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Increased Intracellular Accumulation (increased + intracellular_accumulation)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Microglial glutamate uptake is coupled to glutathione synthesis and glutamate release

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 4 2006
Mikael Persson
Abstract The physiological function of microglial glutamate uptake has been debated as it is about 10% of that measured for astrocytes. This study addresses how glutamate, taken up from the extracellular space, is utilized by microglia. It was found that purified rat microglia incubated for 60 min with 3H-glutamate had an increased intracellular accumulation of 3H-glutamate after 12 h incubation with tumour necrosis factor alpha (TNF-,) but not after incubation with lipopolysaccharide (LPS). Furthermore, LPS- but not TNF-,-treated cells showed an increased efflux of 3H-labelled compounds, presumably glutamate through the XC, system and treatment with LPS or TNF-, increased the microglial glutathione concentrations and led to an increased incorporation of 3H-glutamate into glutathione. Depending on the stimuli, 3,6% of the total labelled contents were found in the form of glutathione and 25,35% in the form of glutamate. These results show that microglial glutamate uptake is directly coupled to glutathione synthesis and release of glutamate and/or glutamate metabolites. Additionally, the increased glutathione contents after LPS or TNF-, treatment were able to reduce microglial cell death after H2O2 challenge, showing a potential (self)-protective function for microglial glutamate transporter expression and glutathione synthesis. [source]

The dual EGFR/HER-2 tyrosine kinase inhibitor lapatinib sensitizes colon and gastric cancer cells to the irinotecan active metabolite SN-38

INTERNATIONAL JOURNAL OF CANCER, Issue 12 2009
Melissa J. LaBonte
Abstract Members of the human epidermal receptor (HER) family are frequently associated with aggressive disease and poor prognosis in multiple malignancies. Lapatinib is a dual tyrosine kinase inhibitor targeting the epidermal growth factor receptor (EGFR) and HER-2. This study evaluated the therapeutic potential of lapatinib, alone and in combination with SN-38, the active metabolite of irinotecan (CPT-11), in colon and gastric cancer cell lines. Concentration-dependent antiproliferative effects of both lapatinib and SN-38 were observed in all colon and gastric cancer cell lines tested but varied significantly between individual cell lines (lapatinib range 0.08,11.7 ,M; SN-38 range 3.6,256 nM). Lapatinib potently inhibited the growth of a HER-2 overexpressing gastric cancer cell line and demonstrated moderate activity in gastric and colon cancer cells with detectable HER-2 expression. The combination of lapatinib and SN-38 interacted synergistically to inhibit cell proliferation in all colon and gastric cancer cell lines tested. Cotreatment with lapatinib and SN-38 also resulted in enhanced cell cycle arrest and the induction of apoptosis with subsequent cellular pharmacokinetic analysis demonstrating that lapatinib promoted the increased intracellular accumulation and retention of SN-38 when compared to SN-38 treatment alone. Finally, the combination of lapatinib and CPT-11 demonstrated synergistic antitumor efficacy in the LoVo colon cancer mouse xenograft model with no apparent increase in toxicity compared to CPT-11 monotherapy. These results provide compelling preclinical rationale indicating lapatinib to be a potentially efficacious chemotherapeutic combination partner for irinotecan in the treatment of gastrointestinal carcinomas. © 2009 UICC [source]

Neuroprotective effects of Triticum aestivum L. against ,-Amyloid-induced cell death and memory impairments

PHYTOTHERAPY RESEARCH, Issue 1 2010
Jung-Hee Jang
Abstract ,-Amyloid (A,) is a key component of senile plaques, neuropathological hallmarks of Alzheimer's disease (AD) and has been reported to induce cell death via oxidative stress. This study investigated the protective effects of Triticum aestivum L. (TAL) on A,-induced apoptosis in SH-SY5Y cells and cognitive dysfunctions in Sprague-Dawley (SD) rats. Cells treated with A, exhibited decreased viability and apoptotic features, such as DNA fragmentation, alterations in mitochondria and an increased Bax/Bcl-2 ratio, which were attenuated by TAL extract (TALE) pretreatment. To elucidate the neuroprotective mechanisms of TALE, the study examined A,-induced oxidative stress and cellular defense. TALE pretreatment suppressed A,-increased intracellular accumulation of reactive oxygen species (ROS) via up-regulation of glutathione, an essential endogenous antioxidant. To further verify the effect of TALE on memory impairments, A, or scopolamine was injected in SD rats and a water maze task conducted as a spatial memory test. A, or scopolamine treatment increased the time taken to find the platform during training trials, which was decreased by TALE pretreatment. Furthermore, one of the active components of TALE, total dietary fiber also effectively inhibited A,-induced cytotoxicity and scopolamine-caused memory deficits. These results suggest that TALE may have preventive and/or therapeutic potential in the management of AD. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Alsin/Rac1 signaling controls survival and growth of spinal motoneurons

ANNALS OF NEUROLOGY, Issue 1 2006
Arnaud Jacquier MSc
Objective Recessive mutations in alsin, a guanine-nucleotide exchange factor for the GTPases Rab5 and Rac1, cause juvenile amyotrophic lateral sclerosis (ALS2) and related motoneuron disorders. Alsin function in motoneurons remained unclear because alsin knock-out mice do not develop overt signs of motoneuron degeneration. Methods To generate an alsin loss-of-function model in an ALS-relevant cell type, we developed a new small interfering RNA electroporation technique that allows efficient knock down of alsin in embryonic rat spinal motoneurons. Results After small interfering RNA,mediated alsin knockdown, cultured motoneurons displayed a reduced apparent size of EEA1-labeled early endosomes and an increased intracellular accumulation of transferrin and L1CAM. Alsin knockdown induced cell death in 32 to 48% of motoneurons and significantly inhibited axon growth in the surviving neurons. Both cellular phenotypes were mimicked by expression of a dominant-negative Rac1 mutant and were completely blocked by expression of a constitutively active Rac1 mutant. Expression of dominant-negative or constitutively active forms of Rab5 had no such effects. Interpretation Our data demonstrate that alsin controls the growth and survival of motoneurons in a Rac1-dependant manner. The strategy reported here illustrates how small interfering RNA electroporation can be used to generate cellular models of neurodegenerative disease involving a loss-of-function mechanism. Ann Neurol 2006;60:105,117 [source]