Amyloid-beta neuroprotection mediated by a targeted antioxidant.

Amyloid-beta (Aβ)-induced neurotoxicity is a major contributor to the pathologies associated with Alzheimer's disease (AD). The formation of reactive oxygen species (ROS), an early response induced by the peptide and oligomeric derivatives of Aβ, plays a significant role in effecting cellular pathogenesis. Here we employ particularly toxic forms of Aβ with cultured primary cortical/hippocampal neurons to elicit ROS and drive cellular dysfunction.

A targeted enzyme approach to sensitization of tyrosine kinase inhibitor-resistant breast cancer cells.

Gefitinib is an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) of potential use in patients with breast cancer. Unfortunately, in clinical studies, gefitinib is often ineffective indicating that resistance to EGFR inhibitors may be a common occurrence in cancer of the breast. EGFR has been shown to be overexpressed in breast cancer, and in particular remains hyperphosphorylated in cell lines such as MDA-MB-468 that are resistant to EGFR inhibitors.

Peroxisomes, oxidative stress, and inflammation.

Peroxisomes are intracellular organelles mediating a wide variety of biosynthetic and biodegradative reactions. Included among these are the metabolism of hydrogen peroxide and other reactive species, molecules whose levels help define the oxidative state of cells. Loss of oxidative equilibrium in cells of tissues and organs potentiates inflammatory responses which can ultimately trigger human disease.

Progeric effects of catalase inactivation in human cells.

Peroxisomes generate hydrogen peroxide, a reactive oxygen species, as part of their normal metabolism. A number of pathological situations exist in which the organelle's capacity to degrade the potentially toxic oxidant is compromised. It is the peroxidase, catalase, which largely determines the functional antioxidant capacity of the organelle, and it is this enzyme that is affected in aging, in certain diseases, and in response to exposure to specific chemical agents.

Reactive oxygen species in tumor necrosis factor-alpha-activated primary human keratinocytes: implications for psoriasis and inflammatory skin disease.

The multifunctional cytokine tumor necrosis factor-alpha (TNF-alpha) is known to play an important role in inflammatory and immunological responses in human skin. Although it has been documented that reactive oxygen species (ROS) are involved in TNF-alpha-induced signaling pathways associated with certain inflammatory diseases, their role in TNF-alpha signaling cascades has not been examined in primary human keratinocytes used as a model of inflammatory skin disease and psoriasis. Employing a series of in vitro and in cellulo approaches, we have demonstrated that in primary human keratinocytes (i) TNF-alpha rapidly induces ROS generation, IkappaB degradation, NF-kappaB p65 nuclear translocation, and ultimately production of inflammatory cytokines; (ii) TNF-alpha-induced cytokine production is mediated both by the mammalian target of rapamycin signaling pathway via NF-kappaB activation and by ROS; (iii) TNF-alpha-dependent NF-kappaB activation (that is, IkappaB degradation and NF-kappaB p65 nuclear translocation) is not mediated by ROS; and (iv) a cell-penetrating derivative of the antioxidant enzyme, catalase, as well as taurine and N-acetyl-cysteine attenuate the TNF-alpha-induced production of cytokines.

Restoration of peroxisomal catalase import in a model of human cellular aging.

Peroxisomes play an important role in human cellular metabolism by housing enzymes involved in a number of essential biochemical pathways. Many of these enzymes are oxidases that transfer hydrogen atoms to molecular oxygen forming hydrogen peroxide. The organelle also contains catalase, which readily decomposes the hydrogen peroxide, a potentially damaging oxidant.

Hypocatalasemic fibroblasts accumulate hydrogen peroxide and display age-associated pathologies.

Human epidemiological studies point to an association of hypocatalasemia and an increased risk of age-related disease. Unfortunately, the cellular and molecular manifestations of hypocatalasemia are only poorly understood. In this analysis, we have extensively characterized hypocatalasemic human fibroblasts and report that they amass hydrogen peroxide and are oxidatively damaged.

Peroxisome senescence in human fibroblasts.

The molecular mechanisms of peroxisome biogenesis have begun to emerge; in contrast, relatively little is known about how the organelle functions as cells age. In this report, we characterize age-related changes in peroxisomes of human cells. We show that aging compromises peroxisomal targeting signal 1 (PTS1) protein import, affecting in particular the critical antioxidant enzyme catalase.