Selective transfers of acetylenic acids to form lecithins

Although acetylenic acids are not normally found in mammalian tissues, octadecynoyl-CoA esters can serve as substrates for rat liver microsomal acyl-CoA: phospholipid acyltransferases. The relatively high rate of transfer to the 2-hydroxyl of 1-acylglycerol-3-phosphorylcholine by the 5-, 9-, and 12-positional cis, trans and yne isomers of acids supports the concept that [pi]-bonds at these positions facilitate esterification irrespective of configuration. The preferred positional isomers for transfer to the 1-hydroxyl, however, are different for the cis and yne derivatives, indicating a sensitivity of the enzyme(s) to configuration. In the latter transfer, an alternating selectivity occurred with the acetylenic isomers between 8 to 13 that was opposite to the pattern for the cis-octadecenoyl transfers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/33918/1/0000184.pd

Positional specificity of cyclopropane ring formation from cis-octadecenoic acid isomers in Escherichia coli

An unsaturated fatty acid auxotroph of Escherichia coli was grown with a series of cis-octadecenoate isomers in which the location of the double bond varied from positions 3 to 17. Each of these fatty acid isomers was incorporated into the cellular lipids, but cyclopropane derivatives were formed to at least a 3-fold greater extent from the cis-9 and cis-11 isomers than from any other positional isomers. The extent of cyclopropane acid formation was observed to be highly dependent on the rate of shaking of the culture. A culture shaking at 340 rev./min converted 8.7% of its oleate to the cyclopropane derivative at stationary phase, whereas a parellel culture shaken at 110 rev./min converted 66% of the oleate to a cyclopropane acid.The inability to observe selectivity or form derivatives from isomers other than the is-9 and cis-11 isomers seems to be due to enzyme specificity rather than a secondary affect of the abnormal unconverted fatty acids on the cell, because the cis-9 isomer is converted to its cyclopropane derivative even in cells grown with abnormal unreactive positional isomers.The preferred substrates for cyclopropanecarboxylic acid formation contained a cis ethylenic bond at either the 9 position or the -7 position. In combination with results of previous studies the specificity reported here supports a concept that two different enzymes may participate in cyclopropane ring synthesis. One enzyme activity may recognize its substrate by the distance from the [pi]-bond to the carboxyl group and the other by the distance to the methyl group.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/21769/1/0000163.pd

EPR study of radical intermediates from the oxidation of 6-ethoxy-2,2,4-trimethyl- and 6-ethoxy-2,2,4,8-tetramethyl-1,2-dihydroquinoline

The EPR spectra of 1,2-dihydro-6-ethoxy-2,2,4-trimethyl- and 1,2-dihydro-6-ethoxy-2,2,4,8-tetramethyl-quinolin-1-yl radicals were observed in heptane solution. The hyperfine splittings showed that this class of radical is extensively delocalised with significant spin density at C(8). Both radicals decayed by second-order processes, the rate constants being 5 × 106 and 4 × 102 dm3 mol–1 s–1, respectively at 273 K. The latter reaction is much slower because the 8-methyl substituent blocks the formation of the 1,8′-dimer. Both radicals reacted with oxygen to give the corresponding nitroxides, although reaction was very slow for the 8-methyl derivative. A mechanism is proposed to rationalise product formation from 1,2-dihydro-6-ethoxy-2,2,4-trimethylquinoline when used as an antioxidan

Quantitative effects of unsaturated fatty acids in microbial mutants : VII. Influence of the acetylenic bond location on the effectiveness of acyl chains

The ability of a series of 18 carbon acetylenic fatty acids to fulfill the unsaturated fatty acid requirements of Escherichia coli and Saccharomyces cerevisiae was investigated. Despite their high melting points (>40[deg]C), several isomers of the acetylenic fatty acids were as efficient or more efficient in supporting growth than the analogous fatty acid having a cis-double bond.The efficiencies of the different positional isomers in supporting cell proliferation varied from essentially 0 cells per fmol for the 2-5 and 13-17 isomers to high values when the acetylenic bond was near the center of the chain: e.g. 45 E. coli and 5.5 S. cerevisiae cells/fmol for the 10 isomer. A striking ineffectiveness of the 9 isomer was observed with E. coli. The 7, 8 and 10 isomers were at least 10-fold more efficient than any of the other positional isomers in supporting the growth of E. coli. In contrast, the 9 isomer was among the most effective acetylenic fatty acids tested with the yeast mutant.Chromatographic analysis of the extracted lipids indicated that each of the acetylenic isomers tested (except [Delta]2 and [Delta]3) could be esterified by the prokaryotic and eukaryotic microorganisms. The content of unsaturated plus cyclopropane acids observed when growth ceased in E. coli cultures supplemented with growth-limiting concentrations of the acetylenic fatty acids ranged from approx. 15 mol% for the 8 isomer to approx. 35 mol% for the 14 and 17 isomers. The 8-11 isomers were observed to be esterified predominantly at the two position in phosphatidylethanolamine of E. coli and in phosphatidylcholine of S. cerevisiae.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/22954/1/0000521.pd

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Electron spin resonance study of the role of vitamin E and vitamin C in the inhibition of fatty acid oxidation in a model membrane

The neutral α-tocopheroxyl radicals, generated in monolayers on silica gel containing α-tocopherol and partly autoxidised methyl linoleate at 90°C, were detected and identified by ESR spectroscopy. Addition of ascorbic acid to the monolayer resulted in the complete quenching of the α-tocopheroxyl radical spectrum. This lends support to the view that ascorbate transfers hydrogen to α-tocopheroxyl radicals thus regenerating α-tocopherol.</p

An electron spin resonance study of fatty acids and esters. Part 2. Hydrogen abstraction from saturated acids and their derivatives

The radicals generated from saturated fatty acids and their derivatives by hydrogen abstraction with photochemically formed t-butoxyi radicals have been investigated. These arise from the various methylene groups in the acids. The relative rates of abstraction from the methylene groups in the α-position, the position adjacent to the terminal methyl, and the remaining chain positions are 2:2:1, respectively, at 290 K, for acids of chain length &gt;C6. With propanoic acid, butanoic acid, and butanonitrile, hydrogen abstraction at the α-methylene group predominates. With 1-lauroyl-2-myristoyl-3- palmitoyl-rac-glycerol, enhanced attack at the position adjacent to the terminal methyl was observed.</p