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Inhibitor Cyclosporin (inhibitor + cyclosporin)

Distribution by Scientific Domains

Life Sciences	100%

Selected Abstracts

Cyclophilin D links programmed cell death and organismal aging in Podospora anserina

AGING CELL, Issue 5 2010
Diana Brust
Summary Cyclophilin D (CYPD) is a mitochondrial peptidyl prolyl- cis,trans -isomerase involved in opening of the mitochondrial permeability transition pore (mPTP). CYPD abundance increases during aging in mammalian tissues and in the aging model organism Podospora anserina. Here, we show that treatment of the P. anserina wild-type with low concentrations of the cyclophilin inhibitor cyclosporin A (CSA) extends lifespan. Transgenic strains overexpressing PaCypD are characterized by reduced stress tolerance, suffer from pronounced mitochondrial dysfunction and are characterized by accelerated aging and induction of cell death. Treatment with CSA leads to correction of mitochondrial function and lifespan to that of the wild-type. In contrast, PaCypD deletion strains are not affected by CSA within the investigated concentration range and show increased resistance against inducers of oxidative stress and cell death. Our data provide a mechanistic link between programmed cell death (PCD) and organismal aging and bear implications for the potential use of CSA to intervene into biologic aging. [source]

Mitochondrial morphology transition is an early indicator of subsequent cell death in Arabidopsis

NEW PHYTOLOGIST, Issue 1 2008
Iain Scott
Summary ,,Mitochondrial morphology and dynamics were investigated during the onset of cell death in Arabidopsis thaliana. Cell death was induced by either chemical (reactive oxygen species (ROS)) or physical (heat) shock. ,,Changes in mitochondrial morphology in leaf tissue, or isolated protoplasts, each expressing mitochondrial-targeted green fluorescent protein (GFP), were observed by epifluorescence microscopy, and quantified. ,,Chemical induction of ROS production, or a mild heat shock, caused a rapid and consistent change in mitochondrial morphology (termed the mitochondrial morphology transition) that preceded cell death. Treatment of protoplasts with a cell-permeable superoxide dismutase analogue, TEMPOL, blocked this morphology change. Incubation of protoplasts in micromolar concentrations of the calcium channel-blocker lanthanum chloride, or the permeability transition pore inhibitor cyclosporin A, prevented both the mitochondrial morphology transition and subsequent cell death. ,,It is concluded that the observed mitochondrial morphology transition is an early and specific indicator of cell death and is a necessary component of the cell death process. [source]

Characteristics and function of cardiac mitochondrial nitric oxide synthase

THE JOURNAL OF PHYSIOLOGY, Issue 4 2009
Elena N. Dedkova
We used laser scanning confocal microscopy in combination with the nitric oxide (NO)-sensitive fluorescent dye DAF-2 and the reactive oxygen species (ROS)-sensitive dyes CM-H2DCF and MitoSOX Red to characterize NO and ROS production by mitochondrial NO synthase (mtNOS) in permeabilized cat ventricular myocytes. Stimulation of mitochondrial Ca2+ uptake by exposure to different cytoplasmic Ca2+ concentrations ([Ca2+]i= 1, 2 and 5 ,m) resulted in a dose-dependent increase of NO production by mitochondria when l -arginine, a substrate for mtNOS, was present. Collapsing the mitochondrial membrane potential with the protonophore FCCP or blocking the mitochondrial Ca2+ uniporter with Ru360 as well as blocking the respiratory chain with rotenone or antimycin A in combination with oligomycin inhibited mitochondrial NO production. In the absence of l -arginine, mitochondrial NO production during stimulation of Ca2+ uptake was significantly decreased, but accompanied by increase in mitochondrial ROS production. Inhibition of mitochondrial arginase to limit l -arginine availability resulted in 50% inhibition of Ca2+ -induced ROS production. Both mitochondrial NO and ROS production were blocked by the nNOS inhibitor (4S)- N -(4-amino-5[aminoethyl]aminopentyl)- N,-nitroguanidine and the calmodulin antagonist W-7, while the eNOS inhibitor l - N5 -(1-iminoethyl)ornithine (l -NIO) or iNOS inhibitor N -(3-aminomethyl)benzylacetamidine, 2HCl (1400W) had no effect. The superoxide dismutase mimetic and peroxynitrite scavenger MnTBAP abolished Ca2+ -induced ROS generation and increased NO production threefold, suggesting that in the absence of MnTBAP either formation of superoxide radicals suppressed NO production or part of the formed NO was transformed quickly to peroxynitrite. In the absence of l -arginine, mitochondrial Ca2+ uptake induced opening of the mitochondrial permeability transition pore (PTP), which was blocked by the PTP inhibitor cyclosporin A and MnTBAP, and reversed by l -arginine supplementation. In the presence of the mtNOS cofactor (6R)-5,6,7,8,-tetrahydrobiopterin (BH4; 100 ,m) mitochondrial ROS generation and PTP opening decreased while mitochondrial NO generation slightly increased. These data demonstrate that mitochondrial Ca2+ uptake activates mtNOS and leads to NO-mediated protection against opening of the mitochondrial PTP, provided sufficient availability of l -arginine and BH4. In conclusion, our data show the importance of l -arginine and BH4 for cardioprotection via regulation of mitochondrial oxidative stress and modulation of PTP opening by mtNOS. [source]

Nordihydroguaiaretic acid induces astroglial death via glutathione depletion

JOURNAL OF NEUROSCIENCE RESEARCH, Issue 14 2007
Joo-Young Im
Abstract Nordihydroguaiaretic acid (NDGA) is known to cause cell death in certain cell types that is independent of its activity as a lipoxygenase inhibitor; however, the underlying mechanisms are not fully understood. In the present study, we examined the cellular responses of cultured primary astroglia to NDGA treatment. Continuous treatment of primary astroglia with 30 ,M NDGA caused >85% cell death within 24 hr. Cotreatment with the lipoxygenase products 5-HETE, 12-HETE, and 15-HETE did not override the cytotoxic effects of NDGA. In assays employing the mitochondrial membrane potential-sensitive dye JC-1, NDGA was found to induce a rapid and almost complete loss of mitochondrial membrane potential. However, the mitochondrial permeability transition pore inhibitors cyclosporin A and bongkrekic acid did not block NDGA-induced astroglial death. We found that treatment with N-acetyl cysteine (NAC), glutathione (GSH), and GSH ethyl ester (GSH-EE) did inhibit NDGA-induced astroglial death. Consistently, NDGA-induced astroglial death proceeded in parallel with intracellular GSH depletion. Pretreatment with GSH-EE and NAC did not block NDGA-induced mitochondrial membrane potential loss, and there was no evidence that reactive oxygen species (ROS) production was involved in NDGA-induced astroglial death. Together, these results suggest that NDGA-induced astroglial death occurs via a mechanism that involves GSH depletion independent of lipoxygenase activity inhibition and ROS stress. © 2007 Wiley-Liss, Inc. [source]