In Situ Regulation of Cytosolic Phospolipase A₂

The 85 kDa cytosolic phospholipase A2 (cPLA2) is an agonist-responsive effector for intracellular signal transduction through the arachidonate cascade. In vitro studies have demonstrated that this enzyme is regulated by sub-micromolar calcium and is specific for arachidonate as the sn-2 fatty acyl group of phospholipid substrates. However, very little data is available regarding in situ mechanisms which govern the activity of cPLA2. The primarily objective of these studies was to develop an in situ system for the study of cPLA2, and investigate mobilization of arachidonate during signal transduction events. Dimethylsulfoxide differentiation of the human lymphoma cell line, U937, induced an enhanced capacity to mobilize arachidonate in response to the calcium ionophore A23187. The arachidonate mobilizing activity in differentiated cells was consistent with characteristics reported for cPLA2 in vitro. Although undifferentiated U937 cells have exceptionally high quantities of cPLA2, A23187-stimulated arachidonate mobilization was low, and not specific for arachidonate. Thus, differentiation of U937 induced cPLA2 regulatory elements that mediate arachidonate mobilization. Differentiation induced significant changes in the capacitative pathway of intracellular calcium elevation. Both the size of intracellular calcium stores, as well as the characteristics of calcium influx channels were altered with differentiation. Agonist-stimulated arachidonate mobilization was coupled to these differentiation-induced alterations. cPLA2 activity was initiated upon agonist-stimulated depletion of intracellular calcium stores, and continued until maximum elevations of intracellular free calcium were attained. The data suggest that cPLA2 may be coupled to the generation of a calcium influx factor, which serves as a communication link between intracellular calcium stores and store-operated calcium influx channels. Consistent with this hypothesis, exogenous free arachidonate activated calcium influx in differentiated U937, consistent with activation of store-operated capacitative calcium influx channels. Based on the data obtained in this study, a model for agonist-stimulated cPLA2 activity is presented. This model suggests a novel role for cPLA2. Apart from the well known role in initiation of the arachidonate cascade, cPLA2 may be part of an intracellular effector system which regulates agonist-stimulated influx of extracellular calcium during activation of the capacitative pathway

Cerium Oxide Nanoparticles: Advances in Biodistribution, Toxicity, and Preclinical Exploration

Antioxidant nanoparticles have recently gained tremendous attention for their enormous potential in biomedicine. However, discrepant reports of either medical benefits or toxicity, and lack of reproducibility of many studies, generate uncertainties delaying their effective implementation. Herein, the case of cerium oxide is considered, a well‐known catalyst in the petrochemistry industry and one of the first antioxidant nanoparticles proposed for medicine. Like other nanoparticles, it is now described as a promising therapeutic alternative, now as threatening to health. Sources of these discrepancies and how this analysis helps to overcome contradictions found for other nanoparticles are summarized and discussed. For the context of this analysis, what has been reported in the liver is reviewed, where many diseases are related to oxidative stress. Since well‐dispersed nanoparticles passively accumulate in liver, it represents a major testing field for the study of new nanomedicines and their clinical translation. Even more, many contradictory works have reported in liver either cerium‐oxide‐associated toxicity or protection against oxidative stress and inflammation. Based on this, finally, the intention is to propose solutions to design improved nanoparticles that will work more precisely in medicine and safely in society

Photoactivated chemotherapy (PACT) : the potential of excited-state d-block metals in medicine

The fields of phototherapy and of inorganic chemotherapy both have long histories. Inorganic photoactivated chemotherapy (PACT) offers both temporal and spatial control over drug activation and has remarkable potential for the treatment of cancer. Following photoexcitation, a number of different decay pathways (both photophysical and photochemical) are available to a metal complex. These pathways can result in radiative energy release, loss of ligands or transfer of energy to another species, such as triplet oxygen. We discuss the features which need to be considered when developing a metal-based anticancer drug, and the common mechanisms by which the current complexes are believed to operate. We then provide a comprehensive overview of PACT developments for complexes of the different d-block metals for the treatment of cancer, detailing the more established areas concerning Ti, V, Cr, Mn, Re, Fe, Ru, Os, Co, Rh, Pt, and Cu and also highlighting areas where there is potential for greater exploration. Nanoparticles (Ag, Au) and quantum dots (Cd) are also discussed for their photothermal destructive potential. We also discuss the potential held in particular by mixed-metal systems and Ru complexes