Niemann–Pick type C1 (NPC1) disease is a rare genetic condition in which the function of the lysosomal cholesterol transporter NPC1 protein is impaired. Consequently, sphingolipids and cholesterol accumulate in lysosomes of all tissues, triggering a cascade of pathological events that culminate in severe systemic and neurological symptoms. Lysosomal cholesterol accumulation is also a key-factor in the development of atherosclerosis and non-alcoholic steatohepatitis (NASH). In these two metabolic diseases, the administration of plant stanol esters has been shown to ameliorate cellular cholesterol accumulation and inflammation. Given the overlap of pathological mechanisms among atherosclerosis, NASH and NPC1 disease, we sought to investigate whether dietary supplementation with plant stanol esters improves the peripheral features of NPC1 disease. To this end, we used an NPC1 murine model featuring an Npc1 null allele (Npc1^nih), creating a dysfunctional NPC1 protein. Npc1^nih mice were fed a two or six percent plant stanol esters–enriched diet over the course of 5 weeks. During this period, hepatic and blood lipid and inflammatory profiles were assessed. Npc1^nih mice fed the plant stanol–enriched diet exhibited lower hepatic cholesterol accumulation, damage and inflammation than regular chow–fed Npc1^nih mice. Moreover, plant stanol consumption shifted circulating T-cells and monocytes in particular towards an anti-inflammatory profile. Overall, these effects were stronger following dietary supplementation with 6% stanols, suggesting a dose-dependent effect. The findings of our study highlight the potential use of plant stanols as an affordable complementary means to ameliorate disorders in hepatic and blood lipid metabolism and reduce inflammation in NPC1 disease.

Niemann-Pick disease, type C1 (NPC1) is a lipid storage disorder in which cholesterol and glycosphingolipids accumulate in late endosomal/lysosomal compartments because of mutations in the NPC1 gene. A hallmark of NPC1 is progressive neurodegeneration of the cerebellum as well as visceral organ damage; however, the mechanisms driving this disease pathology are not fully understood. Phosphoinositides are phospholipids that play distinct roles in signal transduction and vesicle trafficking. Here, we utilized consensus spectra analysis of MS imaging datasets and orthogonal LC–MS analyses to evaluate the spatial distribution of phosphoinositides and quantify them in cerebellar tissue from Npc1-null mice. Our results suggest significant depletion of multiple phosphoinositide species, including phosphatidylinositol (PI), phosphatidylinositol monophosphate (PIP), and bisphosphate (PIP2), in the cerebellum of the Npc1-null mice in both whole-tissue lysates and myelin-enriched fractions. Additionally, we observed altered levels of the regulatory enzyme phosphatidylinositol 4-kinase type 2 α (PI4K2A) in Npc1-null mice. In contrast, the levels of related kinases, phosphatases, and transfer proteins were unaltered in the Npc1-null mouse model as observed by Western blot analysis. Our discovery of phosphoinositide lipid biomarkers for NPC1 opens new perspectives on the pathophysiology underlying this fatal neurodegenerative disease.

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Niemann-Pick disease type C (NPC) disease is a lipid-storage disorder that is caused by mutations in the genes encoding NPC proteins and results in lysosomal cholesterol accumulation. 2-Hydroxypropyl-β-cyclodextrin (CD) has been shown to reduce lysosomal cholesterol levels and enhance sterol homeostatic responses, but CD’s mechanism of action remains unknown. Recent work provides evidence that CD stimulates lysosomal exocytosis, raising the possibility that lysosomal cholesterol is released in exosomes. However, therapeutic concentrations of CD do not alter total cellular cholesterol, and cholesterol homeostatic responses at the ER are most consistent with increased ER membrane cholesterol. To address these disparate findings, here we used stable isotope labeling to track the movement of lipoprotein cholesterol cargo in response to CD in NPC1-deficient U2OS cells. Although released cholesterol was detectable, it was not associated with extracellular vesicles. Rather, we demonstrate that lysosomal cholesterol trafficks to the plasma membrane (PM), where it exchanges with lipoprotein-bound cholesterol in a CD-dependent manner. We found that in the absence of suitable extracellular cholesterol acceptors, cholesterol exchange is abrogated, cholesterol accumulates in the PM, and reesterification at the ER is increased. These results support a model in which CD promotes intracellular redistribution of lysosomal cholesterol, but not cholesterol exocytosis or efflux, during the restoration of cholesterol homeostatic responses.

Jennifer Vogel
May 1, 2020; 69:1032-1041
Pharmacology and Therapeutics

Many chemicals and cellular processes cause oxidative stress that can damage lipids, proteins, or DNA (1). To quickly sense and respond to this ubiquitous threat, organisms have evolved enzymes that neutralize harmful oxidants such as reactive oxygen species and electrophilic compounds (including xenobiotics and their breakdown products) in cells.These antioxidant enzymes include GSH S-transferase (GST),2 NADPH:quinone oxidoreductase 1, thioredoxin, hemeoxygenase-1, and others (2, 3). Many of these proteins are commonly expressed in cells exposed to oxidative stress.The antioxidant response element (ARE) is a major regulatory component of this cellular stress response. The ARE is a conserved, 11-nucleotide-long DNA motif present in the 5'-flanking regions of many genes encoding antioxidant proteins. The laboratory of Cecil Pickett (Fig. 1) at the Merck Frosst Centre for Therapeutic Research in Quebec discovered ARE, a finding reported in the early 1990s in two JBC papers recognized as Classics here (4, 5).jbc;295/12/3929/F1F1F1Figure 1.Cecil Pickett (pictured) and colleagues first described the ARE motif, present in the 5' regions of many genes whose expression is up-regulated by oxidative stress and xenobiotics. Photo courtesy of Cecil Pickett.ARE's discovery was spurred in large part by Pickett's career choice. After completing a PhD in biology and a 2-year postdoc at UCLA in the mid-1970s, he began to work in the pharmaceutical industry.Recruited to Merck in 1978 by its then head of research and development (and later CEO), Roy Vagelos, “I became interested in how drug-metabolizing enzymes were induced by various xenobiotics,” Pickett says.According to Pickett, Vagelos encouraged researchers at the company...

This week, junior doctors in England have taken industrial action for the second time in as many months after failing to reach agreement with the government over their proposed new contract. Tom Moberley and Abi Rimmer, from BMJ Careers, went to the picket lines at Northwick Park Hospital, and University Hospital Lewisham to talk to the doctors,...

A new Rapid Recommendation from The BMJ suggests that for pregnant women, they may wish to avoid certain antiviral treatments for HIV. This recommendation differs from the WHO's, and to discuss why that is, and what makes that difference important, we're joined by Reed Siemieniuk, a physician and methodologist from McMaster University, and Alice...

If you’re lucky enough to not be back at work, you might be feeling like you need to quickly refresh your medical knowledge - and this podcast the BMJ’s education editors take you on a whistlestop tour through the BMJ’s education articles of 2019. Tom Nolan (GP in London) is joined by Navjoyt Ladher (GP in London), Anita Jain (GP in India) and...

Joachim Spranger
Mar 1, 2003; 52:812-817
Pathophysiology

Utility player and Rule 5 selection Connor Joe has been working with the catchers since Reds Spring Training opened. What makes that a little more interesting is that Joe has never caught a game professionally.

Incretin hormone dysregulation contributes to reduced insulin secretion and hyperglycemia in patients with type 2 diabetes mellitus (T2DM). Resistance to glucose-dependent insulinotropic polypeptide (GIP) action may occur through desensitization or downregulation of β-cell GIP receptors (GIP-R). Studies in rodents and cell lines show GIP-R expression can be regulated through peroxisome proliferator–activated receptor (PPAR) response elements (PPREs). Whether this occurs in humans is unknown. To test this, we conducted a randomized, double-blind, placebo-controlled trial of pioglitazone therapy on GIP-mediated insulin secretion and adipocyte GIP-R expression in subjects with well-controlled T2DM. Insulin sensitivity improved, but the insulinotropic effect of infused GIP was unchanged following 12 weeks of pioglitazone treatment. In parallel, we observed increased GIP-R mRNA expression in subcutaneous abdominal adipocytes from subjects treated with pioglitazone. Treatment of cultured human adipocytes with troglitazone increased PPAR binding to GIP-R PPREs. These results show PPAR agonists regulate GIP-R expression through PPREs in human adipocytes, but suggest this mechanism is not important for regulation of the insulinotropic effect of GIP in subjects with T2DM. Because GIP has antilipolytic and lipogenic effects in adipocytes, the increased GIP-R expression may mediate accretion of fat in patients with T2DM treated with PPAR agonists.

The Dallas Cowboys agreed to terms with free-agent offensive lineman Cameron Erving, the team announced Wednesday.

Philadelphia Phillies star Bryce Harper thinks Major League Baseball is "dumb" for its policy that makes the Olympics off-limits for baseball's best players.

Former Auburn defensive tackle Derrick Brown agreed to his rookie contract with the Carolina Panthers on Friday.

David M Nathan
Feb 1, 1992; 15:270-276
Short Report

OBJECTIVE

Topical oxygen has been used for the treatment of chronic wounds for more than 50 years. Its effectiveness remains disputed due to the limited number of robust high-quality investigations. The aim of this study was to assess the efficacy of multimodality cyclical pressure Topical Wound Oxygen (TWO2) home care therapy in healing refractory diabetic foot ulcers (DFUs) that had failed to heal with standard of care (SOC) alone.

As the world gets ready for the Special Olympics Sweden Invitational Games in February, one of the ADA’s member dentists will be watching as the Special Smiles program he founded will be used to screen and attend to the dental needs of the competing athletes.

Over the last 40 years, climate change has been influencing where tropical cyclones form, according to a new study.

As the tropics get wetter, soils are likely experience greater rates of respiration and decomposition, limiting the carbon storage abilities of tropical soils and intensifying global warming.

Horses picked out photographs of their current keepers, and even of former keepers whom they had not seen in months, at a rate much better than chance.

-- Read more on ScientificAmerican.com

They don’t stand on one leg around just anybody but often prefer certain members of the flock.

-- Read more on ScientificAmerican.com

Some years ago, a political scientist conducted an interesting experiment that speaks to the fractured race for the Republican presidential nomination, which now has six candidates, five issues, and four potential front-runners.

WASHINGTON – Four years since the Every Student Succeeds Act (ESSA) was signed into law, all 50 states, the District of Columbia and Puerto Rico have developed accountability plans that include blueprints for serving English Learners (ELs), as well as measuring these students’ progress and being accountable for their outcomes. This marked a significant development, as EL performance was previously not well integrated with factors that determined whether a school was performing well or poorly.

Turn new season cherries into an exotic condiment. These make an elegant accompaniment to pates, terrines, baked ham, roast quail, cheese boards, or serve on antipasto platters to accompany charcuterie or any smoked or cured meats. Add them to a salad containing smoked chicken.

Fresh, bright and delicious.

1 tablespoon extra virgin olive oil 1 large brown onion, thinly sliced 2 large cloves garlic, finely chopped 1 tablespoons finely chopped fresh ginger 1 small red chilli, finely chopped, optional 1 heaped teaspoons ground cumin 1 heaped teaspoon ground coriander teaspoon cinnamon 2 teaspoons #harissa 1 tablespoon sun-dried tomato pesto (or regular tomato paste) 1 kg carrots, peeled and fairly finely sliced 150g red lentils, thoroughly washed 1 x 400g can diced tomatoes 2 teaspoons raw sugar 2-3 teaspoons sea salt, to taste Freshly ground black pepper, to taste Approx.1 litres (6 cups) cool water (double-check next time I make it) Juice - 1 lemon (or lime), to taste 1 x 270ml can coconut cream # My favourite harissa is Chris Manfield's which is available in speciality food shops and on-line

This recipe features on Foodie Tuesday, a weekly segment on 774 Drive with Raf Epstein, 3.30PM, courtesy of David Hall of Pure South Dining.

Delicious gourmet steak, onion and cheese sandwich

2 granny smith apples, coarsely grated 2 beetroots 1/4 tsp. ground clove 2 star anise 1/2 nutmeg finely grated 200ml balsamic vinegar 150g caster sugar

Fresh and easy for summer!

Alejandro Saravia from Pastuso, shared this recipe on Foodie Tuesday, a weekly segment on ABC Radio Melbourne's Drive program at 3.30pm.

3 tbsps. coconut oil oil 2 tbsps. panch phoran spice mix 1 large onion, finely chopped 2 long green chillies, sliced lengthways 6 curry leaves 2 garlic cloves, crushed 1 tbsps. grated ginger 1 tsp. ground turmeric 4 large potatoes, peeled and diced Panch phoran spice mix: 3 tbsp. brown mustard seeds 3 tbsp. fennel seeds 3 tbsp. Nigella seeds 3 tbsp. cumin seeds salt, to taste chopped coriander leaves, to serve

OBJECTIVE

Plasma protein N-glycan profiling integrates information on enzymatic protein glycosylation, which is a highly controlled ubiquitous posttranslational modification. Here we investigate the ability of the plasma N-glycome to predict incidence of type 2 diabetes and cardiovascular diseases (CVDs; i.e., myocardial infarction and stroke).

Ever since we launched our Free COVID-19 Alerting System, we’ve been continuously asked how we made it. In this blog…

For decades, researchers have been studying the effectiveness of different kinds of pick-up lines in order to better understand the psychology of attraction. What they’ve found is that certain types of lines definitely seem to work better than others—and the results have been surprisingly consistent over the years.

Lockdowns and “social distancing” guidelines are changing our intimate lives in major ways. For example, think about people living alone in heavily restricted areas right now. What we’re seeing in our research is that many of these folks are turning to sextech to fill the void in their sexual lives, such as by increasing their participation in activities like sexting and cybersex—and many are trying these things for the very first time. In order to explore the various ways that people are leveraging sextech right now, I spoke to two sextech experts: Dr. Erin Watson and Tasha Falconer.

English language -- Textbooks for foreign speakers.

Greenland -- Discovery and exploration.

Fermented foods.

Adelaide Festival -- History.

Torino : Rosenberg & Sellier, 1890.

London : Adlard, 1904.

London : Longmans, Green, 1903.

Edinburgh : Young J. Pentland, 1895.

London : Caxton Pub. Co, 1908-1909.

London : Macmillan, 1874-1876.