Q is for Quitting (or Rather NOT Quitting) Sugar

Dear Genevieve,

To quit sugar is to quit creating energy in a way that is harmonious to creating cellular energy. (See the principles of the universal of energy here: http://www.functionalps.com/blog/2014/06/21/universal-principle-of-cellular-energy/).

Just because you can, doesn’t mean you should. The Hippocratic Oath states we should, “first, do no harm…” and that is what you must always take into account. Your safety is everything. If it’s inappropriate, inefficient, unhelpful and or harmful to yourself and or others, it is probably not a good idea. Yet it is the diet culture, which has really painted sugar as the bad guy. Our physiology knows otherwise though and will give us cues by dictating our cravings. (See more on cravings at https://ichooseicecream.wordpress.com/2016/08/21/g-is-for-guide/). We are bombarded by so much information that we can’t be so hard on ourselves for being nervous about enjoying sugar. We even have pills ready at our disposal, claiming to curb sugar/appetite cravings. Yet, we know when an animal is sick that he/she is unwell, yet we sick to curb our appetite, especially our appetite for sugar to benefit our health?

Smiling, laughing and other normal physiological activities tell us that a baby is well. This is just a short way of saying that the trillions of cells making up the baby are well. Similarly, when the baby is sick, it is a short way of saying that some or all of the baby’s cells are sick. When we give medicine to the sick baby (or sick grown-up), our hope is that the medicine will make these sick cells well again. But unfortunately we are not sure.” – Gilbert Ling

Then we have articles and people preaching the benefits of quitting sugar and suddenly feeling so much better, with a loss of appetite, bounds of energy and exaggerated weight loss. Yet, what we don’t realise and what these people most likely do not realize is that these results are short and may be at the expense of a long-term healing process. It’s “the honeymoon period” these people are experiencing and when someone finds something that works for them, even just for the moment, you can bet that they will shout from the rooftops to every person they come in contact with, not knowing that these results may be sustained by STRESS HORMONES. From my personal experience, I have found I can become very talkative when starving and then calm right down and be more pleasant when well-fed.

Fundamentally, stress hormones do exactly as the name states – place stress on the body. Since we were born, heck, since the dawn of time, “our cells primary and preferred energy source” has always been glucose. (See article The Nutrition Coach http://www.thenutritioncoach.com.au/anti-ageing/defending-fruit-and-other-noncomplex-carbs/). When we work against our own physiology, we create cellular stress and that causes a rise in stress hormones. What does this mean?

Well from the book, “Don’t Quit Sugar,” by Cassie Platt, we learn that this results in:

  • Damaged metabolism
  • Weakened digestion
  • Decreased immunity
  • Sexual and reproductive issues
  • Impaired glucose metabolism
  • Sleep issues
  • Accelerated ageing

…and more, which your body will indicate, take note and take care…

SUFFERING IS NOT A REQUIREMENT FOR SUCCESS.

….but what about burning of storage fat as an energy source?

(From: Politics & Science: William Blake and Art’s Relationship to Science. Thanks to Light. See: https://l-i-g-h-t.com/transcript-474 )

Dr. Ray Peat: It’s very stressful to get in that condition for most people. Extreme hypoglycemia is needed and that typically turns on lots of cortisol production and that has many undesirable consequences, but the worst thing is that almost everyone, the older you are the more polyunsaturated fats you have built into your tissue and those being mobilized and oxidized damage practically everything. They interfere with mitochondrial respiration but they also break down and have cause oxidative damage to everything outside as well as inside the mitochondria. So for a 10-year old, it is not so damaging because their tissues are usually not so loaded with polyunsaturated fats but for a 30 or 40 year old, it can be really harmful.

John Barkhausen: Okay, all right. See, somebody used the metaphor of burning fats is like a slow burning log and burning sugar is like burning kindling. How do you – what’s your take on that metaphor?

Dr. Ray Peat: With a good hot fire you don’t get any smoke, burning unsaturated fats you get very toxic smoke.

So the lesson is burning sugar is a clean way to create energy. It is synonymous with having a “youthful metabolism” and it’s not into old age or in a less than optimal metabolic state that we become inefficient in doing so. Do not make this task more challenging for your body. Work with it and not against it. We need carbohydrates and your body will give out cues to indicate this. In fact, if you can’t get carbs, your body will safeguard you by finding and making glucose from non-carbohydrate sources. It can do this in by two ways:

  1. Lipolysis: fat breakdown
  2. Gluconeogensis: protein breakdown (amino acids).That means, yes, your body will catabolise itself and get amino acids from wherever, including your own muscles to turn them into glucose. This prevents you from the consequences of insufficient blood sugar

If you don’t get enough sugar or starch, then you’ll use protein for energy.” – Ray Peat, PhD

To help facilitate this process, balancing your blood sugar must be prioritized. Basically, making sure you are physiologically not stressed/starving at any point of the day will improve your sleep. Ultimately, the result is freedom from being governed by stress hormones and improved sleep. Even though, sometimes you cannot control external stressors, you probably could exert some control over your blood sugar. (Read more here from Functional Performance Systems http://www.functionalps.com/blog/2012/11/16/low-blood-sugar-basics/ ). Balancing blood sugar = lowered stress hormones = better sleep = better health. For me, I find it is not enough to make sure I just balance my blood sugar for one meal, but rather all day for better sleep and thus better health.

But in energy-deprived humans, increases of adrenaline oppose the hibernation reaction, alter energy production and the ability to relax, and to sleep deeply and with restorative effect.” – Dr Ray Peat, PhD (Thyroid, insomnia and the insanities http://raypeat.com/articles/articles/thyroid-insanities.shtml)

Feed your body better and both it and your mind will thank you from the better sleep.

“Yes. The first thing when your blood sugar falls because your liver hasn’t stored enough glycogen to turn into glucose, the first reaction is for adrenaline to increase to try to squeeze more glycogen into your circulation, for your brain primarily. And when the glycogen is absolutely gone, the adrenaline keeps activating the breakdown of fat and provides increased amounts of circulating fats to make up for the lack of sugar. But, after the fat becomes a source of energy, your cells still need some sugar to maintain their basic processes, and so they turn protein into sugar. And to do that, they increase cortisol, which breaks down gland (thymus is the first to go). And the cortisol will eat up your muscle and skin and immune system pretty quickly to feed your heart, lungs and brain, to keep them alive. So every time your blood sugar falls, you’re shifting over to fat metabolism and breaking down protein, so that your muscles are one of the places that store glycogen. So as your muscles get smaller, then more burden is put on your liver to keep your blood sugar steady and that makes your liver progressively suffer, and eventually it gets to the point that your brain isn’t getting either the right energy or the right kind of energy. One of the things that happens with aging, is that we progressively, from the time we are born, at birth, we’re very highly saturated in our fats, because they’ve been formed from glucose in utero. And we can only make saturated, mono-unsaturated and omega-9 unsaturated fats when we’re supplied with either sugar or protein. But once we start eating in the ordinary environment, our tissues start loading up on the polyunsaturateds from the environment. By the time a person is 40, the brain is pretty full of either the arachadonic acid series or, if they have eaten a lot of fish, there will be mostly the long highly unsaturated fats, mostly the DHA type of fish-oil derived omega-3 fats. And even with a pretty average diet, the old person’s brain is very highly biased towards the DHA type fats. And if you look at Parkinson’s Disease, their favorite genetic protein — that some people like to say is the cause of Parkinson’s Disease, synuclein — is the Parkinson’s equivalent of the glutamine repeat of Huntington’s, or the amyloid, or tau fibrils of Alzheimer’s Disease. Each disease tends to have its own protein that goes haywire. In the case of Parkinson’s, it’s the alpha-synuclein . And DHA, the fish type of unsaturated fat, causes the synuclein protein to change to its toxic form that appears in Parkinson’s Disease. And saturated fats can protect against that. in Parkinson’s you can see the role of fat, inclining the brain towards that degenerative change in the protein. And since pretty much everyone in the environment accumulates these highly unsaturated fats, especially in their brain, but in all tissues with aging, by the time you’re 30 or 40, you become more and more susceptible to all of the degenerative, inflammatory diseases, very much in proportion to the unsaturated fats. And you can find the breakdown products corresponding to the seriousness of Alzheimer’s Disease or Huntington’s or Multiple Sclerosis. The specific breakdown products, such as acrolein, which comes largely from the omega-3 fats, the various reactive break-down products show that these unstable fats are breaking down at an increased rate in the degenerative brain conditions.” – Dr Ray Peat, PhD (Politics, Science, Autoimmune and Movement Disorders).

Personally, I’m fuelled primarily by carbohydrates with adequate proteins and fats for my context. I’m fuelled by balance and I’m never gonna give that up. Never going to let sugar down, unless it’s in coffee…note: I function best on at least 400g of carbohydrates a day, with 120g protein, but your mileage may vary….

Recently, I was alerted to an article by Chris Masterjohn on making glucose from fatty acids. See that article here: https://chrismasterjohnphd.com/2012/01/07/we-really-can-make-glucose-from-fatty/

It’s a pertinent reminder that just because we can do something, does not mean we should or it’s helpful. And sometimes, we don’t really know how much we are suffering until we are out of a situation. Like being in a bad relationship with someone – you can become so accustomed to being treated less than what you deserve that you become desensitised and believe that is normal. But it is not until you are out of that situation that you realise how much you weren’t coping or how heavily you relied on stress hormones to sustain you. We are strong, until we do not have to be. The same may be applied to going from low-sugar to incorporating sugar again. At first, we feel guilty for indulging in our own happiness, after periods of putting diet culture first and going against our physiology and our own needs, but soon we will feel relaxation and as we heal, with balance in our mind, homeostasis will manifest in both our body and mind.

Staying true to ourselves and our physiology is what leads to integrity. In truth, we will always be glycogen-guzzling machines. Feeding your cells with the right sugars will lower your stress hormones and you will get the glucose you need to support many functions, including your brain (thinking power. Note: the brain is the most voracious guzzler of glycogen) and the production of thyroid hormone. When we bring it back to physiology and actually listen to our cravings rather than people preaching fake science, we are able to exhibit more compassion to ourselves and others and the world is never short of enough kindness, especially when we have an increasing amount of angry-sugar-craving or just plain-starving people around.

For me, I’m fueled primarily by carbohydrates with adequate proteins and fats for my context. I’m fueled by balance and I’m never gonna give that up. Never going to let sugar down, unless it’s in coffee…note: I function best on at least 400g of carbohydrates a day, with 120g protein, but your own mileage may vary.

Context is everything, and it’s individual and empirical.” – Dr Ray Peat, PhD

In closing, I’d like to add with gratitude, Dr Ray Peat’s response to Chris Masterjohn’s article:

You seem to be getting both mileage and power from your sugar.

Chris Masterjohn has written some good articles on cholesterol, but this one isn’t so good. The fact that, under extreme conditions, some fat is converted into glucose, doesn’t make ketosis less harmful; most of the glucose is still coming from tissue proteins, and the pathway they identify, through methylglyoxal, just helps to explain some of the long-range harm done by ketosis, since methylglyoxal made from the glycerol released when tissue triglycerides are metabolized is (along with acrolein and other lipid peroxidation products) a major factor in the degenerative changes produced by diabetic ketosis, or by the increased free fatty acid metabolism caused by trauma. Any extra methylglyoxal from fatty acid conversion adds to the effect of that from triglyceride metabolism and any from lactic acid, to accelerate aging, autoimmunity, neurological degeneration, etc.

Klin Lab Diagn. 2010 Mar;(3):22-36.

[Methylglyoxal–a test for impaired biological functions of exotrophy and endoecology, low glucose level in the cytosol and gluconeogenesis from fatty acids (a lecture)].

[Article in Russian]

Titov VN, Dmitriev LF, Krylin VA, Dmitriev VA.

Abstract

In philogenesis, due to the failure to store a great deal of carbohydrates in vivo as glycogen, all animal species began synthesizing from glucose palminitic fatty acid and depositing it as triglycerides. During biological dysfunction of exotrophy (long starvation, early postnatality, hibernation), cells also accomplish a reverse synthesis of glucose from fatty acids under aerobic conditions. Under physiological conditions, acetyl-CoA that is converted to malate and pyruvate in the glyoxalate cycle is a substrate of glyconeogenesis. Under pathological conditions of hypoxia and deficiency of macroerges, gluconeogenesis occurs without ATP consumption through the methylglyoxal pathway when used as a substrate of ketone bodies via the pathway: butyric acid (butyrate) –> beta-hydroxybutyrate –> acetoacetate –> acetone –> acetol –> methylglyoxal –> S-D-lactol-glutathione –> D-lactate –> pyruvate –> D-lactate. Under physiological conditions, this gluconeogenesis pathway does not function. We believe that with low glucose levels in the cell cytosole (glycopenia), under pathological conditions of hypoxia and due to failure to mitochondria to oxidize fatty acids, gene expression and gluconeogenesis occur through the methylglyoxal pathway. At the same time, the cytosol, intercellular environment, and plasma shows the elevated levels of methylglyoxal and D-lactate that it is converted to by the action of glyoxalases I and II. Under pathological conditions, glycopenia develops in starvation, diabetes, and metabolic acidosis, neoplasms, renal failure, and possibly, metabolic syndrome. The chemical interaction of methylglyoxal with the amino acid residues of lysine and arginine results in the denaturation of circulating and structurized proteins via carbonylation–glycosylation.

 

Mech Ageing Dev. 2016 Apr;155:48-54.

Novel insights in the dysfunction of human blood-brain barrier after glycation.

Hussain M(1), Bork K(1), Gnanapragassam VS(1), Bennmann D(1), Jacobs K(2),

Navarette-Santos A(2), Hofmann B(2), Simm A(2), Danker K(3), Horstkorte R(4).

(1)Institute of Physiological Chemistry, Martin-Luther-University

Halle-Wittenberg, Hollystr. 1, D-06114 Halle (Salle), Germany.

(2)Clinic and Policlinic for Cardiothoracic Surgery, University Hospital Halle,

Ernst-Grube-Str. 40, D-06120 Halle (Saale), Germany.

(3)Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Charitéplatz 1,

10117 Berlin, Germany.

(4)Institute of Physiological Chemistry, Martin-Luther-University

Halle-Wittenberg, Hollystr. 1, D-06114 Halle (Salle), Germany. Electronic

address: ruediger.horstkorte@medizin.uni-halle.de.

The blood-brain barrier (BBB) provides a dynamic and complex interface consisting

of endothelial cells, pericytes and astrocytes, which are embedded in a collagen

and fibronectin-rich basement membrane. This complex structure restricts the

diffusion of small hydrophilic solutes and macromolecules as well as the

transmigration of leukocytes into the brain. It has been shown that carbonyl

stress followed by the formation of advanced glycation endproducts

(AGE=glycation) interfere with the BBB integrity and function. Here, we present

data that carbonyl stress induced by methylglyoxal leads to glycation of

endothelial cells and the basement membrane, which interferes with the

barrier-function and with the expression of RAGE, occludin and ZO-1. Furthermore,

methylglyoxal induced carbonyl stress promotes the expression of the

pro-inflammatory interleukins IL-6 and IL-8. In summary, this study provides new

insights into the relationship between AGE formation by carbonyl stress and brain

microvascular endothelial barrier dysfunction.

 

Diabetes. 2016 Jun;65(6):1699-713.

Methylglyoxal-Induced Endothelial Cell Loss and Inflammation Contribute to the

Development of Diabetic Cardiomyopathy.

Vulesevic B(1), McNeill B(2), Giacco F(3), Maeda K(2), Blackburn NJ(1), Brownlee

M(3), Milne RW(4), Suuronen EJ(5).

(1)Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa,

Ontario, Canada Department of Cellular & Molecular Medicine, University of

Ottawa, Ottawa, Ontario, Canada.

(2)Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa,

Ontario, Canada.

(3)Diabetes Research Center, Departments of Internal Medicine and Pathology,

Albert Einstein College of Medicine, Bronx, NY.

(4)Diabetes and Atherosclerosis Laboratory, University of Ottawa Heart Institute,

Ottawa, Ontario, Canada.

(5)Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa,

Ontario, Canada Department of Cellular & Molecular Medicine, University of

Ottawa, Ottawa, Ontario, Canada esuuronen@ottawaheart.ca.

The mechanisms for the development of diabetic cardiomyopathy remain largely

unknown. Methylglyoxal (MG) can accumulate and promote inflammation and vascular

damage in diabetes. We examined if overexpression of the MG-metabolizing enzyme

glyoxalase 1 (GLO1) in macrophages and the vasculature could reduce MG-induced

inflammation and prevent ventricular dysfunction in diabetes. Hyperglycemia

increased circulating inflammatory markers in wild-type (WT) but not in

GLO1-overexpressing mice. Endothelial cell number was reduced in WT-diabetic

hearts compared with nondiabetic controls, whereas GLO1 overexpression preserved

capillary density. Neuregulin production, endothelial nitric oxide synthase

dimerization, and Bcl-2 expression in endothelial cells was maintained in the

hearts of GLO1-diabetic mice and corresponded to less myocardial cell death

compared with the WT-diabetic group. Lower receptor for advanced glycation end

products and tumor necrosis factor-α (TNF-α) levels were also observed in

GLO1-diabetic versus WT-diabetic mice. Over a period of 8 weeks of hyperglycemia,

GLO1 overexpression delayed and limited the loss of cardiac function. In vitro,

MG and TNF-α were shown to synergize in promoting endothelial cell death, which

was associated with increased angiopoietin 2 expression and reduced Bcl-2

expression. These results suggest that MG in diabetes increases inflammation,

leading to endothelial cell loss. This contributes to the development of diabetic

cardiomyopathy and identifies MG-induced endothelial inflammation as a target for

therapy.

© 2016 by the American Diabetes Association. Readers may use this article as long

as the work is properly cited, the use is educational and not for profit, and the

work is not altered.

 

Mediators Inflamm. 2015;2015:691491.

Role of the RAGE Axis during the Immune Response after Severe Trauma: A

Prospective Pilot Study.

Uhle F(1), Lichtenstern C(1), Brenner T(1), Fleming T(2), Koch C(3), Hecker A(4),

Heiss C(5), Nawroth PP(2), Hofer S(1), Weigand MA(1), Weismüller K(3).

(1)Department of Anesthesiology, Heidelberg University Hospital, 69120

Heidelberg, Germany.

(2)Department of Medicine I and Clinical Chemistry, Heidelberg University

Hospital, 69120 Heidelberg, Germany.

(3)Department of Anaesthesiology and Intensive Care Medicine,

Justus-Liebig-University, 35392 Giessen, Germany.

(4)Department of General and Thoracic Surgery, Justus-Liebig-University, 35392

Giessen, Germany.

(5)Department of Trauma, Hand and Reconstructive Surgery, University Hospital of

Giessen-Marburg GmbH, Campus Giessen, 35392 Giessen, Germany.

BACKGROUND: Severe traumatization induces a complex pathophysiology, driven by

the patient’s own immune system. The initial activation is a result of

damage-associated molecular patterns, which are released from disrupted and dying

cells and recognized by immune receptors, for example, RAGE. In this study we

aimed to evaluate the contribution of the RAGE axis to early and late immune

responses.

METHODS: We enrolled 16 patients with severe trauma together with 10 patients

after major abdominal surgery and 10 healthy volunteers. Blood samples were taken

on admission and every 48 h for a total of 8 days. Plasma concentrations of

various RAGE ligands as well as RAGE isoforms and IL-6 were measured by ELISA.

Monocyte surface expression of RAGE and HLA-DR was assessed by flow cytometry.

RESULTS: High and transient levels of IL-6 and methylglyoxal characterize the

early immune response after trauma, whereas samples from later time points

provide evidence for a secondary release of RAGE ligands.

CONCLUSION: Our results provide evidence for a persisting activation of the RAGE

axis while classical mediators like IL-6 disappear early. Considering the

immunocompromised phenotype of the monocytes, the RAGE ligands might be

substantial contributors to the well-known secondary stage of impaired immune

responsiveness in trauma patients.

 

Eur J Med Chem. 2016 Oct 21;122:702-22.

Multifunctional diamine AGE/ALE inhibitors with potential therapeutical

properties against Alzheimer’s disease.

Lohou E(1), Sasaki NA(2), Boullier A(3), Sonnet P(1).

(1)Université de Picardie Jules Verne, Laboratoire de Glycochimie des

Antimicrobiens et des Agroressouces, LG2A, UMR CNRS 7378, UFR de Pharmacie, 1 Rue

des Louvels, F-80037, Amiens Cedex 01, France.

(2)Université de Picardie Jules Verne, Laboratoire de Glycochimie des

Antimicrobiens et des Agroressouces, LG2A, UMR CNRS 7378, UFR de Pharmacie, 1 Rue

des Louvels, F-80037, Amiens Cedex 01, France. Electronic address:

andre.sasaki@u-picardie.fr.

(3)Université de Picardie Jules Verne, UFR de Médecine, 1 Rue des Louvels,

F-80037, Amiens Cedex 01, France; INSERM U1088, Centre Universitaire de Recherche

en Santé (CURS), Avenue René Laënnec – Salouel, F-80054, Amiens Cedex 01, France;

CHU Amiens Picardie, Avenue René Laënnec – Salouel, F-80054, Amiens Cedex 01,

France.

An important part of pathogenesis of Alzheimer’s disease (AD) is attributed to

the contribution of AGE (Advanced Glycation Endproducts) and ALE (Advanced Lipid

peroxidation Endproducts). In order to attenuate the progression of AD, we

designed a new type of molecules that consist of two trapping parts for reactive

carbonyl species (RCS) and reactive oxygen species (ROS), precursors of AGE and

ALE, respectively. These molecules also chelate transition metals, the promoters

of ROS formation. In this paper, synthesis of the new AGE/ALE inhibitors and

evaluation of their physicochemical and biological properties (carbonyl trapping

capacity, antioxidant activity, Cu(2+)-chelating capacity, cytotoxicity and

protective effect against in vitro MGO-induced apoptosis in the model AD

cell-line PC12) are described. It is found that compounds 40b and 51e possess

promising therapeutic potentials for treating AD.

Copyright © 2016 Elsevier Masson SAS. All rights reserved.

 

J Physiol Biochem. 2017 Feb;73(1):121-131.

Ferulic acid prevents methylglyoxal-induced protein glycation, DNA damage, and

apoptosis in pancreatic β-cells.

Sompong W(1)(2), Cheng H(3), Adisakwattana S(4)(5).

(1)Department of Clinical Chemistry, Faculty of Allied Health Sciences,

Chulalongkorn University, Bangkok, 10330, Thailand.

(2)Research Group of Herbal Medicine for Prevention and Therapeutic of Metabolic

Diseases, Chulalongkorn University, Bangkok, 10330, Thailand.

(3)Department of Comparative Biomedical Sciences, School of Veterinary Medicine,

Louisiana State University, Baton Rouge, LA, 70803, USA.

(4)Research Group of Herbal Medicine for Prevention and Therapeutic of Metabolic

Diseases, Chulalongkorn University, Bangkok, 10330, Thailand.

sirichai.a@chula.ac.th.

(5)Department of Nutrition and Dietetics, Faculty of Allied Health Sciences,

Chulalongkorn University, Bangkok, 10330, Thailand. sirichai.a@chula.ac.th.

Methylglyoxal (MG) can react with amino acids of proteins to induce protein

glycation and consequently the formation of advanced glycation end-products

(AGEs). Previous studies reported that ferulic acid (FA) prevented glucose-,

fructose-, and ribose-induced protein glycation. In this study, FA (0.1-1 mM)

inhibited MG-induced protein glycation and oxidative protein damage in bovine

serum albumin (BSA). Furthermore, FA (0.0125-0.2 mM) protected against

lysine/MG-mediated oxidative DNA damage, thereby inhibiting superoxide anion and

hydroxyl radical generation during lysine and MG reaction. In addition, FA did

not have the ability to trap MG. Finally, FA (0.1 mM) pretreatment attenuated

MG-induced decrease in cell viability and prevented MG-induced cell apoptosis in

pancreatic β-cells. The results suggest that FA is capable of protecting β-cells

from MG-induced cell damage during diabetes.

 

Int J Mol Sci. 2017 Feb 15;18(2). pii: E421.

Methylglyoxal-Derived Advanced Glycation Endproducts in Multiple Sclerosis.

Wetzels S(1)(2), Wouters K(3), Schalkwijk CG(4), Vanmierlo T(5), Hendriks JJ(6).

(1)Department of Internal Medicine, Cardiovascular Research Institute Maastricht,

Maastricht University, 6229 Maastricht, The Netherlands.

suzan.wetzels@uhasselt.be.

(2)Department of Immunology and Biochemistry, Biomedical Research Institute,

Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium.

suzan.wetzels@uhasselt.be.

(3)Department of Internal Medicine, Cardiovascular Research Institute Maastricht,

Maastricht University, 6229 Maastricht, The Netherlands.

kristiaan.wouters@maastrichtuniversity.nl.

(4)Department of Internal Medicine, Cardiovascular Research Institute Maastricht,

Maastricht University, 6229 Maastricht, The Netherlands.

c.schalkwijk@maastrichtuniversity.nl.

(5)Department of Immunology and Biochemistry, Biomedical Research Institute,

Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium.

tim.vanmierlo@uhasselt.be.

(6)Department of Immunology and Biochemistry, Biomedical Research Institute,

Hasselt University, Martelarenlaan 42, 3500 Hasselt, Belgium.

jerome.hendriks@uhasselt.be.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system

(CNS). The activation of inflammatory cells is crucial for the development of MS

and is shown to induce intracellular glycolytic metabolism in pro-inflammatory

microglia and macrophages, as well as CNS-resident astrocytes. Advanced glycation

endproducts (AGEs) are stable endproducts formed by a reaction of the dicarbonyl

compounds methylglyoxal (MGO) and glyoxal (GO) with amino acids in proteins,

during glycolysis. This suggests that, in MS, MGO-derived AGEs are formed in

glycolysis-driven cells. MGO and MGO-derived AGEs can further activate

inflammatory cells by binding to the receptor for advanced glycation endproducts

(RAGE). Recent studies have revealed that AGEs are increased in the plasma and

brain of MS patients. Therefore, AGEs might contribute to the inflammatory status

in MS. Moreover, the main detoxification system of dicarbonyl compounds, the

glyoxalase system, seems to be affected in MS patients, which may contribute to

high MGO-derived AGE levels. Altogether, evidence is emerging for a contributing

role of AGEs in the pathology of MS. In this review, we provide an overview of

the current knowledge on the involvement of AGEs in MS.

 

Int J Biol Macromol. 2017 May;98:664-675.

Formation mechanism of glyoxal-DNA adduct, a DNA cross-link precursor.

Vilanova B(1), Fernández D(2), Casasnovas R(2), Pomar AM(2), Alvarez-Idaboy

JR(3), Hernández-Haro N(4), Grand A(5), Adrover M(2), Donoso J(2), Frau J(2),

Muñoz F(2), Ortega-Castro J(2).

(1)Department de Química, Institut Universitari d’Investigació en Ciències de la

Salut (IUNICS), Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain;

Instituto de Investigación Sanitaria de Palma (IdISPA), 07010 Palma de Mallorca,

Spain. Electronic address: bartomeu.vilanova@uib.es.

(2)Department de Química, Institut Universitari d’Investigació en Ciències de la

Salut (IUNICS), Universitat de les Illes Balears, 07122 Palma de Mallorca, Spain;

Instituto de Investigación Sanitaria de Palma (IdISPA), 07010 Palma de Mallorca,

Spain.

(3)Facultad de Química, Departamento de Física y Química Teórica, Universidad

Nacional Autónoma de México, México D.F. 04510, Mexico.

(4)CEA, INAC-SyMMES, F-38000 Grenoble, France.

(5)Univ. Greboble Alpes, INAC-SCIB, F-38000 Grenoble, France; CEA, INAC-SyMMES,

F-38000 Grenoble, France; Universidad Autónoma de Chile, Carlos Antúnez 1920,

7500566, Providencia, Santiago de, Chile.

DNA nucleobases undergo non-enzymatic glycation to nucleobase adducts which can

play important roles in vivo. In this work, we conducted a comprehensive

experimental and theoretical kinetic study of the mechanisms of formation of

glyoxal-guanine adducts over a wide pH range in order to elucidate the molecular

basis for the glycation process. Also, we performed molecular dynamics

simulations to investigate how open or cyclic glyoxal-guanine adducts can cause

structural changes in an oligonucleotide model. A thermodynamic study of other

glycating agents including methylglyoxal, acrolein, crotonaldehyde,

4-hydroxynonenal and 3-deoxyglucosone revealed that, at neutral pH, cyclic

adducts were more stable than open adducts; at basic pH, however, the open

adducts of 3-deoxyglucosone, methylglyoxal and glyoxal were more stable than

their cyclic counterparts. This result can be ascribed to the ability of the

adducts to cross-link DNA. The new insights may contribute to improve our

understanding of the connection between glycation and DNA cross-linking.

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Author: ichooseicecream

Located in Sydney, Australia.

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