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Aktuellste Publikationen

Cell Signal. 2018 Mar 30;47:101-108. doi: 10.1016/j.cellsig.2018.03.015. [Epub ahead of print]

α-cyano-4-hydroxycinnamate impairs pancreatic cancer cells by stimulating the p38 signaling pathway.

Abstract

Multiple studies are currently targeting dysregulated cancer cell metabolism with distinct combinations of inhibitors. In this study, we evaluated in pancreatic cancer cells metformin, which blocks oxidative phosphorylation, in combination with α-cyano-4-hydroxycinnamate, which has been reported to inhibit the export of lactate from the cytosol. The combination of metformin with α-cyano-4-hydroxycinnamate had a major inhibitory effect on the migration of 6606PDA cells. Monotherapy with α-cyano-4-hydroxycinnamate and especially the combination with metformin also caused significant inhibition of cell proliferation and induced cell death. α-cyano-4-hydroxycinnamate in combination with metformin reduced the export of lactate significantly, whereas α-cyano-4-hydroxycinnamate monotherapy only modestly influenced lactate export. None of these two drugs inhibited the expression of distinct glycolytic enzymes. Interestingly, α-cyano-4-hydroxycinnamate rather inhibited the ERK and very strongly stimulated the p38 signaling pathway in 6606PDA as well as in 7265PDA cells. In addition, the inhibition of the p38 signaling pathway by PH-797804 partially reversed the effect of α-cyano-4-hydroxycinnamate on cell apoptosis in both cell lines. We conclude that α-cyano-4-hydroxycinnamate monotherapy and especially the combinatorial therapy with metformin has strong anti-cancerous effects. α-cyano-4-hydroxycinnamate causes cancer cell apoptosis by a novel mechanism for this drug, namely the stimulation of the p38 signaling pathway.


nt J Mol Sci. 2018 Mar 24;19(4). pii: E972. doi: 10.3390/ijms19040972.

Evaluation of Two Liver Treatment Strategies in a Mouse Model of Niemann-Pick-Disease Type C1.

Abstract

Niemann-Pick-disease type C1 (NPC1) is an autosomal-recessive cholesterol-storage disorder. Besides other symptoms, NPC1 patients develop liver dysfunction and hepatosplenomegaly. The mechanisms of hepatomegaly and alterations of lipid metabolism-related genes in NPC1 disease are still poorly understood. Here, we used an NPC1 mouse model to study an additive hepatoprotective effect of a combination of 2-hydroxypropyl-β-cyclodextrin (HPβCD), miglustat and allopregnanolone (combination therapy) with the previously established monotherapy using HPβCD. We examined transgene effects as well as treatment effects on liver morphology and hepatic lipid metabolism, focusing on hepatic cholesterol transporter genes. Livers of Npc1-/- mice showed hepatic cholesterol sequestration with consecutive liver injury, an increase of lipogenetic gene expression, e.g., HMG-CoA, a decrease of lipolytic gene expression, e.g., pparα and acox1, and a decrease of lipid transporter gene expression, e.g., acat1, abca1 and fatp2. Both, combination therapy and monotherapy, led to a reduction of hepatic lipids and an amelioration of NPC1 liver disease symptoms. Monotherapy effects were related to pparα- and acox1-associated lipolysis/β-oxidation and to fatp2-induced fatty acid transport, whereas the combination therapy additionally increased the cholesterol transport via abca1 and apoE. However, HPβCD monotherapy additionally increased cholesterol synthesis as indicated by a marked increase of the HMG-CoA and srebp-2 mRNA expression, probably as a result of increased hepatocellular proliferation.

KEYWORDS:

NPC1 mutant; allopregnanolone; cyclodextrin; liver dysfunction; miglustat


Sci Rep. 2018 Jan 24;8(1):1529. doi: 10.1038/s41598-018-19547-z.

Young and healthy C57BL/6 J mice performing sprint interval training reveal gender- and site-specific changes to the cortical bone.

Abstract

Physical exercise is considered to impede the bone loss associated with physiological ageing however, a training program that efficiently leads to bone accrual in the healthy does not yet exist. We turned to the C57BL/6 J mouse and designed a sprint interval training for treadmill that was tailored to the individual performance limits. It consisted of four weeks with five training sessions each, followed by another four weeks with three. After completion of the training period, mice were sacrificed and the hind legs were analyzed via µCT and MRI for changes in bone parameters and muscle volume, respectively. Increased performance limits in both sexes confirmed an effect of the treadmill training. However, while male tibiae after eight weeks revealed a significant reduction of cortical bone mass at the distal metaphysis, the cross sectional analysis of female tibiae showed a transient decrease of cortical bone mass after four weeks that was reversed into a significant accrual after eight weeks of training and occurred over the entire length of the tibia. The observed net reduction of female bone mass after four weeks of training is suggestive of a remodelling process which may be delayed in the males.