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

Heme Oxygenase-1/sterol interactions in Alzheimer's disease

As average life expectancy increases, understanding the pathogenesis of age related degenerative brain disease such as Alzheimer's is of paramount importance. The brain is the most cholesterol dense human organ and normal neurophysiology is highly dependant upon this sterol. Sterol dys-regulation has been widely implicated in the pathogenesis of neurodegeneration, yet investigative efforts have failed to determine how these essential disturbances drive disease progression. The heme oxygenases (HOs) are dynamic sensors of cellular oxidative stress and likely mediators of tissue redox homeostasis across the phylogenetic spectrum. However, the heme catabolic process has proven to be one of janus face! Up-regulation of heme oxygenase-1 and altered cholesterol metabolism are characteristic of Alzheimer-diseased (AD) neural tissues. Our lab has previously demonstrated the propensity for HO-1 overexpression to impact sterol homeostasis. Herein, we query the mechanisms behind these HO-1/sterol interactions in vitro (cultured rat astroglia) and examine this relationship in post-mortem human AD brain (Religious Orders Study) and in vivo by comparing two mouse models; 1) a novel HO-1 transgenic mouse (GFAP.HMOX1) engineered to selectively express human HO-1 in the astrocytic compartment and 2) the previously described triple transgenic AD mouse (3xTg-AD). Data garnered from our experimentation indicate that HO-1 is a profound effecter of sterol regulation in the central nervous system and suggests that, under various conditions of cellular stress, HO-1 differentially impacts patterns of brain sterols and oxysterols. We present a novel model of brain sterol regulation in AD across the pathological spectrum and delineate the importance of HO-1 in this process. Aberrancy of HO-1/sterol dynamics akin to those reviewed herein constitute a ubiquitous pathway of pathological aging and, hence, a robust target for therapeutic intervention in AD and similar degenerative diseases.Comprendre la pathogenèse d'une maladie dégénérative du cerveau telle la maladie d'Alzheimer est d'une importance primordiale pour notre population vieillissante. Le cerveau est l'organe du corps humain avec le plus haut taux de cholestérol, et la neurophysiologie normale dépend fortement de ce stérol. La dysrégulation du stérol a été largement impliquée dans la pathogenèse de la neurodégénérescence, mais les efforts de recherche n'ont pas réussi à déterminer comment ces perturbations nécessaires causent la maladie. Les oxygénases hème sont des capteurs dynamiques de stress oxydatif cellulaire et des médiateurs probables de l'homéostasie redox tissulaire à travers le spectre phylogénétique. Toutefois, le processus catabolique hème s'est avéré être l'un des visages de janus! La surexpression de l'hème oxygénase-1 et le métabolisme du cholestérol altéré est caractéristique des tissues neurologiques affectés par la maladie d'Alzheimer. Notre laboratoire a précédemment démontré que la propension de HO-1 surexpression peut avoir un impacte sur l'homéostasie des stérols. Dans les présentes, nous enquêtons les mécanismes derrière ces interactions HO-1/sterol in vitro (astrocytes de rat en culture) et examinons cette relation dans le cerveau atteint d'Alzheimer post-mortem (Religious Order Study) et in vivo en comparant deux modèles de souris; 1) une souris HO-1 transgénique (GFAP.HMOX1) conçue pour faire ressortir de façon sélective de la HO-1 humain dans le compartiment astrocytic et 2) une souris transgénique triple d'Alzheimer (3xTg-AD), décrite précédemment. Les données résultantes de notre expérimentation indiquent que la HO-1 est un profond effecteur de la régulation des stérols dans le système nerveux central et suggère que, dans diverses conditions de stress cellulaire, la HO-1 impact de façon différentielle les modes des stérols et oxystérols du cerveau. Nous présentons un nouveau modèle de régulation neurosterol d'Alzheimer's à travers le spectre pathologique et délimitons l'importance de la HO-1 dans ce processus. Mauvais dynamiques HO-1/stérol semblables à celles examinées dans les présentes constitue une voie omniprésente du vieillissement pathologique et, par conséquent, une cible solide pour l'intervention thérapeutique de la maladie d'Alzheimer et de maladies dégénératives similaires

Chicago Quantatative Alliance Investment Challenge

The purpose of my thesis was to explore investment management, and to learn how to mitigate risk while generating abnormal returns. As a group, we implemented academically researched and proven investment methods with the goal of creating a well-managed portfolio. We gauged our performance by our overall return and risk adjusted return. By utilizing investment methods and consistently rebalancing our portfolio we were able to maximize our return and win the competition

2017 Chicago Quantitative Alliance Investment Challenge: University of Arizona CQA Investment Strategy

The CQA challenge is a 6 month competition that starts in October and ends in March. In this competition, student teams from 54 universities across the world are competing to build a long-short, market neutral equity portfolio that would generate the most risk-adjusted return in the given time horizon while operating under a few specific portfolio constraints. Each team is ranked against each other based on risk-adjusted return and sharpe ratio. Our team consisted of 5 senior finance students at the University of Arizona. Together, we developed our own unique market outlook and portfolio strategy in order to successfully invest $1,000,000 in (hypothetical) capital. We used industry tilts towards financials, energy, and consumer discretionary sectors and factor tilts towards momentum and value stocks as our main drivers of return while minimizing market exposure by keeping our beta between -0.25 and +0.25. The University of Arizona finished the competition in first place in overall portfolio ranking with a return of 12.23% and in fifth place for sharpe ratio at 1.43

Defining Personas of People Living with Chronic Pain: An Ethnographic Research Study

Melissa Cullens,1 Cyan James,1 Meran Liu,1 Amaresh Vydyanathan,2– 4 Naum Shaparin,3– 5 Michael Schatman,6,7 Jacob Hascalovici2,3,5,8 1Clearing Relief Labs Inc., New York City, NY, USA; 2Relief Medical Group P.A, New York City, NY, USA; 3Department of Anesthesiology, Albert Einstein College of Medicine, Bronx, NY, USA; 4Multidisciplinary Pain Program, Montefiore Medical Center, Bronx, NY, USA; 5The Arthur S. Abramson Department of Physical Medicine and Rehabilitation, Albert Einstein College of Medicine, Bronx, NY, USA; 6Department of Anesthesiology, Perioperative Care and Pain Medicine, NYU Grossman School of Medicine, New York City, NY, USA; 7Department of Population Health – Division of Medical Ethics, NYU Grossman School of Medicine, New York City, NY, USA; 8Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USACorrespondence: Jacob Hascalovici, Relief Medical Group P.A, 169 Madison Ave, Suite 2412, New York City, New York City, 10016, USA, Email [email protected]: Pain is the leading reason for which people seek medical care in the United States, and chronic pain (CP) affects approximately 50 million people in the US Pain perception is deeply personal, is highly correlated with behavioral and emotional disorders, and is greatly influenced by physiological and environmental factors. The patient-provider relationship can have profound implications for clinical outcomes within the context of treating CP. However, limited access to pain specialists, the complex nature of many CP-causing conditions, the absence of instruments for objective pain measurement, and the need to foster a trust-based patient-provider relationship throughout treatment pose unique challenges.Objective: To support a more optimal CP care delivery system that leverages a healthy therapeutic patient-provider relationship, we systematically gathered deeper knowledge of the behaviors, interpersonal dynamics, home environment, values, and mindsets of people who experience CP.Methods: We employed ethnographic research methods to collect and analyze data on views, habits, strategies, attitudes, and life circumstances of a range of participants living with CP. We aggregated, analyzed, and summarized participant data to identify trends and similarities.Results: Our findings suggest that patients can be broadly categorized into five predominant pain typologies, or “personas”, which are characterized by respective symptom durations, care management preferences, values, communication styles, and behaviors.Conclusion: Identifying CP personas may enhance the ability to personalize CP care and help foster more robust therapeutic relationships, which may lead to greater trust, improved patient satisfaction, and better clinical outcomes.Keywords: chronic pain, personas, biopsychosocial, doctor–patient relationshi

Changes in cholesterol biosynthetic and transport pathways after excitotoxicity

10.1111/j.1471-4159.2009.06449.xJournal of Neurochemistry112134-41JONR