NPY family of hormones: clinical relevance and potential use in gastrointestinal disease.

The neuropeptide Y (NPY), peptide YY (PYY) and pancreatic polypeptide (PP) family of hormones exhibit a wide variety of biological actions on the mammalian gastrointestinal tract through known G-protein coupled receptor pathways. At least four receptor subtypes, denoted as Y(1), Y(2), Y(4) an Y(5), each with specific affinities to NPY ligands, serve as regulators of mucosal function, gastrointestinal motility and secretion. Investigations to date, however, have implicated the NPY peptides as mediators in the pathogenesis of numerous gastrointestinal disorders, including malabsorption, short gut, inflammatory bowel diseases, and forms of pancreatitis. Our understanding of these diseases and the interactions of NPY peptides have been advanced by the development of receptor agonists and antagonists that can be used experimentally in animal models. Potent selective PYY agonists have been developed that exhibit clinical potential as proabsorptive agents. NPY receptor agonists and antagonists as well as mice harboring null mutations in the Y(1) and Y(4) receptors have provided novel approaches in preventing intestinal inflammation and diarrhea. The use of competitive antagonists and Y(2) receptor knockouts have also aided in understanding secretory tone and electrogenic ion transport in the colon. In the pancreas, PYY suppresses amylase and cytokine release, which would be desirable in the clinical therapy of pancreatitis. Protein/DNA array analysis has revealed that PYY reduces transcription factor binding activity and disrupts signal transduction pathways activated by TNF-alpha in acinar cells. The present review gives an overview of NPY research in gastrointestinal disease and discusses its clinical relevance and potential use as therapy.

Adiposity, type 2 diabetes and the metabolic syndrome in breast cancer.

Upper body obesity and the related metabolic disorder type 2 diabetes have been identified as risk factors for breast cancer, and associated with late-stage disease and a poor prognosis. Components of the metabolic syndrome, including visceral adiposity, insulin resistance, hyperglycemia and hyperinsulinemia, with or without clinically manifest diabetes mellitus, low serum high-density lipoprotein cholesterol and hypertension have all been related to increased breast cancer risk. The biochemical mechanisms include extraglandular oestrogen production, reduced sex hormone-binding globulin with consequent elevation of the bioactive plasma free oestradiol and increased insulin biosynthesis, all of which exert mitogenic effects on both untransformed and neoplastic breast epithelial cells. Obesity, type 2 diabetes and the metabolic syndrome also have in common an increased production of leptin and a decreased production of adiponectin by adipose tissue, with consequent elevations and reductions, respectively, in the circulating levels of these two adipokines. These changes in plasma leptin and adiponectin, acting through endocrine and paracrine mechanisms, have been associated in several studies with an increase in breast cancer risk and, perhaps, to more aggressive tumours; studies in vitro showed that leptin stimulates, and adiponectin inhibits, tumour cell proliferation and the microvessel angiogenesis which is essential for breast cancer development and progression.

Vitamin E and the Y4 agonist BA-129 decrease prostate cancer growth and production of vascular endothelial growth factor.

BACKGROUND: A biologically active form of vitamin E, alpha-tocopherol succinate (ATS), has been shown to induce apoptosis of hormone-refractory prostate cancer in vitro and inhibit cell growth in vivo. The gastrointestinal hormone peptide YY (PYY) has growth inhibitory activity against multiple cancer cell lines and is synergistic with ATS against breast and pancreatic cancer growth. BA-129, a specific Y4 receptor agonist, has growth inhibitory effects on pancreatic cancer in vitro. We investigated the effects of BA-129 and ATS on prostate cancer growth and evaluated their effects on vascular endothelial growth factor (VEGF) production. METHODS: A hormone-refractory human prostate cancer cell line, PC-3, was treated with ATS alone at 10 pg/ml, PYY or BA-129 alone at doses of 75 and 500 pmol/ml, or a combination of the two agents. Cell growth was measured by MTT assay and hemocytometry using trypan blue. Quantitative measurement of VEGF was performed by ELISA. Statistical analysis was achieved by ANOVA. RESULTS: ATS exhibited significant (P < 0.05) growth inhibitory effects in prostate cancer cells. PYY also inhibited growth (P < 0.05). ATS treatment reduced VEGF production (P < 0.05). PYY treatment increased VEGF. When ATS was given in combination with BA-129, VEGF production was further reduced (P < 0.05). CONCLUSIONS: Both PYY and ATS inhibit growth in hormone-refractory prostate cancer, with augmentation when used in combination. VEGF production is inhibited by vitamin E, but increased by PYY. ATS abolishes the augmented VEGF response to PYY. Our data suggest that PYY is involved in the regulation of VEGF production and prostate cancer growth.

Effect of creatine monohydrate on cardiac function in a rat model of endotoxemia.

BACKGROUND: Reports have attributed cardiac failure during acute models of endotoxemia to a lack of high-energy phosphates. This study was undertaken to investigate whether creatine (Cr) administered during perfusion could enhance myocardial protection and improve recovery of cardiac function in a rat model of endotoxemia. METHODS: Acute endotoxemia was induced in rats by a bolus injection of Escherichia coli endotoxin (LPS: 4 mg/kg, ip) while control rats were injected with an equal volume of 0.9% normal saline. To assess the adequacy of energy metabolism, freeze-clamped hearts were obtained from animals to study the concentrations of endogenous ATP, phosphocreatine (PCr), inorganic phosphate (P(i)), and intracellular pH by (31)P-cryomagnetic resonance spectroscopy. In a separate experiment, isolated hearts were perfused via a Langendorff column with Krebs-Henseleit buffer containing different concentrations of creatine monohydrate (1, 3, or 10 mM). Cardiac performance was evaluated via a paced (300 bpm) isovolumetric balloon preparation. Measurements of cardiac function including left ventricular developed pressure (LVDP), the maximum rates of ventricular pressure rise (LV +dP/dt) and fall (LV -dP/dt), and coronary flow were made for both LPS and saline-treated animals. RESULTS: High-energy phosphate ratios of PCr/ATP and PCr/P(i) in hearts declined significantly at 4 h after endotoxin treatment. As anticipated, LVDP and LV +dP/dt(max) at a given preload and heart rate were significantly (P < 0.05) lower at 4 h when measured at the same time point. The functional recovery of these parameters was not improved by the addition of creatine monohydrate to the perfusion buffer. Creatine produced a significant (P < 0.05) negative inotropic effect in hearts from saline-treated animals. The LVDP was reduced by 30% at the lowest concentration and by 50% at the highest concentration of creatine monohydrate. Furthermore, creatine significantly (P < 0.05) reduced LV -dP/dt(max) in both saline and LPS-treated rats. These data demonstrate that exogenous creatine does not contribute to myocardial preservation in endotoxemia. CONCLUSIONS: Energy stores in the rat heart decline early in endotoxemia accompanied by reduced myocardial performance, suggesting that the ability of the heart to perform mechanical work is impaired. Cardiac dysfunction in an acute model of endotoxemia was not improved with exogenous creatine during perfusion. Creatine's effects were primarily lusitropic by delaying the onset of myocardial relaxation in all hearts. The deleterious effects of exogenous creatine monohydrate in normal hearts should be examined in future experimental studies.