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H.Z. Malina, B. Frueh; Xanthurenic Acid-induced Cell Apopptosis, Actin Polymerization, and Unfolded Prion Protein Formation in Retinal Astrocytes . Invest. Ophthalmol. Vis. Sci. 2003;44(13):4557.
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Purpose: Xanthurenic acid is an endogenous substance formed upon tryptophan degradation. We have reported that xanthurenic acid leads to induction of caspase-9, -8, and -3 (www.BioMedCentral.com) Here, we report that xanthurenic acid, in the concentration-dependent manner, induces apoptotic cell death and drives a new post-apoptotic process of proteins polymerization. Methods: The present studies were performed in human primary cells cultures of retinal astrocytes. Western blots analysis, immuno-fluorescence, and confocal microscopy were used. Results: In the presence of 10 micromoles xanthurenic acid cytochrome c was released from mitochondria. The cytochrome c-release was associated with a translocation of BH3-proteins (Bad, Bid, Bax, Bak) into mitochondria. At 20 micromoles of xanthurenic acid cytochrome c was not released, but AIF was translocated into nucleus. The apoptosis was associated with gelsolin cleavage, which did not lead to actin severing and capping. We observed F-actin cytoskeleton elongation, G-actin anarchic polymerization, and strong staining of the post-mortem cytoskeleton with antibody against N-half of gelsolin. Aggregates of prion protein were detected using specific antibody. Conclusion: In conclusion, xanthurenic acid induces the apoptosis-like cell death. The cell death is not an end of the process, but a begin of pathological process leading to protein polymerization and unfolded proteins aggregation. The mechanism is observed in the development of the aging associated diseases like atherosclerosis, retinal degeneration, senile cataract, Alzheimer’s, and prion diseases. Acknowledgements This work was supported by grant awarded to H. Z. M. by Swiss National Foundation (32-59183.99), and MSE Pharmazeutika GMBH (Bad Homburg, Germany).
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