TY  - JOUR
A1  - Worku, Netsanet
A1  - Stich, August
A1  - Daugschies, Arwid
A1  - Wenzel, Iris
A1  - Kurz, Randy
A1  - Thieme, Rene
A1  - Kurz, Susanne
A1  - Birkenmeier, Gerd
T1  - Ethyl Pyruvate Emerges as a Safe and Fast Acting Agent against Trypanosoma brucei by Targeting Pyruvate Kinase Activity
JF  - PLoS ONE
N2  - Background 
Human African Trypanosomiasis (HAT) also called sleeping sickness is an infectious disease in humans caused by an extracellular protozoan parasite. The disease, if left untreated, results in 100% mortality. Currently available drugs are full of severe drawbacks and fail to escape the fast development of trypanosoma resistance. Due to similarities in cell metabolism between cancerous tumors and trypanosoma cells, some of the current registered drugs against HAT have also been tested in cancer chemotherapy. Here we demonstrate for the first time that the simple ester, ethyl pyruvate, comprises such properties. 

Results 
The current study covers the efficacy and corresponding target evaluation of ethyl pyruvate on T. brucei cell lines using a combination of biochemical techniques including cell proliferation assays, enzyme kinetics, phasecontrast microscopic video imaging and ex vivo toxicity tests. We have shown that ethyl pyruvate effectively kills trypanosomes most probably by net ATP depletion through inhibition of pyruvate kinase (Ki = 3.0\(\pm\)0.29 mM). The potential of ethyl pyruvate as a trypanocidal compound is also strengthened by its fast acting property, killing cells within three hours post exposure. This has been demonstrated using video imaging of live cells as well as concentration and time dependency experiments. Most importantly, ethyl pyruvate produces minimal side effects in human red cells and is known to easily cross the blood-brain-barrier. This makes it a promising candidate for effective treatment of the two clinical stages of sleeping sickness. Trypanosome drug-resistance tests indicate irreversible cell death and a low incidence of resistance development under experimental conditions. 

Conclusion 
Our results present ethyl pyruvate as a safe and fast acting trypanocidal compound and show that it inhibits the enzyme pyruvate kinase. Competitive inhibition of this enzyme was found to cause ATP depletion and cell death. Due to its ability to easily cross the blood-brain-barrier, ethyl pyruvate could be considered as new candidate agent to treat the hemo-lymphatic as well as neurological stages of sleeping sickness.
KW  - human african trypanosomiasis
KW  - glycolysis
KW  - transport
KW  - protein
KW  - cruzi
KW  - chemotherapy
KW  - metabolism
KW  - in vitro
KW  - drugs
KW  - sleeping sickness
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-150002
VL  - 10
IS  - 9
ER  - 
TY  - JOUR
A1  - Stepniak, Beata
A1  - Kästner, Anne
A1  - Poggi, Giulia
A1  - Mitjans, Marina
A1  - Begemann, Martin
A1  - Hartmann, Annette
A1  - Van der Auwera, Sandra
A1  - Sananbenesi, Farahnaz
A1  - Krüger-Burg, Dilja
A1  - Matuszko, Gabriela
A1  - Brosi, Cornelia
A1  - Homuth, Georg
A1  - Völzke, Henry
A1  - Benseler, Fritz
A1  - Bagni, Claudia
A1  - Fischer, Utz
A1  - Dityatev, Alexander
A1  - Grabe, Hans-Jörgen
A1  - Rujescu, Dan
A1  - Fischer, Andre
A1  - Ehrenreich, Hannelore
T1  - Accumulated common variants in the broader fragile X gene family modulate autistic phenotypes
JF  - EMBO Molecular Medicine
N2  - Fragile X syndrome (FXS) is mostly caused by a CGG triplet expansion in the fragile X mental retardation 1 gene (FMR1). Up to 60% of affected males fulfill criteria for autism spectrum disorder (ASD), making FXS the most frequent monogenetic cause of syndromic ASD. It is unknown, however, whether normal variants (independent of mutations) in the fragile X gene family (FMR1, FXR1, FXR2) and in FMR2 modulate autistic features. Here, we report an accumulation model of 8 SNPs in these genes, associated with autistic traits in a discovery sample of male patients with schizophrenia (N = 692) and three independent replicate samples: patients with schizophrenia (N = 626), patients with other psychiatric diagnoses (N = 111) and a general population sample (N = 2005). For first mechanistic insight, we contrasted microRNA expression in peripheral blood mononuclear cells of selected extreme group subjects with high-versus low-risk constellation regarding the accumulation model. Thereby, the brain-expressed miR-181 species emerged as potential "umbrella regulator", with several seed matches across the fragile X gene family and FMR2. To conclude, normal variation in these genes contributes to the continuum of autistic phenotypes.
KW  - permutation
KW  - miR-181
KW  - PGAS
KW  - FXR2
KW  - FXR1
KW  - FMR2
KW  - FMR1
KW  - identification
KW  - protein
KW  - fraxe mental retardation
KW  - CGG repeat
KW  - CPG Island
KW  - schizophrenia
KW  - expression
KW  - males
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-136893
VL  - 7
IS  - 12
ER  -