The rigid duplex cyclodextrin 6 composed of two α-cyclodextrin macrocycles connected with two disulfide bonds in “transannular” (C6I, C6IV) positions was prepared from partially debenzylated α-cyclodextrin 1 in four steps in 73% overall yield. In the last key step involving oxidative coupling of the thiol 5, predominance of the target duplex 6 can be attained under conditions of thermodynamic control. The structure of duplex cyclodextrin was established by MS as well as 2-D NMR methods and confirmed by a single-crystal X-ray analysis. The ability of the duplex cyclodextrin 6 to bind α,ω-alkanediols (C9−C14) and 1-alkanols (C9 and C10) was studied by isothermal titration calorimetry in aqueous solutions. The stability constants of the complexes gradually increase with the alkyl chain length and reach an unprecedently high value of K = 8.6 × 109 M−1 for 1,14-tetradecanediol. It was found that the doubly bridged dimer 6 exhibits higher binding affinity toward the series of α,ω-alkanediols than the singly bridged analogue 10 by about 2 orders of magnitude in K (M−1) or 3.1−3.3 kcal/mol in ΔG°, the enhancement being due to enthalpic factors. Theoretical calculations using DFT-D methods suggest that the enthalpic contribution stems from dispersion interactions.

In patients with PAOD stage II considerable effects on functional capacity and important dimensions of quality of life can be achieved by a short exercise and education program.

Background: Chronic liver disease is a growing epidemic leading to fibrosis and cirrhosis. TGF-β is the pivotal pro-fibrogenic cytokine which activates hepatic stellate cells (HSC), yet, other molecules can substantially modulate TGF-β signalling in the course of liver fibrosis. Expression of the axon guidance molecules Semaphorins (SEMAs), which signal through Plexins and Neuropilins (NRPs), have been associated with liver fibrosis in HBV-induced chronic hepatitis. However, their function in the regulation of HSCs has not yet been described. Results: SEMA3C is the most enriched member of the Semaphorin family in liver samples from cirrhotic patients. Higher expression of SEMA3C in patients with NASH, alcoholic hepatitis or HBV-induced hepatitis discriminates those with a more pro-fibrotic transcriptomic profile. SEMA3C expression is also elevated in different mouse models of liver fibrosis and in isolated HSCs upon activation. In keeping with this, deletion of SEMA3C in activated HSCs reduces myofibroblast marker expression. Conversely, SEMA3C overexpression exacerbates TGF-β-mediated myofibroblast activation, as shown by increased SMAD2/3 phosphorylation and target gene expression. Among SEMA3C receptors, only NRP2 expression is maintained upon activation of isolated HSCs. Interestingly, lack of NRP2 in those cells reduces myofibroblast marker expression. Finally, deletion of either SEMA3C or NRP2, specifically in activated HSCs, reduces liver fibrosis in mice. Conclusion: SEMA3C is a novel marker for activated HSCs that plays a fundamental role in the acquisition of the myofibroblastic phenotype and liver fibrosis.