31 research outputs found
Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells
Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood.
As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in
many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism.
However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides
are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many
diseases, such as Alzheimer’s disease, cancer, fatty liver disease and type-2 diabetes, treatment with
gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also
affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently
analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase
in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the
decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common
intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting
that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria
and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which
could be important in diseases, such as Alzheimer’s disease
Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer’s Disease
Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin
D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more
than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D
hypovitaminosis is associated with many diseases, such as Alzheimer’s disease (AD), vitamin D
supplementation seems to be particularly useful for this vulnerable age population. Importantly, in
addition to vitamin D, several analogues are known and used for different medical purposes. These
vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D
receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the
commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol,
and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential
effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are
summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and
is commonly represented in the elderly population. It is usually caused by extracellular accumulation
of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of
intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the
pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D
supply and discusses the specifics of administering various vitamin D analogues compared with
vitamin D in geriatric patients, especially those suffering from AD
Aspartame and Its Metabolites Cause Oxidative Stress and Mitochondrial and Lipid Alterations in SH-SY5Y Cells
Due to a worldwide increase in obesity and metabolic disorders such as type 2 diabetes,
synthetic sweeteners such as aspartame are frequently used to substitute sugar in the diet. Possible
uncertainties regarding aspartame’s ability to induce oxidative stress, amongst others, has led to the
recommendation of a daily maximum dose of 40 to 50 mg per kg. To date, little is known about the
effects of this non-nutritive sweetener on cellular lipid homeostasis, which, besides elevated oxidative
stress, plays an important role in the pathogenesis of various diseases, including neurodegenerative
diseases such as Alzheimer’s disease. In the present study, treatment of the human neuroblastoma
cell line SH-SY5Y with aspartame (271.7 µM) or its three metabolites (aspartic acid, phenylalanine,
and methanol (271.7 µM)), generated after digestion of aspartame in the human intestinal tract,
resulted in significantly elevated oxidative stress associated with mitochondrial damage, which was
illustrated with reduced cardiolipin levels, increased gene expression of SOD1/2, PINK1, and FIS1,
and an increase in APF fluorescence. In addition, treatment of SH-SY5Y cells with aspartame or
aspartame metabolites led to a significant increase in triacylglycerides and phospholipids, especially
phosphatidylcholines and phosphatidylethanolamines, accompanied by an accumulation of lipid
droplets inside neuronal cells. Due to these lipid-mediating properties, the use of aspartame as a
sugar substitute should be reconsidered and the effects of aspartame on the brain metabolism should
be addressed in vivo
Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells
Oxidative stress is closely linked to Alzheimer’s disease (AD), and is detected peripherally
as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between
the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of
proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD
brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide,
as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether
bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the
neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine,
phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2
)-induced oxidative stress due to an elevated expression of the
ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12
elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase
(AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2
-induced
oxidative stress
Mono- versus polyaxial locking plates in distal femur fractures – a biomechanical comparison of the Non-Contact-Bridging- (NCB) and the PERILOC-plate
Molecular marks for epigenetic identification of developmental and cancer stem cells
Epigenetic regulations of genes by reversible methylation of DNA (at the carbon-5 of cytosine) and numerous reversible modifications of histones play important roles in normal physiology and development, and epigenetic deregulations are associated with developmental disorders and various disease states, including cancer. Stem cells have the capacity to self-renew indefinitely. Similar to stem cells, some malignant cells have the capacity to divide indefinitely and are referred to as cancer stem cells. In recent times, direct correlation between epigenetic modifications and reprogramming of stem cell and cancer stem cell is emerging. Major discoveries were made with investigations on reprogramming gene products, also known as master regulators of totipotency and inducer of pluoripotency, namely, OCT4, NANOG, cMYC, SOX2, Klf4, and LIN28. The challenge to induce pluripotency is the insertion of four reprogramming genes (Oct4, Sox2, Klf4, and c-Myc) into the genome. There are always risks of silencing of these genes by epigenetic modifications in the host cells, particularly, when introduced through retroviral techniques. In this contribution, we will discuss some of the major discoveries on epigenetic modifications within the chromatin of various genes associated with cancer progression and cancer stem cells in comparison to normal development of stem cell. These modifications may be considered as molecular signatures for predicting disorders of development and for identifying disease states