@article{ReichelHoenigLiebischetal.2015,
  author    = {Reichel, Martin and Hoenig, Stefanie and Liebisch, Gerhard and L{\"u}th, Anja and Kleuser, Burkhard and Gulbins, Erich and Schmitz, Gerd and Kornhuber, Johannes},
  title     = {Alterations of plasma glycerophospholipid and sphingolipid species in male alcohol-dependent patients},
  series = {Biochimica et biophysica acta : Molecular and cell biology of lipids},
  volume    = {1851},
  journal   = {Biochimica et biophysica acta : Molecular and cell biology of lipids},
  number    = {11},
  publisher = {Elsevier},
  address   = {Amsterdam},
  issn      = {1388-1981},
  doi       = {10.1016/j.bbalip.2015.08.005},
  pages     = {1501 -- 1510},
  year      = {2015},
  abstract  = {Background: Alcohol abuse is a major risk factor for somatic and neuropsychiatric diseases. Despite their potential clinical importance, little is known about the alterations of plasma glycerophospholipid (GPL) and sphingolipid (SPL) species associated with alcohol abuse. Methods: Plasma GPL and SPL species were quantified using electrospray ionization tandem mass spectrometry in samples from 23 male alcohol-dependent patients before and after detoxification, as well as from 20 healthy male controls. Results: A comparison of alcohol-dependent patients with controls revealed higher phosphatidylcholine (PC; P-value = 0.008) and phosphatidylinositol (PI; P-value = 0.001) concentrations in patients before detoxification, and higher PI (P-value = 0.001) and phosphatidylethanolamine (PE)-based plasmalogen (PEP; P-value = 0.003) concentrations after detoxification. Lysophosphatidylcholines (LPC) were increased by acute intoxication (P-value = 0.002). Sphingomyelin (SM) concentration increased during detoxification (P-value = 0.011). The concentration of SM 23:0 was lower in patients (P-value = 2.79 x 10(-5)), and the concentrations of ceramide Cer d18:1/16:0 and Cer d18:1/18:0 were higher in patients (P-value = 2.45 x 10(-5) and 3.73 x 10(-5)). Activity of lysosomal acid sphingomyelinase (ASM) in patients correlated positively with the concentrations of eight LPC species, while activity of secreted ASM was inversely correlated with several PE, PI and PC species, and positively correlated with the molar ratio of PC to SM (Pearson's r = 0.432; P-value = 0.039). Conclusion: Plasma concentrations of numerous GPL and SPL species were altered in alcohol-dependent patients. These molecules might serve as potential biomarkers to improve the diagnosis of patients and to indicate health risks associated with alcohol abuse. Our study further indicates that there are strong interactions between plasma GPL concentrations and SPL metabolism. (C) 2015 Elsevier B.V. All rights reserved.},
  language  = {en}
}
@article{BhabakKleuserHuwileretal.2013,
  author    = {Bhabak, Krishna P. and Kleuser, Burkhard and Huwiler, Andrea and Arenz, Christoph},
  title     = {Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues},
  series = {Bioorganic \& medicinal chemistry : a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines},
  volume    = {21},
  journal   = {Bioorganic \& medicinal chemistry : a Tetrahedron publication for the rapid dissemination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines},
  number    = {4},
  publisher = {Elsevier},
  address   = {Oxford},
  issn      = {0968-0896},
  doi       = {10.1016/j.bmc.2012.12.014},
  pages     = {874 -- 882},
  year      = {2013},
  abstract  = {Induction of apoptosis mediated by the inhibition of ceramidases has been shown to enhance the efficacy of conventional chemotherapy in several cancer models. Among the inhibitors of ceramidases reported in the literature, B-13 is considered as a lead compound having good in vitro potency towards acid ceramidase. Furthermore, owing to the poor activity of B-13 on lysosoamal acid ceramidase in living cells, LCL-464 a modified derivative of B-13 containing a basic omega-amino group at the fatty acid was reported to have higher potency towards lysosomal acid ceramidase in living cells. In a search for more potent inhibitors of ceramidases, we have designed a series of compounds with structural modifications of B-13 and LCL-464. In this study, we show that the efficacy of B-13 in vitro as well as in intact cells can be enhanced by suitable modification of functional groups. Furthermore, a detailed SAR investigation on LCL-464 analogues revealed novel promising inhibitors of aCDase and nCDase. In cell culture studies using the breast cancer cell line MDA-MB-231, some of the newly developed compounds elevated endogenous ceramide levels and in parallel, also induced apoptotic cell death. In summary, this study shows that structural modification of the known ceramidase inhibitors B-13 and LCL-464 generates more potent ceramidase inhibitors that are active in intact cells and not only elevates the cellular ceramide levels, but also enhances cell death.},
  language  = {en}
}