Exploration of Long-Chain Vitamin E Metabolites for the Discovery of a Highly Potent, Orally Effective, and Metabolically Stable 5-LOX Inhibitor that Limits Inflammation.

Endogenous long-chain metabolites of vitamin E (LCMs) mediate immune functions by targeting 5-lipoxygenase (5-LOX) and increasing the systemic concentrations of resolvin E3, a specialized proresolving lipid mediator. SAR studies on semisynthesized analogues highlight α-amplexichromanol (27a), which allosterically inhibits 5-LOX, being considerably more potent than endogenous LCMs in human primary immune cells and blood. Other enzymes within lipid mediator biosynthesis were not substantially inhibited, except for microsomal prostaglandin E2 synthase-1. Compound 27a is metabolized by sulfation and β-oxidation in human liver-on-chips and exhibits superior metabolic stability in mice over LCMs. Pharmacokinetic studies show distribution of 27a from plasma to the inflamed peritoneal cavity and lung. In parallel, 5-LOX-derived leukotriene levels decrease, and the inflammatory reaction is suppressed in reconstructed human epidermis, murine peritonitis, and experimental asthma in mice. Our study highlights 27a as an orally active, LCM-inspired drug candidate that limits inflammation with superior potency and metabolic stability to the endogenous lead

Untersuchungen zur Ern\ue4hrungsbiologie der Renken (Coregonus spec.) des Starnberger Sees

Volume: 9Start Page: 225End Page: 23

Seasonal patterns in the abundance, size, and production of profundal Chironomidae in Starnberger See (Bavaria, FRG) (Diptera, Chironomidae)

Volume: 12Start Page: 261End Page: 27

Identification of RamA, a Novel LuxR-type Transcriptional Regulator of Genes Involved in Acetate Metabolism of Corynebacterium glutamicum

In Corynebacterium glutamicum, the acetate-activating enzymes phosphotransacetylase and acetate kinase and the glyoxylate cycle enzymes isocitrate lyase and malate synthase are coordinately up-regulated in the presence of acetate in the growth medium. This regulation is due to transcriptional control of the respective pta-ack operon and the aceA and aceB genes, brought about at least partly by the action of the negative transcriptional regulator RamB. Using cell extracts of C. glutamicum and employing DNA affinity chromatography, mass spectrometry, and peptide mass fingerprinting, we identified a LuxR-type transcriptional regulator, designated RamA, which binds to the pta-ack and aceA/aceB promoter regions. Inactivation of the ramA gene in the genome of C. glutamicum resulted in mutant RG2. This mutant was unable to grow on acetate as the sole carbon and energy source and, in comparison to the wild type of C. glutamicum, showed very low specific activities of phosphotransacetylase, acetate kinase, isocitrate lyase, and malate synthase, irrespective of the presence of acetate in the medium. Comparative transcriptional cat fusion experiments revealed that this deregulation takes place at the level of transcription. By electrophoretic mobility shift analysis, purified His-tagged RamA protein was shown to bind specifically to the pta-ack and the aceA/aceB promoter regions, and deletion and mutation studies revealed in both regions two binding motifs each consisting of tandem A/C/TG4-6T/C or AC4-5A/G/T stretches separated by four or five arbitrary nucleotides. Our data indicate that RamA represents a novel LuxR-type transcriptional activator of genes involved in acetate metabolism of C. glutamicum

Menieroclerus gen. nov.: A new genus for Thanasimodes nigropiceus (Kuwert, 1893) (Coleoptera: Cleridae: Clerinae)

Opilo nigropiceus Kuwert was described from a specimen collected in Bagamoyo on the north coast of Tanzania, though the description was devoid of informative morphological detail (Kuwert 1893). Without comment, Schenkling (1915) transferred O. nigropiceus to Thanasimodes Murray, a genus erected by Murray (1867) for a single specimen from 'Old Calabar' (south Nigeria) described as Thanasimodes metallicus Murray. Thanasimodes presently contains ten species and is distributed widely throughout Africa, from South Africa to the northernmost countries (Corporaal 1950; Gerstmeier 1998)

Menieroclerus gen. nov.: A new genus for Thanasimodes nigropiceus (Kuwert, 1893) (Coleoptera: Cleridae: Clerinae)

Opilo nigropiceus Kuwert was described from a specimen collected in Bagamoyo on the north coast of Tanzania, though the description was devoid of informative morphological detail (Kuwert 1893). Without comment, Schenkling (1915) transferred O. nigropiceus to Thanasimodes Murray, a genus erected by Murray (1867) for a single specimen from 'Old Calabar' (south Nigeria) described as Thanasimodes metallicus Murray. Thanasimodes presently contains ten species and is distributed widely throughout Africa, from South Africa to the northernmost countries (Corporaal 1950; Gerstmeier 1998)