Mechanisms underlying the hormetic effect of conjugated linoleic acid: Focus on Nrf2, mitochondria and NADPH oxidases.

Nuclear factor erythroid 2-related factor2 (Nrf2) is a redox-sensitive transcription factor. Its activation by low dietary intake of ligands leads to antioxidant effects (eustress), while pro-oxidant effects (oxidative distress) may be associated with high doses. NADPH oxidases (NOXs) and the mitochondrial electron transport chain are the main sources of intracellular ROS, but their involvement in the biphasic/hormetic activity elicited by Nrf2 ligands is not fully understood. In this study, we investigated the involvement of NOX expression and mitochondrial function in the hormetic properties of omega-3 typically present in fish oil (FO) and conjugated linoleic acid (CLA) in the mouse liver. Four-week administration of FO, at both low and high doses (L-FO and H-FO) improves Nrf2-activated cyto-protection (by phase 2 enzymes), while a significant increase in respiration efficiency occurs in the liver mitochondria of H-FO BALB/c mice. Eustress conditions elicited by low dose CLA (L-CLA) are associated with increased activity of phase 2 enzymes, and with higher NOX1-2, mitochondrial defences, mitochondrial uncoupling protein 2 (UCP2), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) expression, compared with controls. Steatogenic effects (lipid accumulation and alteration of lipid metabolism) elicited by high CLA (H-CLA) elicited that are associated with oxidative distress, increased mitochondrial complex I/III activity and reduced levels of phase 2 enzymes, in comparison with L-CLA-treated mice. Our results confirm the steatogenic activity of H-CLA and first demonstrate the role of NOX1 and NOX2 in the eustress conditions elicited by L-CLA. Notably, the negative association of the Nrf2/PGC-1α axis with the different CLA doses provides new insight into the mechanisms underlying the hormetic effect triggered by this Nrf2 ligand.

Polyionic vaccine adjuvants: another look at aluminum salts and polyelectrolytes

Adjuvants improve the adaptive immune response to a vaccine antigen by modulating innate immunity or facilitating transport and presentation. The selection of an appropriate adjuvant has become vital as new vaccines trend toward narrower composition, expanded application, and improved safety. Functionally, adjuvants act directly or indirectly on antigen presenting cells (APCs) including dendritic cells (DCs) and are perceived as having molecular patterns associated either with pathogen invasion or endogenous cell damage (known as pathogen associated molecular patterns [PAMPs] and damage associated molecular patterns [DAMPs]), thereby initiating sensing and response pathways. PAMP-type adjuvants are ligands for toll-like receptors (TLRs) and can directly affect DCs to alter the strength, potency, speed, duration, bias, breadth, and scope of adaptive immunity. DAMP-type adjuvants signal via proinflammatory pathways and promote immune cell infiltration, antigen presentation, and effector cell maturation. This class of adjuvants includes mineral salts, oil emulsions, nanoparticles, and polyelectrolytes and comprises colloids and molecular assemblies exhibiting complex, heterogeneous structures. Today innovation in adjuvant technology is driven by rapidly expanding knowledge in immunology, cross-fertilization from other areas including systems biology and materials sciences, and regulatory requirements for quality, safety, efficacy and understanding as part of the vaccine product. Standardizations will aid efforts to better define and compare the structure, function and safety of adjuvants. This article briefly surveys the genesis of adjuvant technology and then re-examines polyionic macromolecules and polyelectrolyte materials, adjuvants currently not known to employ TLR. Specific updates are provided for aluminum-based formulations and polyelectrolytes as examples of improvements to the oldest and emerging classes of vaccine adjuvants in use.