Gene/Protein Disease Symptom Drug Enzyme Compound
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To evaluate the participation of mitochondrial damage, oxygen radicals and cell death in diabetes mellitus, we designed a way to investigate INS-1 cells, rat pancreatic beta-cell line, to die by treatment with alloxan which generate reactive oxygen species (ROS). Incubation of INS-1 cells with alloxan for 24 h resulted in a decrease in viability of cells as well as inhibition of glucose-stimulated insulin release; this could be prevented by antioxidants, vitamin E and butylated hydroxyanisol (BHA). The formation of a DNA ladder and the distribution of phosphatidylserine at the external surface of plasma membrane were observed as indicators of apoptosis in the cells treated with alloxan at concentrations below 0.5 mM. The formation of DNA ladder was prevented by vitamin E, BHA and catalase, suggesting that the ROS is involved in the process of apoptosis in INS-1 cells treated with alloxan. Lower levels of intracellular ATP, collapse of mitochondrial membrane potential and release of cytochrome c from mitochondria were also observed in INS-1 cells treated with alloxan, suggesting that alloxan caused the damage of mitochondria in cells and was related to the process of apoptosis. In contrast, rat liver RLC-18 cells treated with alloxan were not observed in the decrease of viability. It follows from the present study that mitochondrial damages by ROS generated from alloxan is linked to apoptosis in INS-1 cells.
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PMID:Apoptosis and mitochondrial damage in INS-1 cells treated with alloxan. 1151 Apr 77

Mitochondrial production of reactive oxygen species and oxidation of cardiolipin are key events in initiating apoptosis. We reported that group VIA Ca(2+)-independent phospholipase A(2) (iPLA(2)beta) localizes in and protects beta-cell mitochondria from oxidative damage during staurosporine-induced apoptosis. Here, we used iPLA(2)beta-null (iPLA(2)beta(-/-)) mice to investigate the role of iPLA(2)beta in the repair of mitochondrial membranes. We show that islets isolated from iPLA(2)beta(-/-) mice are more sensitive to staurosporine-induced apoptosis than those from wild-type littermates and that 2 wk of daily ip administration of staurosporine to iPLA(2)beta(-/-) mice impairs both the animals' glucose tolerance and glucose-stimulated insulin secretion by their pancreatic islets. Moreover, the iPLA(2)beta inhibitor bromoenol lactone caused mitochondrial membrane peroxidation and cytochrome c release, and these effects were reversed by N-acetyl cysteine. The mitochondrial antioxidant N-t-butyl hydroxylamine blocked staurosporine-induced cytochrome c release and caspase-3 activation in iPLA(2)beta(-/-) islets. Furthermore, the collapse of mitochondrial membrane potential in INS-1 insulinoma cells caused by high glucose and fatty acid levels was attenuated by overexpressing iPLA(2)beta. Interestingly, iPLA(2)beta was expressed only at low levels in islet beta-cells from obesity- and diabetes-prone db/db mice. These findings support the hypothesis that iPLA(2)beta is important in repairing oxidized mitochondrial membrane components (e.g. cardiolipin) and that this prevents cytochrome c release in response to stimuli that otherwise induce apoptosis. The low iPLA(2)beta expression level in db/db mouse beta-cells may render them vulnerable to injury by reactive oxygen species.
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PMID:Protection of pancreatic beta-cells by group VIA phospholipase A(2)-mediated repair of mitochondrial membrane peroxidation. 2046 52

Mono(2-ethylhexyl) phthalate (MEHP) is the main metabolite of di(2-ethylhexyl) phthalate (DEHP) in organisms and is commonly used as a plasticizer. Exposure to DEHP impairs the function of islet beta cells (INS-1 cells), which is related to insulin resistance and type 2 diabetes. At present, some research data have also confirmed that MEHP has a certain damage effect on INS-1 cells. In our experiment, we found that MEHP would lead to the increase of reactive oxygen species (ROS) and the upregulation of autophagy. And downregulated ROS production by N-acetyl-L-cysteine could also reduce autophagy. In addition, MEHP-induced lysosomal membrane permeability (LMP) subsequently released cathepsin D. Additionally, MEHP induced the collapse of mitochondrial transmembrane potential and release of cytochrome c. Addition of autophagy inhibitor 3-methyladenine relieved MEHP-induced apoptosis as assessed by the expression of cleaved caspase 3, cleaved caspase 9, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay, indicating that MEHP-induced apoptosis was autophagy dependent. Cathepsin D inhibitor, pepstatin A, suppressed MEHP-induced mitochondria release of cytochrome c and apoptosis as well. Meanwhile, pyrroloquinoline quinone (PQQ), a new B vitamin, improved the above phenomenon. Taken together, our results indicate that MEHP induces autophagy-dependent apoptosis in INS-1 cells by lysosomal-mitochondrial axis. PQQ improved this process by downregulating ROS and provided a degree of protection. Our study provides a new perspective for MEHP on the cytotoxic mechanism and PQQ protection in INS-1 cells.
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PMID:Pyrroloquinoline quinone protected autophagy-dependent apoptosis induced by mono(2-ethylhexyl) phthalate in INS-1 cells. 3166 91