Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly.

ALOX12 and ALOX15 encode arachidonate lipoxygenases which produce lipid metabolites involved in inflammatory processes. Metabolites generated by ALOX12 and ALOX15 can activate the expression of the potent pro-inflammatory cytokine IL-6, and produce endogenous ligands for PPARG. In this study, polymorphisms in ALOX12, ALOX15, IL6 and PPARG were investigated for association with bone properties in young and elderly Swedish women

Identification of Candidate Gene Regions in the Rat by Co-Localization of QTLs for Bone Density, Size, Structure and Strength.

Susceptibility to osteoporotic fracture is influenced by genetic factors that can be dissected by whole-genome linkage analysis in experimental animal crosses. The aim of this study was to characterize quantitative trait loci (QTLs) for biomechanical and two-dimensional dual-energy X-ray absorptiometry (DXA) phenotypes in reciprocal F2 crosses between diabetic GK and normo-glycemic F344 rat strains and to identify possible co-localization with previously reported QTLs for bone size and structure. The biomechanical measurements of rat tibia included ultimate force, stiffness and work to failure while DXA was used to characterize tibial area, bone mineral content (BMC) and areal bone mineral density (aBMD). F2 progeny (108 males, 98 females) were genotyped with 192 genome-wide markers followed by sex- and reciprocal cross-separated whole-genome QTL analyses. Significant QTLs were identified on chromosome 8 (tibial area; logarithm of odds (LOD) = 4.7 and BMC; LOD = 4.1) in males and on chromosome 1 (stiffness; LOD = 5.5) in females. No QTLs showed significant sex-specific interactions. In contrast, significant cross-specific interactions were identified on chromosome 2 (aBMD; LOD = 4.7) and chromosome 6 (BMC; LOD = 4.8) for males carrying F344mtDNA, and on chromosome 15 (ultimate force; LOD = 3.9) for males carrying GKmtDNA, confirming the effect of reciprocal cross on osteoporosis-related phenotypes. By combining identified QTLs for biomechanical-, size- and qualitative phenotypes (pQCT and 3D CT) from the same population, overlapping regions were detected on chromosomes 1, 3, 4, 6, 8 and 10. These are strong candidate regions in the search for genetic risk factors for osteoporosis

A scaffold replacement approach towards new sirtuin 2 inhibitors

Sirtuins (SIRT1-SIRT7) are an evolutionary conserved family of NAD(+)-dependent protein deacylases regulating the acylation state of epsilon-N-lysine residues of proteins thereby controlling key biological processes. Numerous studies have found association of the aberrant enzymatic activity of SIRTs with various diseases like diabetes, cancer and neurodegenerative disorders. Previously, we have shown that substituted 2-alkyl-chroman-4-one/chromone derivatives can serve as selective inhibitors of SIRT2 possessing an antiproliferative effect in two human cancer cell lines. In this study, we have explored the bioisosteric replacement of the chroman-4-one/chromone core structure with different less lipophilic bicyclic scaffolds to overcome problems associated to poor physiochemical properties due to a highly lipophilic substitution pattern required for achieve a good inhibitory effect. Various new derivatives based on the quinolin-4(1H)-one scaffold, bicyclic secondary sulfonamides or saccharins were synthesized and evaluated for their SIRT inhibitory effect. Among the evaluated scaffolds, the benzothiadiazine-1,1-dioxide-based compounds showed the highest SIRT2 inhibitory activity. Molecular modeling studies gave insight into the binding mode of the new scaffold-replacement analogues.Peer reviewe

Pseudopeptides with a centrally positioned alkene-based disulphide bridge mimetic stimulate kallikrein-related peptidase 3 activity

Peer reviewe

A biocatalytic route to P-chirogenic compounds by lipase-catalyzed desymmetrization of a prochiral phosphine-borane.

[reaction: see text] Available methods for synthesis of P-chirogenic compounds are limited. We set out to find biocatalytical means to introduce asymmetry in a phosphine-borane. After screening different lipases, Candida antarctica lipase B was found to give excellent results in the desymmetrization of prochiral phosphine-boranes. Both enantiomers can be obtained in up to >98% optical purity via acetylation or hydrolysis in processes that allow recycling of the substrates