The oxysterol 27-hydroxycholesterol increases β-amyloid and oxidative stress in retinal pigment epithelial cells

<p>Abstract</p> <p>Background</p> <p>Alzheimer's disease (AD) and age-related macular degeneration (AMD) share several pathological features including β-amyloid (Aβ) peptide accumulation, oxidative damage, and cell death. The causes of AD and AMD are not known but several studies suggest disturbances in cholesterol metabolism as a culprit of these diseases. We have recently shown that the cholesterol oxidation metabolite 27-hydroxycholesterol (27-OHC) causes AD-like pathology in human neuroblastoma SH-SY5Y cells and in organotypic hippocampal slices. However, the extent to which and the mechanisms by which 27-OHC may also cause pathological hallmarks related to AMD are ill-defined. In this study, the effects of 27-OHC on AMD-related pathology were determined in ARPE-19 cells. These cells have structural and functional properties relevant to retinal pigmented epithelial cells, a target in the course of AMD.</p> <p>Methods</p> <p>ARPE-19 cells were treated with 0, 10 or 25 μM 27-OHC for 24 hours. Levels of Aβ peptide, mitochondrial and endoplasmic reticulum (ER) stress markers, Ca²⁺homeostasis, glutathione depletion, reactive oxygen species (ROS) generation, inflammation and cell death were assessed using ELISA, Western blot, immunocytochemistry, and specific assays.</p> <p>Results</p> <p>27-OHC dose-dependently increased Aβ peptide production, increased levels of ER stress specific markers caspase 12 and gadd153 (also called CHOP), reduced mitochondrial membrane potential, triggered Ca²⁺dyshomeostasis, increased levels of the nuclear factor κB (NFκB) and heme-oxygenase 1 (HO-1), two proteins activated by oxidative stress. Additionally, 27-OHC caused glutathione depletion, ROS generation, inflammation and apoptotic-mediated cell death.</p> <p>Conclusions</p> <p>The cholesterol metabolite 27-OHC is toxic to RPE cells. The deleterious effects of this oxysterol ranged from Aβ accumulation to oxidative cell damage. Our results suggest that high levels of 27-OHC may represent a common pathogenic factor for both AMD and AD.</p

Global Sustainability Under Uncertainty: How Do Multinationals Craft Regulatory Policies?

Multinational corporations are increasingly mindful of the significance of sustainability transitions and the need for operations that are energy efficient and environmentally sound. Achieving sustainability under conditions of uncertainty entails the involvement of multiple stakeholders in initiating and carrying outsustainability-focused initiatives. Using longitudinal analysis of Royal Dutch Shell’s sustainability policies, we developed an integrated model to elucidate how uncertainty influences sustainability policies in the specific context of multinational corporations (hereinafter – MNCs). We identified three phases in theevolution of Shell’s sustainability innovation: a self-reflective phase (2000–2003) characterized by intense pressure from climate advocacy groups, an investment phase (2004–2006) for which the MNC attempted to rise to the waste disposal and pollution challenge through renewable sources of energy, and a reorganization phase (2007–2010) to streamline operations. We also uncovered themes that influence how regulatory policies are crafted: responding positively to the “community’s voice”, risk spreading through joint ventures, revenue transparency for government accountability and reporting innovation that confronts hard truths. The practical implications are outlined

Embracing the variety of sustainable business models: A prolific field of research and a future research agenda

Investigating the benefits of sustainable business models for our societies is an important and timely topic. This Special Volume contributes to current research by exploring a variety of sustainable models in use around the world. The accepted articles provide an overview of the various organizational forms, management mechanisms, sustainability solutions, challenges, theoretical lenses and empirical evidence, i.e. fundamental elements in the study of sustainable business models. In this introductory paper, the thirty-seven articles included in this Special Volume are presented, organized in four approaches to sustainable business models: 1/the generalist approach, 2/the technology-based approach, 3/the entrepreneurship and innovation approach and 4/the behavioral approach. In conclusion, avenues for future research are formulated, with a call for solid theory building, more sophisticated research methods, focus on the interplay of sustainable with existing conventional business models, and systemic consideration of the role of governments in advancing sustainable business models