Methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate decreases specificity protein transcription factors and inhibits pancreatic tumor growth: role of microRNA-27a.

The anticancer agent 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) and its methyl ester (CDDO-Me) typically induce a broad spectrum of growth-inhibitory, proapoptotic, and antiangiogenic responses. Treatment of Panc1, Panc28, and L3.6pL pancreatic cancer cells with low micromolar concentrations of CDDO or CDDO-Me resulted in growth inhibition, induction of apoptosis, and down-regulation of cyclin D1, survivin, vascular endothelial growth factor (VEGF), and its receptor (VEGFR2).

Tolfenamic acid decreases c-Met expression through Sp proteins degradation and inhibits lung cancer cells growth and tumor formation in orthotopic mice.

The nonsteroidal anti-inflammatory drug (NSAID), tolfenamic acid (TA) is emerging as a new anti-cancer agent. TA induces the degradation of specific Specificity protein (Sp) transcription factors, Sp1, Sp3 and Sp4 which are associated with tumor growth and metastasis. In this study we have evaluated the effect of TA on lung cancer using both in vitro and in vivo models.

Lifespan profiles of Alzheimer's disease-associated genes and products in monkeys and mice.

Alzheimer's disease (AD) is characterized by plaques of amyloid-beta (Abeta) peptide, cleaved from amyloid-beta protein precursor (AbetaPP). Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates.

Tolfenamic acid enhances pancreatic cancer cell and tumor response to radiation therapy by inhibiting survivin protein expression.

Survivin is overexpressed in most human cancers, including pancreatic adenocarcinoma. Expression of survivin is regulated by specificity protein (Sp) proteins and related to resistance to radiation therapy. Tolfenamic acid induces Sp protein degradation in several cancer cell lines.

Alzheimer's disease (AD)-like pathology in aged monkeys after infantile exposure to environmental metal lead (Pb): evidence for a developmental origin and environmental link for AD.

The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic beta-amyloid (Abeta) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (beta-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants.

The environment, epigenetics and amyloidogenesis.

Alzheimer's Disease (AD) is a progressive, irreversible neurodegenerative disease. Despite several genetic mutations (Haass et al., J.

New and evolving concepts in the neurotoxicology of lead.

Lead (Pb) is a xenobiotic metal with no known essential function in cellular growth, proliferation, or signaling. Decades of research characterizing the toxicology of Pb have shown it to be a potent neurotoxicant, especially during nervous system development. New concepts in the neurotoxicology of Pb include advances in understanding the mechanisms and cellular specificity of Pb.

Environmental and dietary risk factors in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects millions in the aging population worldwide and will affect millions more in the next 20 years. Over 90% of all cases are sporadic, with genetics playing a minor role in the etiology of AD. Therefore, it is crucial to investigate the environment and diet as primary risk factors in AD pathology.

How and when environmental agents and dietary factors affect the course of Alzheimer's disease: the "LEARn" model (latent early-life associated regulation) may explain the triggering of AD.

Alzheimer's disease (AD) is currently the most prominent form of dementia among the elderly. Although AD manifests in late adult life, it is not clear when the disease actually starts and how long the neuropathological processes take to develop AD. The major unresolved question is the timing and the nature of triggering leading to AD.

Lead exposure: expression and activity levels of Oct-2 in the developing rat brain.

Lead is a highly neurotoxic metal, and the developing central nervous system is particularly vulnerable to the effects of lead. In this study, transcription factors (TFs) that are altered due to lead exposure were identified using macroarray analysis. Rat pups were lactationally exposed to 0.

Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with clinical manifestations appearing in old age, however, the initial stages of this disease may begin early in life. AD is characterized by the presence of excessive deposits of aggregated beta-amyloid (Abeta) peptides, which are derived from the beta-amyloid precursor protein (APP) following processing by beta-secretase and gamma-secretase. Recently, we have reported that developmental exposure of rats to Pb resulted in latent elevation of APP mRNA, APP, and Abeta in old age.

Ontogenetic alterations in prototypical transcription factors in the rat cerebellum and hippocampus following perinatal exposure to a commercial PCB mixture.

Polychlorinated biphenyls (PCBs) are prevalent in the environment despite the ban of their use for decades and offer a model system to understand developmental neurotoxicity of persistent pollutants. Disturbances in brain development and cognition are among the neurotoxic manifestations of PCBs. The cellular and molecular basis for PCB-induced developmental neurotoxicity is still unclear; however, a series of in vitro and some in vivo studies have revealed that the disruption of Ca(2+) homeostasis and Ca(2+)-mediated signal transduction play a significant role.

Determining the ability of xenobiotic metals to bind a specific protein domain by electrophoresis.

Environmental metals are potentially toxic and can interfere with the metal-binding motifs of various critical proteins. This unit describes an electrophoretic method that can be used to measure the ability of a xenobiotic metal to bind a zinc-finger motif. Information gained using this protocol can lead to the identification of protein targets of metals and shed better light on their mechanisms of action.

Lead induced effects on acetylcholinesterase activity in cerebellum and hippocampus of developing rat.

Exposure to low-levels of lead (Pb) during early development has been implicated in behavioral abnormalities and cognitive deficits in children. The present study is focused on developmental changes in hippocampus and cerebellum of rats following perinatal exposure to Pb. Pregnant rats were exposed to 0.

Intracellular signaling pathways involved in mediating the effects of lead on the transcription factor Sp1.

It has been well established that exposure to Pb during critical periods of brain development results in both cognitive and behavioral deficits. Although the mechanism by which Pb induces developmental neurotoxicity is unknown, it may involve alterations in transcription of genes that are essential for growth and differentiation. Recent studies reveal that Pb interferes with growth and differentiation by acting on the transcription factor Sp1.

Lead-induced developmental perturbations in hippocampal Sp1 DNA-binding are prevented by zinc supplementation: in vivo evidence for Pb and Zn competition.

Zinc finger protein (ZFP) transcription factors are essential for regulation of gene expression in the developing brain. We previously reported that Pb exposure perturbed the DNA-binding of ZFP such as Sp1 and Egr-1 in the cerebellum, which play critical role in CNS development. In this study, we focused on hippocampal Sp1 DNA-binding and mRNA expression in neonatal Pb-exposed animals.