Decrease In Lysosomal Stability Research Articles

Diversity of the molecular responses to separate wastewater effluents in freshwater mussels

The environmental safety of pharmaceutical and personal care products (PPCPs) requires a crucial examination. The aim of this study was to evaluate the responses of biomarkers of stress and toxicity in freshwater mussels to the effect of commonly found PPCPs in wastewater. We treated male mussels Unio tumidus, from an undisturbed site with ibuprofen (IBU, 250ngL−1), triclosan (TCS, 500ngL−1), or estrone (E1, 100ngL−1) for 14days. Untreated mussels from this site (C) and mussels inhabiting a polluted area (P) were also examined after a similar time of being kept in the laboratory. The consequences of chronic exposure of the mussels in the P-group were reflected in elevated concentrations of oxyradicals (1.4 times), oxidized glutathione (4.3 times), lipofuscin (2.2 times), and DNA-strand breaks in the digestive gland (DG) in comparison to the C-group, higher levels of caspase-3 activity in the DG, and vitellogenin-like proteins in gonads among all studied groups. Exposed mussels demonstrated some common responses with mussels in the P-group: elevated levels of lactate/pyruvate ratio, lipofuscin (IBU and E1), DNA fragmentation (TCS and E1), and caspase-3 activity (TCS and E1). Exposed to PPCPs mussels also showed elevation of ethoxyresorufin-O-deethylase and/or glutathione-S-transferase activity in the DG and a decrease in lysosomal stability in hemocytes (TCS and E1). The TCS group was distinguished by having the highest level of DNA-fragmentation and the lowest concentrations of total glutathione, oxyradicals, lipofuscin, pyruvate, and lactate, reflecting total metabolic depression. These results show that selected PPCPs at low concentrations alter a variety of physiological processes in this animal model system.

Hsp70 stabilizes lysosomes and reverts Niemann–Pick disease-associated lysosomal pathology

Heat shock protein 70 (Hsp70) is an evolutionarily highly conserved molecular chaperone that promotes the survival of stressed cells by inhibiting lysosomal membrane permeabilization, a hallmark of stress-induced cell death. Clues to its molecular mechanism of action may lay in the recently reported stress- and cancer-associated translocation of a small portion of Hsp70 to the lysosomal compartment. Here we show that Hsp70 stabilizes lysosomes by binding to an endolysosomal anionic phospholipid bis(monoacylglycero)phosphate (BMP), an essential co-factor for lysosomal sphingomyelin metabolism. In acidic environments Hsp70 binds with high affinity and specificity to BMP, thereby facilitating the BMP binding and activity of acid sphingomyelinase (ASM). The inhibition of the Hsp70-BMP interaction by BMP antibodies or a point mutation in Hsp70 (Trp90Phe), as well as the pharmacological and genetic inhibition of ASM, effectively revert the Hsp70-mediated stabilization of lysosomes. Notably, the reduced ASM activity in cells from patients with Niemann-Pick disease (NPD) A and B-severe lysosomal storage disorders caused by mutations in the sphingomyelin phosphodiesterase 1 gene (SMPD1) encoding for ASM-is also associated with a marked decrease in lysosomal stability, and this phenotype can be effectively corrected by treatment with recombinant Hsp70. Taken together, these data open exciting possibilities for the development of new treatments for lysosomal storage disorders and cancer with compounds that enter the lysosomal lumen by the endocytic delivery pathway.

Effect of exercise, hypoxia, and epinephrine on lysosomes and plasma enzymes

In order to study the possible relation of hepatic lysosomal stability and enzyme release from the liver during stress, rats were sacrificed after swimming exercise, hypoxia, and epinephrine injections. Each of the stresses caused a decrease in hepatic lysosomal stability, an increase in plasma ornithine carbamoyltransferase (OCT), a liver specific enzyme, and increases in plasma creatine phosphokinase (CPK) and aspartate aminotransferase (AAT). With exercise, the decrease in lysosomal stability and the increase in OCT were first seen at one hour. The OCT increase preceded the lysosomal changes after hypoxia and followed the lysosomal changes after epinephrine injection. Prednisolone reduced the lysosomal and CPK (but not the OCT and AAT) changes with exercise, but had no effect with hypoxia or epinephrine injections. Adrenalectomy delayed the lysosomal changes and eliminated the increase in OCT after hypoxia and epinephrine. The varying time sequence of hepatic lysosomal changes and enzyme release with these stresses suggests that these two phenomena are not causally related.

Nutrition and lysosomal activity. The influence of vitamin E deficiency and its duration on the stability of lysosomes in the kidneys of rats.

1. Experiments on rats were made to find whether the increased liability of the kidney-cortex tubules to autolysis post mortem, which is a well-established abnormality in vitamin E deficiency, can be correlated with changes in lysosomal activity. Parallel observations were made on the development of certain other abnormalities characteristic of avitaminosis E. 2. In rats killed after long periods (8-10 months) of subsistence on a standard vitamin E-deficient diet, containing lard, both the rate of kidney autolysis post mortem and the enzyme activity of lysosome preparations from the fresh tissues were much greater than in controls. A greater percentage difference was usually found in the ;free' enzyme fraction than in ;bound' or ;total' activity. 3. In rats killed after graded periods (3-8 months) of deficiency, two abnormalities (decreased resistance of the erythrocytes to haemolysis, and brown discoloration of the uterus) were already evident at a stage (3-4 months) when the liability to rapid kidney autolysis had not begun. At this point the enzymic activity of kidney extracts differed little between deficient animals and controls given alpha-tocopherol. As the duration of deficiency advanced, parallel increases occurred in the rate of kidney autolysis and in lysosomal instability. 4. When cod-liver oil, rich in polyunsaturated fatty acids but freed from vitamin A, was substituted for lard in the diet, the time (1(1/2) months) required for the inducement of both rapid kidney autolysis and decreased lysosomal stability was greatly shortened. The time for the inducement of brown discoloration of the uterus was not shortened and the kidney abnormalities appeared while the uterus was still normal. 5. Confirmation was thus obtained for the view that the various tissues of the rat respond differently to the relationship between the adequacy of the vitamin E status and the intake of polyunsaturated fatty acids. The kidney-cortex tubules, as evidenced by autolysis post mortem and the corresponding decrease in lysosomal stability, may be classed among those tissues that are most sensitive to the effect of high intakes of polyunsaturated acids.