Reduced kidney lipoprotein lipase and renal tubule triglyceride accumulation in cisplatin-mediated acute kidney injury.

Peroxisome proliferator-activated receptor-α (PPARα) activation attenuates cisplatin (CP)-mediated acute kidney injury by increasing fatty acid oxidation, but mechanisms leading to reduced renal triglyceride (TG) accumulation could also contribute. Here, we investigated the effects of PPARα and CP on expression and enzyme activity of kidney lipoprotein lipase (LPL) as well as on expression of angiopoietin protein-like 4 (Angptl4), glycosylphosphatidylinositol-anchored-HDL-binding protein (GPIHBP1), and lipase maturation factor 1 (Lmf1), which are recognized as important proteins that modulate LPL activity. CP caused a 40% reduction in epididymal white adipose tissue (WAT) mass, with a reduction of LPL expression and activity.

Transgenic expression of proximal tubule peroxisome proliferator-activated receptor-alpha in mice confers protection during acute kidney injury.

Our previous studies suggest that peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a critical role in regulating fatty acid beta-oxidation in kidney tissue and this directly correlated with preservation of kidney morphology and function during acute kidney injury. To further study this, we generated transgenic mice expressing PPARalpha in the proximal tubule under the control of the promoter of KAP2 (kidney androgen-regulated protein 2). Segment-specific upregulation of PPARalpha expression by testosterone treatment of female transgenic mice improved kidney function during cisplatin or ischemia-reperfusion-induced acute kidney injury.

Prevention of cisplatin-induced kidney epithelial cell apoptosis with a Cu superoxide dismutase-mimetic [copper2II(3,5-ditertiarybutylsalicylate)4(ethanol)4].

Copper(2)(II)(3,5-ditertiarybutylsalicylate)(4)(ethanol)(4), Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), was synthesized and characterized for evaluation as an anti-apoptotic superoxide dismutase (SOD)-mimetic in an in vitro 50 microM cis-diamminedichloroplatinum(II), [Pt(II)(NH(3))(2)(Cl)(2)]-treated kidney proximal tubule epithelial cell (LLC-PK) preparation. Synthesized Cu(2)(II)(3,5-DTBS)(4)(Eth)(4) was characterized by elemental analysis, FTIR spectrophotometry, and X-ray crystallography. The IC(50) for SOD-mimetic reactivity of Cu(2)(II)(3,5-DTBS)(4)(Eth)(4), determined with the xanthine/xanthine oxidase/nitroblue tetrazolium (NBT) system, was found to be 2.

Fibrate prevents cisplatin-induced proximal tubule cell death.

Background: In previous studies we have shown that cisplatin inhibits peroxisome proliferator-activated receptor-alpha (PPAR-alpha) activity and consequently fatty acid oxidation, and these events precede proximal tubule cell death. In addition the use of fibrate class of PPAR-alpha ligands ameliorate renal function by preventing both inhibition of fatty acid oxidation and proximal tubule cell death.

Methods: LLC-PK1 cells were treated with cisplatin and apoptosis was established by the presence of nuclear fragmentation and by cell cycle analysis.

Folic acid-mediated inhibition of serum-induced activation of EGFR promoter in colon cancer cells.

Although accumulating evidence suggests a chemopreventive role for folic acid (FA) in colorectal carcinogenesis, the underlying mechanisms are largely unknown. Previously, we reported that supplemental FA inhibits the expression and activation of epidermal growth factor receptor (EGFR) in colon cancer cell lines. To determine the mechanism(s) by which FA affects EGFR function, we have examined whether and to what extent supplemental FA or its metabolites 5-methyltetrahydrofolate (MTF), dihydrofolate (DF), and tetrahydrofolate (TF) will modulate basal and serum-induced activation of the EGFR promoter in the HCT-116 colon cancer cell line.

Folic acid mediated attenuation of loss of heterozygosity of DCC tumor suppressor gene in the colonic mucosa of patients with colorectal adenomas.

Loss of heterozygosity (LOH) and/or inactivation of tumor suppressor genes are implicated in the initiation and progression of many malignancies, including colorectal cancer. Although accumulating evidence suggests a chemopreventive role for folate in colorectal cancer, regulatory mechanisms are poorly understood. The primary objective of the current investigation was to determine whether folic acid would prevent LOH of the three tumor suppressor genes, deleted in colorectal cancer (DCC), adenomatous polyposis coli (APC) and p53 in macroscopically normal appearing rectal mucosa of patients with adenomatous polyps.

Expression of EGF-receptor related protein (ERRP) decreases in gastric mucosa during aging and carcinogenesis.

Aging and gastrointestinal malignancies, including that of the stomach are associated with increased activation of EGF-receptor (EGFR). Although the intracellular events that regulate this process are poorly understood, we hypothesize that loss of ERRP (EGFR-related protein; GenBank accession number AF187818), a recently identified negative regulator of EGFR, that possesses a substantial homology to the ligand binding extracellular domain of EGFR, may contribute to this event. In support of our hypothesis, we have observed that in Fischer-344 rats, whereas aging is associated with increased activation of EGFR in the gastric mucosa, expression of ERRP decreases inthis tissue during this period.

Epidermal growth factor receptor-related protein: a potential therapeutic agent for colorectal cancer.

Background & Aims: Epidermal growth factor receptor is frequently implicated in epithelial cancers and is, therefore, being considered as a potential target for therapy. Recently, we reported the isolation and characterization of epidermal growth factor receptor-related protein, a negative regulator of epidermal growth factor receptor. To discern whether epidermal growth factor receptor-related protein could be an effective therapeutic agent for colorectal cancer, we generated epidermal growth factor receptor-related protein fusion protein and studied its effect on the growth of colon cancer cells in vivo and in vitro.