Arachidonic Acid Causes Cytochrome c Release from Heart Mitochondria

Paola, Marco Di; Cocco, Tiziana; Lorusso, Michele

doi:10.1006/bbrc.2000.3653

Cited by 32 publications

(19 citation statements)

References 37 publications

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“…The cells were scraped into a suspension with a rubber cell lifter and lysated by sonication. Cytosol and mitochondrial pellet were separated as described previously (Di Paola et al, 2000) to study the cytochrome c release. Homogenized proteins were determined by the Bradford method.…”

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

“…Liver mitochondria were prepared by the differential centrifugation technique (Di Paola et al, 2000). Livers from adult male Wistar rats were excised, finely minced, and homogenized in 10 volumes of cold isolation medium containing 0.25 M sucrose, 0.1 mM EGTA, and 0.25 mM PMSF in 10 mM Tris-Cl (pH 7.4).…”

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

“…Mitochondrial swelling was determined as described previously (Di Paola et al, 2000) using 50 mM HEPES (pH 7.4) buffer in a reaction mixture containing 0.25 M sucrose,1 g/ml rotenone, and 10 mM succinate at 25°C, in the presence of 150 M Aza or 150 M 6-MP with or without 1 M CsA. The reaction was initiated by adding the mitochondria (0.25 mg/ml), and changes in absorbance were recorded at 540 nm in a Beckmann DU 7400 spectrophotometer, equipped with a thermostat controlled and magnetically stirred automatic sampling unit.…”

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

“…The respiratory activity of rat liver mitochondria was measured polarographically in a Rank Brothers oxygraph at 25°C following a previously described procedure (Di Paola et al, 2000) with minor modifications, by suspending mitochondria at 0.1 mg/ml in a basic reaction mixture containing 75 mM sucrose, 50 mM KCl, 30 mM Tris-Cl, pH 7.4, 2 mM KH 2 PO 4 , 10 M EGTA, 10 mM succinate, and 1 g/ml rotenone. After 5 min to reach equilibrium, 150 M Aza or 150 M 6-MP with or without 1 M CsA was added.…”

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

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Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

Menor¹,

Fernández‐Moreno²,

Fueyo³

et al. 2004

J Pharmacol Exp Ther

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Azathioprine is an immunosuppressant drug widely used. Our purpose was to 1) determine whether its associated hepatotoxicity could be attributable to the induction of a necrotic or apoptotic effect in hepatocytes, and 2) elucidate the mechanism involved. To evaluate cellular responses to azathioprine, we used primary culture of isolated rat hepatocytes. Cell metabolic activity, reduced glutathione, cell proliferation, and lactate dehydrogenase release were assessed. Mitochondria were isolated from rat livers, and swelling and oxygen consumption were measured. Mitogen-activated protein kinase pathways and proteins implicated in cell death were analyzed. Azathioprine decreased the viability of hepatocytes and induced the following events: intracellular reduced glutathione (GSH) depletion, metabolic activity reduction, and lactate dehydrogenase release. However, the cell death was not accompanied by DNA laddering, procaspase-3 cleavage, and cytochrome c release.The negative effects of azathioprine on the viability of hepatocytes were prevented by cotreatment with N-acetyl-L-cysteine. In contrast, 6-mercaptopurine showed no effects on GSH content and metabolic activity. Azathioprine effect on hepatocytes was associated with swelling and increased oxygen consumption of intact isolated rat liver mitochondria. Both effects were cyclosporine A-sensitive, suggesting an involvement of the mitochondrial permeability transition pore in the response to azathioprine. In addition, the drug's effects on hepatocyte viability were partially abrogated by c-Jun N-terminal kinase and p38 kinase inhibitors. In conclusion, our findings suggest that azathioprine effects correlate to mitochondrial dysfunction and activation of stress-activated protein kinase pathways leading to necrotic cell death. These negative effects of the drug could be prevented by coincubation with N-acetyl-L-cysteine.

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Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

Section: Azathioprine Acts On Hepatocyte Mitochondria Involving Mapk 669mentioning

confidence: 99%

See 2 more Smart Citations

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

Menor¹,

Fernández‐Moreno²,

Fueyo³

et al. 2004

J Pharmacol Exp Ther

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“…Such "sterically stabilized" particles have been shown to have circulating half lives longer than the conventional solid lipid nanoparticles (SLNs). 6) This prolongation is almost independent of the injected dose and of particle diameter of 50-300 nm. Thus they can function as reservoir systems and penetrate into accessible sites, such as tumors, other than mononuclear systems.…”

mentioning

confidence: 94%

In Vitro and in Vivo Study of Two Types of Long-Circulating Solid Lipid Nanoparticles Containing Paclitaxel.

Chen

Yang

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

214

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Paclitaxel, a diterpenoid derived from the needles and bark of the Pacific yew tree, is a potent inhibitor of cell replication, blocking cells in the late G 2 -mitotic phase of the cell cycle by stabilizing the microtuble cytoskeleton. Clinical trials have shown that paclitaxel has antineoplastic activity, particularly against primary epithelial ovarian carcinoma, breast cancer, colon, head and neck cancers and non-small cell lung cancer.1) Paclitaxel is a hydrophobic molecule and poorly soluble in water, for which reason it is solubilized in a 50 : 50 mixture of Cremophor EL (a polyethoxylated castor oil) and ethanol. Cremophor EL is associated with a number of side effect, including hypersensitivity, nephrotoxicity and neurotoxicity. Furthermore, Cremophor EL dissolves phthalate plastics from commonly used polyvinyl chloride bags and intravenous infusion lines.2) The use of Cremophor EL as a vehicle also appears to alter the biochemical properties of lipoproteins, such as high-density lipoprotein; it has also been shown to mediate partially the cytotoxic activities of paclitaxel in primary cultures of tumor cells from patients.3) Although a premeditation regimen with corticosteroids and antihistamine reduces the incidence of serious hypersensitivity reactions, milder reactions have still been found to occur in 5-30% of treated patients. 3)Colloidal drug carriers such as liposomes and nanoparticles can be used to improve the therapeutics index of both established and new drugs by modifying their distribution, thus increasing their efficiency and/or reducing their toxicity. This is because the drug distribution then follows the carrier, rather than depending on the physicochemical properties of the drug. 4)Despite the promising results achieved with "first-generation" drug carrier systems, their value is limited by their distribution and, in particular, by their recognition by the mononuclear phagocyte system. The major breakthrough, however, was the use of surfactant substituted with poly(ethylene glycol) (PEG) chains with molecular weight of 1000-5000.5) This provides a "cloud" of hydrophilic chains at the particle surface, which repels plasma protein. Such "sterically stabilized" particles have been shown to have circulating half lives longer than the conventional solid lipid nanoparticles (SLNs).6) This prolongation is almost independent of the injected dose and of particle diameter of 50-300 nm. Thus they can function as reservoir systems and penetrate into accessible sites, such as tumors, other than mononuclear systems.Stearic acid is a type of native physiologic molecule. It is bioacceptable and biodegradable in the human body, and thus is a good carrier material. Brij78 (polyoxyethylene 20 stearyl ether) is a nonion surfactant. Its hydrophilic end is a chain of PEG; and its hydrophobic end is stearyl alcohol. PEG-DSPE is a phospholipid substituted with PEG. The aim of this study is to prepare surface-modified long-circulating stearic acid nanoparticles containing paclitaxel, and compare two PEGylated na...

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X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

Turk

Theda

Fatemi

et al. 2020

Intl J of Devlp Neuroscience

144

113

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Adrenoleukodystrophy (ALD) is a rare X‐linked disease caused by a mutation of the peroxisomal ABCD1 gene. This review summarizes our current understanding of the pathogenic cell‐ and tissue‐specific roles of lipid species in the context of experimental therapeutic strategies and provides an overview of critical historical developments, therapeutic trials and the advent of newborn screening in the USA. In ALD, very long‐chain fatty acid (VLCFA) chain length‐dependent dysregulation of endoplasmic reticulum stress and mitochondrial radical generating systems inducing cell death pathways has been shown, providing the rationale for therapeutic moiety‐specific VLCFA reduction and antioxidant strategies. The continuing increase in newborn screening programs and promising results from ongoing and recent therapeutic investigations provide hope for ALD.

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Arachidonic Acid Causes Cytochrome c Release from Heart Mitochondria

Cited by 32 publications

References 37 publications

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

Azathioprine Acts upon Rat Hepatocyte Mitochondria and Stress-Activated Protein Kinases Leading to Necrosis: Protective Role of N-Acetyl-L-cysteine

In Vitro and in Vivo Study of Two Types of Long-Circulating Solid Lipid Nanoparticles Containing Paclitaxel.

X‐linked adrenoleukodystrophy: Pathology, pathophysiology, diagnostic testing, newborn screening and therapies

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