Chemopreventive and renal protective effects for docosahexaenoic acid (DHA): implications of CRP and lipid peroxides

Background

The fish oil-derived ω-3 fatty acids, like docosahexanoic (DHA), claim a plethora of health benefits. We currently evaluated the antitumor effects of DHA, alone or in combination with cisplatin (CP) in the EAC solid tumor mice model, and monitored concomitant changes in serum levels of C-reactive protein (CRP), lipid peroxidation (measured as malondialdehyde; MDA) and leukocytic count (LC). Further, we verified the capacity of DHA to ameliorate the lethal, CP-induced nephrotoxicity in rats and the molecular mechanisms involved therein.

Results

EAC-bearing mice exhibited markedly elevated LC (2-fold), CRP (11-fold) and MDA levels (2.7-fold). DHA (125, 250 mg/kg) elicited significant, dose-dependent reductions in tumor size (38%, 79%; respectively), as well as in LC, CRP and MDA levels. These effects for CP were appreciably lower than those of DHA (250 mg/kg). Interestingly, DHA (125 mg/kg) markedly enhanced the chemopreventive effects of CP and boosted its ability to reduce serum CRP and MDA levels. Correlation studies revealed a high degree of positive association between tumor growth and each of CRP (r = 0.85) and leukocytosis (r = 0.89), thus attesting to a diagnostic/prognostic role for CRP. On the other hand, a single CP dose (10 mg/kg) induced nephrotoxicity in rats that was evidenced by proteinuria, deterioration of glomerular filtration rate (GFR, -4-fold), a rise in serum creatinine/urea levels (2–5-fold) after 4 days, and globally-induced animal fatalities after 7 days. Kidney-homogenates from CP-treated rats displayed significantly elevated MDA- and TNF-α-, but reduced GSH-, levels. Rats treated with DHA (250 mg/kg, but not 125 mg/kg) survived the lethal effects of CP, and showed a significant recovery of GFR; while their homogenates had markedly-reduced MDA- and TNF-α-, but -increased GSH-levels. Significant association was detected between creatinine level and those of MDA (r = 0.81), TNF-α ) r = 0.92) and GSH (r = -0.82); implying causal relationships.

Conclusion

DHA elicited prominent chemopreventive effects on its own, and appreciably augmented those of CP as well. The extent of tumor progression in various mouse groups was highly reflected by CRP levels (thus implying a diagnostic/prognostic role for CRP). Further, this study is the first to reveal that DHA can obliterate the lethal CP-induced nephrotoxicity and renal tissue injury. At the molecular level, DHA appears to act by reducing leukocytosis, systemic inflammation, and oxidative stress.     

Protein degradation and apoptotic death in lymphocytes during Fiv infection: activation of the ubiquitin-proteasome proteolytic system

The movement of a cell through the sequential phases of apoptosis is accompanied by a progressive decrease in cell size with loss in protein mass. In lymphocytes from Hiv-infected persons, protein loss during apoptosis is due to increased protein degradation rather than decreased synthesis. To identify and characterize the proteolytic enzymes or enzyme systems involved in this process, we studied several features of protein turnover in lymphocytes from peripheral blood and lymph nodes during the natural and experimental infection by feline immunodeficiency virus (Fiv). This animal model allowed us to integrate in vivo results with in vitro observations of protein damage. Here we report that protein breakdown in apoptotic cells is concomitant with the activation of the ATP and ubiquitin-dependent multicatalytic system (proteasome). We suggest that proteasome activation is part of the proteolytic cascade in the execution phases of apoptosis in AIDS.     

Chronic inflammation and the effect of IGF-I on muscle strength and power in older persons

Deregulation of the inflammatory response plays a major role in the age-related decline of physical performance. The causal pathway leading from inflammation to disability has not been fully clarified, but several researches suggest that interleukin-6 (IL-6) causes a reduction of physical performance in elderly through its effect on muscle function. In vitro studies demonstrated that IL-6 inhibits the secretion of insulin-like growth factor I (IGF-I) and its biological activity, suggesting that the negative effect of IL-6 on muscle function might be mediated through IGF-I. We evaluated the joint effect of IGF-I and IL-6 on muscle function in a population-based sample of 526 persons with a wide age range (20-102 yr). After adjusting for potential confounders, such as age, sex, body mass index, IL-6 receptor, and IL-6 promoter polymorphism, IL-6, IGF-I, and their interaction were significant predictors of handgrip and muscle power. In analyses stratified by IL-6 tertiles, IGF-I was an independent predictor of muscle function only in subjects in the lowest IL-6 tertile, suggesting that the effect of IGF-I on muscle function depends on IL-6 levels. This mechanism may explain why IL-6 is a strong risk factor for disability.     

Linkage analysis of a derived glucose phenotype in the Genetic Analysis Workshop 13 simulated data using a variety of Haseman-Elston based regression methods

A variety of Haseman-Elston type regression procedures were used to perform a genome scan across five chromosomes, using replicates 1-5 of the Genetic Analysis Workshop 13 simulated data. The traits of interest were variables corresponding to 'baseline' and 'slope' effects derived from the fasting glucose phenotypes. Performance in terms of detecting the locations of known trait loci was poor for all methods, even when all five replicates were combined to produce a large data set (9230 sib pairs). All methods performed well, however, when applied to new simulated data in which the true genetic effects were allowed to explain a greater proportion of the overall variance.     

Synthesis and pharmacological characterisation of 2,4-dicarboxy-pyrroles as selective non-competitive mGluR1 antagonists

Metabotropic glutamate receptors (mGluRs) are an unusual family of G-protein coupled receptor (GPCR), and are characterised by a large extracellular N-terminal domain that contains the glutamate binding site. We have identified a new class of non-competitive metabotropic glutamate receptor 1 (mGluR1) antagonists, 2,4-dicarboxy-pyrroles which are endowed with nanomolar potency. They interact within the 7 transmembrane (7TM) domain of the receptor and show antinociceptive properties when tested in a number of different animal models.     

Serum IL-1beta levels in health and disease: a population-based study. 'The InCHIANTI study'

Interleukin-1 plays a role in normal homeostasis and in the inflammatory response which is deemed to be responsible for the development of major chronic diseases that are highly prevalent in the elderly. Aim of this study is to evaluate the factors influencing the serum levels of Interleukin-1 beta, in a large and representative population. Data were from the InCHIANTI project, a study of factors contributing to the decline of mobility in late life, which sampled people living in two sites in the surroundings of Florence. Blood samples were obtained from 1,292 participants and frozen aliquots were stored at -80 degrees C. The serum levels of several cytokines were measured by enzyme linked immunosorbent assay using an ultrasensitive commercial kit. Interleukin-1 beta serum levels were associated with congestive heart failure (p > 0.001) and angina (p = 0.02), with Ca2+ serum levels (p = 0.02), and with a history of dyslipidemia (p = 0.05). We found no association between serum IL-1beta level and age, sex, consumption of cardioactive drugs and serum levels of IL-1Ra, IL-6, sIL-6R, IL-10 and TNF-alpha. Our data could lend support to the hypothesis that IL-1beta is mainly involved in the functional alterations of cardiomyocytes under conditions marked by mononuclear cell infiltration and by downregulation of calcium.     

Nitrogen dynamics in the intact grasses Poa trivialis and Panicum maximum receiving contrasting supplies of nitrogen

The C(3) grass Poa trivialis and the C(4) grass Panicum maximum were grown in sand culture and received a complete nutrient solution with nitrogen supplied as 1.5 mol m(-3) NH(4)NO(3). (15)N tracer techniques were used to quantify the relative use of root uptake and mobilization in supplying nitrogen to growing leaves in intact plants which either continued to receive nitrogen or which received the complete nutrient solution without nitrogen. The allocation of both (15)N-labelled nitrogen uptake and unlabelled mobilized nitrogen indicated that, under their conditions of growth, the sink strength of growing leaves was relatively greater in P. maximum than P. trivialis. The supply of nitrogen by mobilization to side tillers of P. trivialis was completely stopped as the external nitrogen supply was reduced, whilst in P. maximum some allocation of mobilized nitrogen to side tillers, roots and growing leaves was maintained. In both plant species receiving an uninterrupted supply of nitrogen the allocation pattern of mobilized nitrogen differed from that of nitrogen derived from root uptake. Differences exist in the degree to which P. trivialis and P. maximum utilized uptake and mobilization to supply nitrogen to the growing leaves. In P. trivialis roots were always a net sink of mobilized nitrogen, irrespective of the external nitrogen supply. In P. maximum, roots were a net sink of mobilized nitrogen when external nitrogen was withdrawn, but exhibited both source and sink behaviour when nitrogen supply was continued.