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

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Reconciling conflicting clinical studies of antioxidant supplementation as HIV therapy: a mathematical approach

<p>Abstract</p> <p>Background</p> <p>Small, highly reactive molecules called reactive oxygen species (ROS) play a crucial role in cell signalling and infection control. However, high levels of ROS can cause significant damage to cell structure and function. Studies have shown that infection with the human immunodeficiency virus (HIV) results in increased ROS concentrations, which can in turn lead to faster progression of HIV infection, and cause CD4⁺T-cell apoptosis. To counteract these effects, clinical studies have explored the possibility of raising antioxidant levels, with mixed results.</p> <p>Methods</p> <p>In this paper, a mathematical model is used to explore this potential therapy, both analytically and numerically. For the numerical work, we use clinical data from both HIV-negative and HIV-positive injection drug users (IDUs) to estimate model parameters; these groups have lower baseline concentrations of antioxidants than non-IDU controls.</p> <p>Results</p> <p>Our model suggests that increases in CD4⁺T cell concentrations can result from moderate levels of daily antioxidant supplementation, while excessive supplementation has the potential to cause periods of immunosuppression.</p> <p>Conclusion</p> <p>We discuss implications for HIV therapy in IDUs and other populations which may have low baseline concentrations of antioxidants.</p