Biomedical subjects

Jesus A Velho

Publications and source records attributed to Jesus A Velho.

4 recordsLinked to original sources

PubMed2006

Role of mitochondria in the immune response to cancer: a central role for Ca2+.

This study demonstrates that Ca2+ stimulates mitochondrial energy metabolism during spleen lymphocyte activation in response to the ascitic Walker 256 tumor in rats. Intracellular Ca2+ concentrations, phosphorylated protein kinase C (pPKC) levels, Bcl-2 protein contents, interleukin-2 (IL-2) levels, mitochondrial uncoupling protein-2 (UCP-2) contents and reactive oxygen species (ROS) were significantly elevated in these activated lymphocytes. Mitochondria of activated lymphocytes exhibited high free Ca2+ concentrations in the matrix and enhanced oligomycin-sensitive oxygen consumption, indicating an increased rate of oxidative phosphorylation. The production of ROS was largely decreased by diphenylene iodinium in the activated lymphocytes, suggesting that NADPH oxidase is the prevalent source of these species. Accumulation of UCP-2 and the anti-apoptotic protein Bcl-2 is probably important to prevent mitochondrial dysfunction and cell death elicited by the sustained high levels of intracellular Ca2+ and ROS and may explain the observed higher resistance from activated lymphocytes against the opening of the mitochondrial membrane permeability pore (MPT). All these changes were blocked by pretreatment of the rats with verapamil, an L-type Ca2+ channel antagonist. These data demonstrate a central role of Ca2+ in the control of mitochondrial bioenergetics in spleen lymphocytes during the immune response to cancer.

Animals↗

PubMed2005

Statins induce calcium-dependent mitochondrial permeability transition.

Statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) are used in the treatment of hypercholesterolemic patients to reduce risk of cardiovascular diseases because of their cholesterol lowering action. Other lipid independent protective actions of statins have been reported. However, some adverse side effects have, also, been described. We report, here, that liver mitochondria isolated from hypercholesterolemic LDL receptor knockout mice treated during 15 days with therapeutic doses (100 mg/kg, p.o.) of lovastatin presented a higher susceptibility to develop membrane permeability transition (MPT). In experiments in vitro, lovastatin-induced MPT in a dose-dependent manner (10-80 microM) by a mechanism sensitive to cyclosporin A (cyclophilin sequestrant), dithiothreitol (reducing agent), adenine nucleotide carrier inhibitor (ADP), catalase (H2O2 reductant) and EGTA (calcium chelator). In agreement with the inhibition of the mitochondrial swelling by dithiothreitol, lovastatin, also, decreased the content of total mitochondrial membrane protein thiol groups. Simvastatin had similar effects on mitochondria; however, pravastatin, a hydrophilic statin, had a weaker effect in inducing MPT. In conclusion, statins can act directly on mitochondria either in vivo or in vitro inducing permeability transition, which is a process involved in cell death.

Adenosine Diphosphate↗

PubMed2005

Iron complexing activity of mangiferin, a naturally occurring glucosylxanthone, inhibits mitochondrial lipid peroxidation induced by Fe2+-citrate.

Mangiferin, a naturally occurring glucosylxanthone, has been described as having antidiabetic, antiproliferative, immunomodulatory and antioxidant activities. In this study we report for the first time the iron-complexing ability of mangiferin as a primary mechanism for protection of rat liver mitochondria against Fe(2+)-citrate induced lipid peroxidation. Thiobarbituric acid reactive substances and antimycin A-insensitive oxygen consumption were used as quantitative measures of lipid peroxidation. Mangiferin at 10 microM induced near-full protection against 50 microM Fe(2+)-citrate-induced mitochondrial swelling and loss of mitochondrial transmembrane potential (DeltaPsi). The IC(50) value for mangiferin protection against Fe(2+)-citrate-induced mitochondrial thiobarbituric acid reactive substance formation (9.02+/-1.12 microM) was around 10 times lower than that for tert-butylhydroperoxide mitochondrial induction of thiobarbituric acid reactive substance formation. The xanthone derivative also inhibited the iron citrate induction of mitochondrial antimycin A-insensitive oxygen consumption, stimulated oxygen consumption due to Fe(2+) autoxidation and prevented Fe(3+) ascorbate reduction. Absorption spectra of mangiferin-Fe(2+)/Fe(3+) complexes also suggest the formation of a transient charge transfer complex between Fe(2+) and mangiferin, accelerating Fe(2+) oxidation and the formation of a more stable Fe(3+)-mangiferin complex unable to participate in Fenton-type reaction and lipid peroxidation propagation phase. In conclusion, these results show that in vitro antioxidant activity of mangiferin is related to its iron-chelating properties and not merely due to the scavenging activity of free radicals. These results are of pharmacological relevance since mangiferin and its naturally contained extracts could be potential candidates for chelation therapy in diseases related to abnormal intracellular iron distribution or iron overload.

Animals↗

PubMed2004

Oxidative stress in atherosclerosis-prone mouse is due to low antioxidant capacity of mitochondria.

Atherosclerotic disease remains a leading cause of death in westernized societies, and reactive oxygen species (ROS) play a pivotal role in atherogenesis. Mitochondria are the main intracellular sites of ROS generation and are also targets for oxidative damage. Here, we show that mitochondria from atherosclerosis-prone, hypercholesterolemic low-density lipoprotein (LDL) receptor knockout mice have oxidative phosphorylation efficiency similar to that from control mice but have a higher net production of ROS and susceptibility to develop membrane permeability transition. Increased ROS production was observed in mitochondria isolated from several tissues, including liver, heart, and brain, and in intact mononuclear cells from spleen. In contrast to control mitochondria, knockout mouse mitochondria did not sustain a reduced state of matrix NADPH, the main source of antioxidant defense against ROS. Experiments in vivo showed faster liver secretion rates and de novo synthesis of triglycerides and cholesterol in knockout than in control mice, suggesting that increased lipogenesis depleted the reducing equivalents from NADPH and generated a state of oxidative stress in hypercholesterolemic knockout mice. These data provide the first evidence of how oxidative stress is generated in LDL receptor defective cells and could explain the increased LDL oxidation, cell death, and atherogenesis seen in familiar hypercholesterolemia.

Animals↗