboxamide (2a) had good anti-inflammatory effects in an animal model.     

Relationship between the expression of Rab family GTPases and neuropeptide hormones in the brain of Bombyx mori

Rab proteins are small GTPases that play essential roles in vesicle transport. In this study, we examined the expression of Rab proteins and neuropeptide hormones in the brain of the silkworm, Bombyx mori. We produced antibodies against B. mori Rab1 and Rab14 in rabbits. Immunoblotting of samples of brain tissue from B. mori revealed a single band for each antibody. Rab1 and Rab14 immunohistochemical labeling in the brain of B. mori was restricted to neurons of the pars intercerebralis and dorsolateral protocerebrum. Rab1, Rab7 and Rab14 co-localized with bombyxin. Rab1 and Rab7 co-localized with eclosion hormone. Rab1 co-localized with prothoracicotropic hormone. These results suggest that Rab1, Rab7 and Rab14 may be involved in neuropeptide transport in the brain of B. mori. This is the first report on the specificity of Rab proteins for the secretion of different neuropeptides in insects.     

Age-related effects of major and trace element concentrations in rat liver and their mutual relationships

The concentrations of 22 major and trace elements in livers from rats aging from 5 to 113 weeks old were determined. The rats investigated were the same rats previously reported with respect to 29 elements in bones (femur) and 26 elements in kidneys. The samples were decomposed with high-purity nitric acid and hydrogen peroxide. Seven elements (Na, Mg, P, K, Ca, Fe and Zn) were determined by inductively coupled plasma atomic emission spectrometry (ICP-AES), and 15 elements (Mn, Co, Cu, As, Se, Rb, Sr, Mo, Cd, Sn, Sb, Cs, Ba, Pb and Bi) were determined by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of variance (ANOVA) for age variations indicated that the concentrations of many elements, such as Mg, P, K, Mn, Fe, Cu, Zn, Sr, Mo and Cd, were almost constant across the ages of the rats with the exception of 5 weeks old (p > 0.05). Arsenic, Pb and Bi showed significant increasing trends, while Na and Co showed decreasing trends (p < 0.01). Selenium showed a decreasing trend except at the initial stage of 5–9 weeks old. Calcium, Rb, Sn, Sb, Cs and Ba showed significant age-related variations, but their patterns were not monotonic. The liver clearly contrasts with the kidneys, in which many elements showed significant age-related variations with increasing trends. The concentration ranges of Mg, P, K, Mn, Cu, Zn, and Mo were controlled within 15% across all ages of rats. The homeostasis of the aforementioned elements may be well established in the liver. The toxic elements, such as Cd, Pb and Bi, showed a narrow concentration range among age-matched rats.     

An Assay of Sterigmatocystin and Related Metabolites of Aspergillus versicolor by High Speed Liquid Chromatography

Among several type cultures that assimilated 1-hexadecene, Corynebacterium equi IFO 3730 was found to best accumulate 1, 2-epoxyhexadecane. The purified product exhibited +9.64 (c = 3.71, n-hexane) and was confirmed to have the (R) absolute configuration by correlating to known analogous compounds. The optical purity was determined to be 100% by PMR measurement of 1-methoxy-2-hexadecanol which was derived stereospecifically from the epoxide. The highest yield (41 % based on consumed 1-hexadecene) was achieved when 2.0% of octane and 0.1 % of Tween 80 were added to the medium containing 0.5 % of the olefin. C. equi also assimilated terminal olefins other than 1-hexadecene and produced the corresponding epoxides from substrates which have carbon chains longer than fourteen.     

Structural Analysis of Sydowic Acid by X-ray Diffraction

Streptomyces sp. No. 280 produced several kinds of amylase inhibitors (amylase inhibitor A, B, B' and C). Two amylase inhibitors (designated as AI-A₁ and AI-A₂) were obtained from an amylase inhibitor A fraction by paper chromatography. AI-A₁ inhibited muscle phosphorylase a much more than AI-A₂ and was hydrolyzed by sweet potato β-amylase whereas AI-A₂ was not. Both amylase inhibitors had a carbohydrate and were hydrolyzed by some kinds of amylases or acids. They lost their inhibitory activity against phosphorylase a after treatment with acids or hog pancreatic α-amylase, but they showed increased inhibitory activity toward porcine small intestinal sucrase.

Both AI-A₁ and AI-A₂ were composed of glucose and a basic moiety which gave a positive ninhydrin reaction. The molecular weights of AI-A₁ and AI-A₂ were estimated to be approximately 1300 ? 1500 by gel filtration on a Sephadex G-15 column. The nitrogen content of the amylase inhibitors was found to be about 1.3% by elementary analysis     

A New Metabolite,Parasiticolide A,from Aspergillus parasiticus

Two β-glucosidases, G1 and G2, were purified from the culture supernatant of Penicillium herquei Banier and Sartory. Both the purified enzymes were homogeneous on polyacrylamide disc gel electrophoresis. The molecular weights of G1 and G2 were estimated to be 125,000 and 122,000, respectively, by sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis. G1 and G2 contained 12.7% and 16.1% carbohydrate as glucose, and had isoelectric points of 5.02 and 5.24, respectively. Both enzymes had optimum pHs of 4.0~4.5 and optimum temperatures at 60°C, but pH - and thermo-stabilities of G1 were higher than those of G2. Both enzymes were active not only on p-nitrophenyl β-d-glucopyranoside, salicin, and the p-glucobioses tested but also on laminarin. CM-Cellulose was a very poor substrate for both enzymes. The activities of G1 toward the substrates except for laminarin and CM-cellulose were apparently higher than those of G2. Both enzymes acted on cellobiose to produce a transfer product.     

Isolation of a Spore Germination Inhibitor from a Cellular Slime Mold Dictyostelium discoideum

The functional properties of gluten obtained by treating with chymotrypsin at alkali pH were investigated. The gluten was treated by chymotrypsin at pH 10.0 and 20°C, and was found to be deamidated to a state that was scarcely subject to proteolysis by chymotrypsin. The degree of deamidation of the gluten reached about 25% by this treatment for 2 hr. The functional properties of the gluten thus obtained were investigated in regard to deamidation. The enzymatically deamidated gluten greatly improved such functional properties as solubility and emulsifying ability. In particular, the solubility of the treated gluten was remarkably high in the pH range of 5 to 8, in which native gluten is insoluble. It was apparent that the improvement in functional properties of gluten was mainly due to the deamidation induced by treating with chymotrypsin at pH 10.0 and 20°C.     

Environmental perturbations influence telomere dynamics in long-lived birds in their natural habitat

Telomeres are regarded as markers of biological or cellular ageing because they shorten with the degree of stress exposure. Accordingly, telomere lengths should show different rates of change when animals are faced with different intensities of environmental challenges. However, a relationship between telomere length and the environment has not yet been tested within a natural setting. Here, we report longitudinal telomere dynamics in free-living, black-tailed gulls (Larus crassirostris) through the recapture of birds of a known age over 2–5 consecutive years. The rate of change in telomere lengths differed with respect to year but not sex or age. The years when gulls showed stable telomere lengths or increases in telomere lengths (from 2009 to 2010) and decreases in telomere lengths (from 2010 to 2011) were characterized by El Niño and the Great Japan Earthquake, respectively. Both events are suspected to have had long-lasting effects on food availability and/or weather conditions. Thus, our findings that telomere dynamics in long-lived birds are influenced by dramatic changes in environmental conditions highlight the importance of environmental fluctuations in affecting stress and lifespan.     

A passive integrated transponder tag implanted by a new alternative surgical method: effects on the oriental weather loach (Misgurnus anguillicaudatus) and application in a small irrigation system

We validated the effects of a passive integrated transponder (PIT) tagging process on the oriental weather loach Misgurnus anguillicaudatus. Laboratory experiments were conducted to assess the effects of PIT tagging on fish survival, growth, wound healing, and tag omission. Two tagging protocols, standard syringe injection versus insertion through a small hole pierced by a fine needle-shaped awl, were compared using a 12.5 × 2.07 mm² tag. A control group was also included. In comparison with the awl technique, syringe injection heightened the mortality of the loach and delayed healing of the wound caused by tag insertion. No effects of either PIT tagging method were detected on the growth of surviving loach. We also field-tested similarly tagged populations within a river-based irrigation system of Sado Island, Japan. Two different sized tags (long, 12.5 × 2.07 mm²; short, 8.5 × 2.12 mm²) were compared by using antenna loggers which detected fish movement through gates and automatically logged tagged fish’s tag IDs and timestamps. By comparing logged data and actual fish collection surveys both below and above the gates, 77% and 30% of actual loach movements were confirmed to have been successfully logged for the long and short tags, respectively. The awl insertion technique with the longer tag is therefore recommended for use in similar studies of smaller fish species.     

Change in Body Fat Mass Is Independently Associated with Executive Functions in Older Women: A Secondary Analysis of a 12-Month Randomized Controlled Trial

Objectives

To investigate the independent contribution of change in sub-total body fat and lean mass to cognitive performance, specifically the executive processes of selective attention and conflict resolution, in community-dwelling older women.

Methods

This secondary analysis included 114 women aged 65 to 75 years old. Participants were randomly allocated to once-weekly resistance training, twice-weekly resistance training, or twice-weekly balance and tone training. The primary outcome measure was the executive processes of selective attention and conflict resolution as assessed by the Stroop Test. Sub-total body fat and lean mass were measured by dual-energy x-ray absorptiometry (DXA) to determine the independent association of change in both sub-total body fat and sub-total body lean mass with Stroop Test performance at trial completion.

Results

A multiple linear regression model showed reductions in sub-total body fat mass to be independently associated with better performance on the Stroop Test at trial completion after accounting for baseline Stroop performance, age, baseline global cognitive state, baseline number of comorbidities, baseline depression, and experimental group. The total variance explained was 39.5%; change in sub-total body fat mass explained 3.9% of the variance. Change in sub-total body lean mass was not independently associated with Stroop Test performance (P>0.05).

Conclusion

Our findings suggest that reductions in sub-total body fat mass – not sub-total lean mass – is associated with better performance of selective attention and conflict resolution.