COVID-19-Associated dyslipidemia: Implications for mechanism of impaired resolution and novel therapeutic approaches

Authors : Alexander V SorokinSotirios K KarathanasisZhi-Hong YangLita FreemanKazuhiko KotaniAlan T Remaley

Abstract

The current coronavirus disease 2019 (COVID-19) pandemic presents a global challenge for managing acutely ill patients and complications from viral infection. Systemic inflammation accompanied by a “cytokine storm,” hemostasis alterations and severe vasculitis have all been reported to occur with COVID-19, and emerging evidence suggests that dysregulation of lipid transport may contribute to some of these complications. Here, we aim to summarize the current understanding of the potential mechanisms related to COVID-19 dyslipidemia and propose possible adjunctive type therapeutic approaches that modulate lipids and lipoproteins. Specifically, we hypothesize that changes in the quantity and composition of high-density lipoprotein (HDL) that occurs with COVID-19 can significantly decrease the anti-inflammatory and anti-oxidative functions of HDL and could contribute to pulmonary inflammation. Furthermore, we propose that lipoproteins with oxidized phospholipids and fatty acids could lead to virus-associated organ damage via overactivation of innate immune scavenger receptors. Restoring lipoprotein function with ApoA-I raising agents or blocking relevant scavenger receptors with neutralizing antibodies could, therefore, be of value in the treatment of COVID-19. Finally, we discuss the role of omega-3 fatty acids transported by lipoproteins in generating specialized proresolving mediators and how together with anti-inflammatory drugs, they could decrease inflammation and thrombotic complications associated with COVID-19.

Keywords: COVID-19; dyslipidemia; inflammation; lipoproteins; oxidation.

Full Article : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361619/

Group X Secreted Phospholipase A2 Releases ω3 Polyunsaturated Fatty Acids, Suppresses Colitis, and Promotes Sperm Fertility

Abstract

Within the secreted phospholipase A2 (sPLA2) family, group X sPLA2 (sPLA2-X) has the highest capacity to hydrolyze cellular membranes and has long been thought to promote inflammation by releasing arachidonic acid, a precursor of pro-inflammatory eicosanoids. Unexpectedly, we found that transgenic mice globally overexpressing human sPLA2-X (PLA2G10-Tg) displayed striking immunosuppressive and lean phenotypes with lymphopenia and increased M2-like macrophages, accompanied by marked elevation of free ω3 polyunsaturated fatty acids (PUFAs) and their metabolites. Studies using Pla2g10-deficient mice revealed that endogenous sPLA2-X, which is highly expressed in the colon epithelium and spermatozoa, mobilized ω3 PUFAs or their metabolites to protect against dextran sulfate-induced colitis and to promote fertilization, respectively. In colitis, sPLA2-X deficiency increased colorectal expression of Th17 cytokines, and ω3 PUFAs attenuated their production by lamina propria cells partly through the fatty acid receptor GPR120. In comparison, cytosolic phospholipase A2 (cPLA2α) protects from colitis by mobilizing ω6 arachidonic acid metabolites, including prostaglandin E2. Thus, our results underscore a previously unrecognized role of sPLA2-X as an ω3 PUFA mobilizer in vivo, segregated mobilization of ω3 and ω6 PUFA metabolites by sPLA2-X and cPLA2α, respectively, in protection against colitis, and the novel role of a particular sPLA2-X-driven PUFA in fertilization.

Keywords: arachidonic acid (AA) (ARA), colitis, inflammation, lipid metabolism, membrane, Phospholipase A, polyunsaturated fatty acid (PUFA), prostaglandin, sperm

Source : Journal Of Biological Chemistry

ChooseLife : Yet more evidence, of the beneficial properties imbued in individuals, who choose to pay head to Budwig et al. and seek to gain a better balance in their Omega3 to Omega6 ratios. I wouldn’t be without my Flaxoil/Flaxseeds, neither would my… too much!

THE EFFECTS OF SUGAR ON THE BRAIN AND MEMORY

by Dr.Dave on Jan 5, 2016     

Americans are undeniably great consumers of added sugar. The average person’s intake is over 126 grams of sugar daily which is way too much. Sugar per se is not harmful but too much of it is detrimental to health. High sugar consumption has long been linked to weight gain, and the development of obesity and lifestyle diseases such as heart disease and diabetes. More recent studies show that sugar can also induce memory problems and neuroinflammation.

A study conducted at the University of Southern California (USC) revealed that intakse of high fructose corn syrup (HFCS) at levels similar to those in commonly available sugary beverages can trigger memory problems and brain inflammation. In the study, adolescent rats consuming high quantities of HFCS were subsequently found to have impaired hippocampal-dependent spatial learning and memory when subjected to the Barne’s Maze test. Rats consuming a sucrose solution experienced moderate learning impairment. Adult rats given either HFCS or sucrose did not show any problems with spatial learning, glucose tolerance or neuroinflammatory markers. According to Scott Kanoski, one of the proponents of the research, the brain is vulnerable to dietary influences during critical periods of development, like adolescence. He further explained that a diet high in added sugar can not only cause weight gain and metabolic problems, but also impair brain function and cognitive ability.

This is supported by an earlier study at the University of California in Los Angeles (UCLA) that tested the effects of fructose and omega-3 fatty acid consumption among rats. Two groups of rats were initially trained to find their way out of a maze. The results showed that long-term consumption of a high fructose diet by the rats negatively affected their cognitive function and ability to recall while omega 3 fatty acids were able to counteract those effects. After six weeks, the rats that consumed fructose forgot the previously learned escape route and developed signs of insulin resistance. The impaired learning and memory problems exhibited by this group of rats was attributed to insulin’s inability to regulate how cells use and store sugar.

Sucrose and high fructose corn syrup are liquid sweeteners often added to processed foods and common beverages such as soft drinks and juices. These added sugars are quickly absorbed in the blood where it lowers the production of brain-derived neurotrophic factor (BDNF), a substance known to influence the formation of new memories and regulate learning. Individuals with impaired glucose tolerance were found to have low levels of this chemical. Low levels of BDNF have also been associated with depression and dementia.

So before you drink your favorite juice or munch on a delectable dessert, remember that added sugars from such beverage and food items are likely culprits for health complications including poor memory and cognitive damage. Avoiding foods with added sugars will help you stay fit and keep your mind healthy.

References:

  1. https://www.washingtonpost.com/news/wonk/wp/2015/02/05/where-people-around-the-world-eat-the-most-sugar-and-fat/
  2. http://www.worldhealth.net/news/sugar-triggers-memory-problems-and-neuroinflammati/
  3. http://newsroom.ucla.edu/releases/this-is-your-brain-on-sugar-ucla-233992
  4. http://www.forbes.com/sites/daviddisalvo/2012/04/01/what-eating-too-much-sugar-does-to-your-brain/
  5. http://www.besthealthnutritionals.com/blog/2014/07/22/eating-sweets-can-rot-your-brain/
  6. http://www.dailymail.co.uk/health/article-2683174/Is-SUGAR-responsible-rising-dementia-cases-High-levels-glucose-cause-memory-loss-study-finds.html
  7. https://pressroom.usc.edu/sugar-linked-to-memory-problems-in-adolescent-rats/
  8. https://www.psychologytoday.com/blog/neuronarrative/201204/what-eating-too-much-sugar-does-your-brain

https://www.integrativepsychiatry.net/blog/the-effects-of-sugar-on-the-brain-and-memory/

Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association

Ann C. Skulas-RayPeter W.F. WilsonWilliam S. HarrisEliot A. BrintonPenny M. Kris-EthertonChesney K. RichterTerry A. JacobsonMary B. EnglerMichael MillerJennifer G. RobinsonConrad B. BlumDelfin Rodriguez-LeyvaSarah D. de FerrantiFrancine K. Weltyand On behalf of the American Heart Association Council on Arteriosclerosis, Thrombosis and Vascular Biology; Council on Lifestyle and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Cardiovascular and Stroke Nursing; and Council on Clinical Cardiology

Originally published : 19 Aug 2019 https://doi.org/10.1161/CIR.0000000000000709

Summary and Conclusions

Prescription n-3 FAs at the FDA-approved dose of 4 g/d are safe and generally well tolerated. At this dose, triglyceride lowering of ≥30% has been reported in clinical trials of subjects with VHTG (triglycerides ≥500 mg/dL), in whom these agents are FDA approved.

In VHTG, the goal of therapy is to reduce triglyceride levels to <500 mg/dL and to lessen the risk of pancreatitis, although this may not be achieved with n-3 FA monotherapy, so additional triglyceride-lowering pharmacological treatment may be indicated. In the context of HTG (triglycerides, 200–499 mg/dL), 4 g/d prescription n-3 FA effectively lowers triglycerides by ≈20% to 30% and does not significantly increase LDL-C.

In all patients, established recommendations for diet and lifestyle should also be followed.11 In the largest studies of 4 g/d EPA+DHA or EPA-only as adjuncts to statin therapy, non–HDL-C and apo B were modestly decreased, suggesting reductions in total atherogenic lipoproteins.

Use of n-3 FA may be accompanied by mild gastrointestinal complaints (such as “fishy burps” or nausea), but taking n-3 FA with meals may reduce gastrointestinal side effects and improve absorption of O3AEE and IPE. In clinical trials completed to date, <5% of subjects have discontinued omega-3 agents because of side effects.

The triglyceride-lowering efficacy and generally excellent safety and tolerability of n-3 FAs make them valuable tools for healthcare providers. The use of n-3 FAs (4 g/d) for improving ASCVD risk in patients with HTG is supported by a 25% reduction in major adverse cardiovascular end points in REDUCE-IT, a randomized placebo-controlled trial of EPA-only in high-risk patients on statin therapy.

Results from the STRENGTH trial, a randomized placebo-controlled cardiovascular outcomes trial of 4 g/d prescription EPA+DHA in patients with HTG and low HDL-C on statins, are anticipated in 2020. We conclude that prescription n-3 FAs, whether EPA+DHA or EPA-only, at a dose of 4 g/d, are clinically useful for reducing triglycerides, after any underlying causes are addressed and diet and lifestyle strategies are implemented, either as monotherapy or as an adjunct to other triglyceride-lowering therapies 

Full : https://www.ahajournals.org/doi/10.1161/CIR.0000000000000709

ChooseLife Notes : It is well established that EPA and DHA are both readily created by ALA, so similar results should be expected from Flax Oil.

Dietary Flaxseed Supplementation Ameliorates Inflammation and Oxidative Tissue Damage in Experimental Models of Acute Lung Injury in Mice

Paul KinniryYassine AmraniAnil VachaniCharalambos C. SolomidesEvguenia ArguiriAlexander WorkmanJack CarterMelpo Christofidou-Solomidou

The Journal of Nutrition, Volume 136, Issue 6, June 2006, Pages 1545-1551, https://doi.org/10.1093/jn/136.6.1545

Published: 01 June 2006 Article history

ABSTRACT

Flaxseed (FS) is a nutritional supplement with high concentrations of (n-3) fatty acids and lignans that have anti-inflammatory and antioxidant properties. The use of FS in the prevention or treatment of acute lung disease is unknown. In this study, we evaluated diets with high FS content in experimental murine models of acute lung injury and inflammation. The kinetics of lignan accumulation in blood, following 10% FS supplementation, was determined using liquid chromatography tandem mass spectrometry. Mice were fed isocaloric control and 10% FS-supplemented diets for at least 3 wk and challenged by hyperoxia (80% oxygen), intratracheal instillation of lipopolysacharide, or acid aspiration. Bronchoalveolar lavage was evaluated for white blood cells, neutrophils, and proteins after a 24 h postintratracheal challenge of hydrochloric acid or lipopolysacharide, or after 6 d of hyperoxia. Lung lipid peroxidation was assessed by tissue malondialdehyde concentrations. The plasma concentrations of the FS lignans, enterodiol and enterolactone, were stable after mice had eaten the diets for 2 wk. Following hyperoxia and acid aspiration, bronchoalevolar lavage neutrophils decreased in FS-supplemented mice (P = 0.012 and P = 0.027, respectively), whereas overall alveolar white blood cell influx tended to be lower (P = 0.11). In contrast, neither lung injury nor inflammation was ameliorated by FS following lipopolysacharide instillation. Lung malondialdehyde levels were lower in hyperoxic mice than in unchallenged mice (P = 0.0001), and decreased with FS treatment following acid aspiration (P = 0.011). Dietary FS decreased lung inflammation and lipid peroxidation, suggesting a protective role against pro-oxidant-induced tissue damage in vivo.

Omega-3 Fatty Acid Supplementation Improves Endothelial Function in Primary Antiphospholipid Syndrome: A Small-Scale Randomized Double-Blind Placebo-Controlled Trial

Sheylla M. Felau, Lucas P. Sales, […], and Fabiana B. Benatti

Abstract

Endothelial cells are thought to play a central role in the pathogenesis of antiphospholipid syndrome (APS). Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation has been shown to improve endothelial function in a number of diseases; thus, it could be of high clinical relevance in APS. The aim of this study was to evaluate the efficacy of n-3 PUFA supplementation on endothelial function (primary outcome) of patients with primary APS (PAPS). A 16-week randomized clinical trial was conducted with 22 adult women with PAPS. Patients were randomly assigned (1:1) to receive placebo (PL, n = 11) or n-3 PUFA (ω-3, n = 11) supplementation. Before (pre) and after (post) 16 weeks of the intervention, patients were assessed for endothelial function (peripheral artery tonometry) (primary outcome). Patients were also assessed for systemic markers of endothelial cell activation, inflammatory markers, dietary intake, international normalized ratio (INR), and adverse effects. At post, ω-3 group presented significant increases in endothelial function estimates reactive hyperemia index (RHI) and logarithmic transformation of RHI (LnRHI) when compared with PL (+13 vs. −12%, p = 0.06, ES = 0.9; and +23 vs. −22%, p = 0.02, ES = 1.0). No changes were observed for e-selectin, vascular adhesion molecule-1, and fibrinogen levels (p > 0.05). In addition, ω-3 group showed decreased circulating levels of interleukin-10 (−4 vs. +45%, p = 0.04, ES = −0.9) and tumor necrosis factor (−13 vs. +0.3%, p = 0.04, ES = −0.95) and a tendency toward a lower intercellular adhesion molecule-1 response (+3 vs. +48%, p = 0.1, ES = −0.7) at post when compared with PL. No changes in dietary intake, INR, or self-reported adverse effects were observed. In conclusion, 16 weeks of n-3 PUFA supplementation improved endothelial function in patients with well-controlled PAPS. These results support a role of n-3 PUFA supplementation as an adjuvant therapy in APS. Registered at http://ClinicalTrials.gov as NCT01956188.

Frying oil consumption worsened colon cancer and colitis in mice, study shows

Research compared effects of fresh and thermally processed oil

Date : August 23, 2019

Source : University of Massachusetts at Amherst

Summary : Food scientists have shown that feeding frying oil to mice exaggerated colonic inflammation, enhanced tumor growth and worsened gut leakage, spreading bacteria or toxic bacterial products into the bloodstream.

Foods fried in vegetable oil are popular worldwide, but research about the health effects of this cooking technique has been largely inconclusive and focused on healthy people. For the first time, UMass Amherst food scientists set out to examine the impact of frying oil consumption on inflammatory bowel disease (IBD) and colon cancer, using animal models.

In their paper published Aug. 23 in Cancer Prevention Research, lead author and Ph.D. student Jianan Zhang, associate professor Guodong Zhang, and professor and department head Eric Decker showed that feeding frying oil to mice exaggerated colonic inflammation, enhanced tumor growth and worsened gut leakage, spreading bacteria or toxic bacterial products into the bloodstream.

“People with colonic inflammation or colon cancer should be aware of this research,” says Jianan Zhang.

Guodong Zhang, whose food science lab focuses on the discovery of new cellular targets in the treatment of colon cancer and how to reduce the risks of IBD, stresses that “it’s not our message that frying oil can cause cancer.”

Rather, the new research suggests that eating fried foods may exacerbate and advance conditions of the colon. “In the United States, many people have these diseases, but many of them may still eat fast food and fried food,” says Guodong Zhang. “If somebody has IBD or colon cancer and they eat this kind of food, there is a chance it will make the diseases more aggressive.”

For their experiments, the researchers used a real-world sample of canola oil, in which falafel had been cooked at 325 F in a standard commercial fryer at an eatery in Amherst, Massachusetts. “Canola oil is used widely in America for frying,” Jianan Zhang says.

Decker, an expert in lipid chemistry performed the analysis of the oil, which undergoes an array of chemical reactions during the frying process. He characterized the fatty acid profiles, the level of free fatty acids and the status of oxidation.

A combination of the frying oil and fresh oil was added to the powder diet of one group of mice. The control group was fed the powder diet with only fresh oil mixed in. “We tried to mimic the human being’s diet,” Guodong Zhang says.

Supported by grants from the U.S. Department of Agriculture, the researchers looked at the effects of the diets on colonic inflammation, colon tumor growth and gut leakage, finding that the frying oil diet worsened all the conditions. “The tumors doubled in size from the control group to the study group,” Guodong Zhang says.

To test their hypothesis that the oxidation of polyunsaturated fatty acids, which occurs when the oil is heated, is instrumental in the inflammatory effects, the researchers isolated polar compounds from the frying oil and fed them to the mice. The results were “very similar” to those from the experiment in which the mice were fed frying oil, suggesting that the polar compounds mediated the inflammatory effects.

While more research is needed, the researchers hope a better understanding of the health impacts of frying oil will lead to dietary guidelines and public health policies.

“For individuals with or prone to inflammatory bowel disease,” Guodong Zhang says, “it’s probably a good idea to eat less fried food.”

https://www.umass.edu/newsoffice/article/study-shows-frying-oil-consumption

Omega-3 polyunsaturated fatty acid inhibits the malignant progression of hepatocarcinoma by inhibiting the Wnt/β-catenin pathway

F.-Z. Chang, Q. Wang, Q. Zhang, L.-L. Chang, W. Li

Department of Gastroenterology, Qingdao Hiser Medical Group, Qingdao, China. Leewei22011@163.com

OBJECTIVE: Omega-3 polyunsaturated fatty acid (ω-3 PUFA) has been found to possess anti-cancer potential in previous studies. However, the underlying mechanism of ω-3 PUFA in protecting hepatocarcinoma has not been fully elucidated. This study aims to explore the function of ω-3 PUFA in the development of hepatocarcinoma and its potential mechanism.

PATIENTS AND METHODS: In this study, human hepatocarcinoma cell line Hep G2 was treated with ω-3 PUFA. Cell counting kit-8 (CCK-8) and cell cloning assay were applied to detect the proliferation of Hep G2 cells. In addition, flow cytometry was performed to analyze the cell cycle and apoptosis rate. At the same time, the effect of ω-3 PUFA on invasion and metastasis of hepatocarcinoma cells were analyzed by transwell assay. Moreover, protein levels of key factors in Wnt/β-catenin pathway were detected by Western blot.

RESULTS: Cell proliferation of Hep G2 cells was decreased after ω-3 PUFA treatment in a time- and dose-dependent manner. CCK-8 assay showed that the IC50 value was 12.8 ± 0.67 μmol/L, 8.8 ± 0.43 μmol/L and 4.6 ± 0.42 μmol/L after ω-3 PUFA treatment for 24 h, 48 h and 72 h, respectively. Besides, ratio of Hep G2 cells blocked at G2/M phase after ω-3 PUFA treatment (5 μmol/L, 10 μmol/L and 20 μmol/L) was increased in a dose-dependent manner (p<0.05). Meanwhile, ω-3 PUFA could increase cell apoptosis (p<0.05) and inhibit cell proliferation. In addition, ω-3 PUFA reduced protein expressions of total, cytoplasmic and nuclear β-catenin in Hep G2 cells, indicating that the Wnt/β-catenin pathway is inhibited. Decreased expression levels of Dvl-2, Dvl-3, GSK-3β (p-ser9), c-myc and survivin, and increased expression levels of GSK-3 (p-tyr216) and Axin-2 were observed in Hep G2 cells treated with ω-3 PUFA, but no significant alteration in total GSK-3β protein level was observed (p>0.05).

CONCLUSIONS: Omega-3 PUFA regulates the malignant progression of hepatocarcinoma by inhibiting proliferation and promoting apoptosis of hepatocarcinoma cells via Wnt/β-catenin signaling pathway.

Sourced = https://www.europeanreview.org/article/15504

ChooseLife Notes : This is overlapping data, from the studies on carcinoma apoptosis, which have been compiled here = http://chooselife.co.uk/index.php/flax/ Though this study does not make clear the form of Omega3 used.

Supplementation with EPA and DHA reduces high levels of circulating proinflammatory cytokines in aging adults: a randomized, controlled study

Full Publication

Background

High levels of circulating proinflammatory cytokines are characteristic of inflammaging, a term coined to describe age-related chronic systemic inflammation involved in the etiology of many age-related disorders including nonhealing wounds. Some studies have shown that supplementing diets with n-3 polyunsaturated fatty acids (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) lowers systemic levels of key proinflammatory cytokines associated with inflammaging. However, findings from the few studies that have focused exclusively on older adults are inconclusive. As such, the objective of this randomized controlled study was to test the effects of EPA+DHA therapy on circulating levels of proinflammatory cytokines in adults in middle to late adulthood.

Methods

Plasma levels of fatty acids and interleukin (IL)-6, IL-1β and tumor necrosis factor-α (TNF-α) were measured in 35 participants with chronic venous leg ulcers (mean age: 60.6 years) randomnly assigned to 8 weeks of EPA+DHA therapy (2.5 g/d) or placebo therapy.

Results

EPA+DHA therapy had a significant lowering effect on levels of IL-6, IL-1β and TNF-α after 4 weeks of therapy and an even greater lowering effect after 8 weeks of therapy. Further, after adjusting for baseline difference, the treatment group had significantly lower levels of IL-6 (p = .008), IL-1β (p < .001), and TNF-α (p < .001) at Week 4 and at Week 8 [IL-6 (p = .007), IL-1β (p < .001), and TNF-α (p < .001)] compared to the control group.

Conclusion

Adults in middle to late adulthood receiving EPA+DHA therapy demonstrated significantly greater reductions in circulating levels of proinflammatory cytokines compared with those receiving placebo therapy. EPA+DHA therapy may be an effective low-risk dietary intervention for assuaging the harmful effects of inflammaging.