A high proportion of energy from ketone oxidation is transferred to the electron transport chain at the start (as NADH+), in comparison to the energy from fat, where a high proportion is transferred ‘downstream’ (as FADH). This means that, even though there is a high amount of ‘potential energy’ in a fat molecule, less of this can be transferred to ATP.   
For those with gummy results, don’t throw away the bread. I found toasting it in oven on 425 works better than toaster and makes the bread edible if your loaf did come out gummy. Also, by accident, I left a piece in oven and preheated oven later for something else I was making and found my extremely crispy toasted bread which made a GREAT baguette! Now I’m making a bunch like this to eat with different creamed cheese spreads! The only real success I’ve had making this bread is in sub or roll form, otherwise, I too experienced some dense/gummy results, moreso, using the coconut flour recipe though.
I made this late last night and awoke this morning to a beautiful loaf of delicious bread. It even smelled like bread baking. I had to use a mix of blanched and unblanched almond flour due to running out of blanched. I used NOW psyllium powder which is finer in texture than Jay Robb but all I had on hand so I weighed it (like everything else) but didn’t run it through the blender. I also added a dropper full of stevia glycerite to add a subtle sweetness. I’ve made the bun version before and they were really good but the stevia addition seemed to round out the taste and enhance the flavor in a very satisfying way. It rose beautifully and fell slightly but evenly upon cooling overnight. This loaf is perfect! Tomato sandwich, here I come.
Good day every one i want to inform the general public how i was cured from Herpes Virus Patient for good Five years i was loosing hope on myself my Boyfriend ran away from me because of my situation one day i was online and i saw testimony on how Dr ozalogbo help a lady to cure herpes virus,so i still continued searching and then, i saw a testimony of someone again who has been healed from “HIV AIDS by this same Man Dr ozalogbo and she also gave the email address of this man and advise we should contact him for any sickness that he would be of help, so i emailed Dr ozalogbo telling him about my HERPES Virus he told me not to worry that i was going to be cured…oh i never believed it,well after all the procedures and remedy given to me by this man 2 weeks later i started experiencing changes all over me as the Dr ozalogbo assured me,after some time i went to my doctor to confirm if i have be finally healed,behold it was TRUE,that is why i want you to join me in thanking Dr ozalogbo for saving my life if you need his help please contact him via email: (ozalogboshrine@yahoo.com) or whatsapp him with he’s cell phone number;+2348162562991 he is a true healer…..
My bread came out a teeny bit “eggy”…which wasn’t bad, I still enjoyed it. Maybe some egg yolk made it in the batter??? Anyway, the slight egginess made me think of French toast. So with the last few pieces, that’s what I made. I mixed an egg, heavy cream, and a little vanilla to coat the bread…used browned butter to sub for syrup…then topped off with Swerve confectioners sugar. It was delicious!
4. Tapia P. C. Sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: “Mitohormesis” for health and vitality. Medical Hypotheses. 2006;66(4):832–843. doi: 10.1016/j.mehy.2005.09.009. [PubMed] [CrossRef] [Google Scholar]
Formation of O2•− at complexes I and III primarily occurs in the mitochondrial matrix, but some of the O2•− produced at complex III is produced in the intermembrane space [63]. Within the matrix, O2•− is rapidly dismutated into hydrogen peroxide (H2O2) by manganese superoxide dismutase (SOD2) [41, 53]. Some O2•− may escape into the mitochondrial intermembrane space [64] and cytosol [65], where copper/zinc superoxide dismutase (SOD1) can dismutate it into H2O2 [41]. The large majority of mitochondrial H2O2 is removed by peroxiredoxin (Prx) 3, followed by much smaller contributions from Prx5 and glutathione peroxidases (GPx) 1 and 4 [66]. GPx also removes other peroxides, including lipid hydroperoxides [41]. Catalase is another antioxidant enzyme capable of removing H2O2 but is primarily located in peroxisomes and is therefore unlikely to directly remove mitochondrial H2O2 [41, 66]. However, H2O2 can be transported out of mitochondria [67], and it is possible that the majority of mitochondrial H2O2 is removed in the cytosol. Since Prxs and GPxs rely on NADPH for recycling of their cofactors (thioredoxins and glutathione, resp.) [41], and since NADH is required for recycling of NADPH [68], activity of these enzymes would decrease availability of NADH for oxidative phosphorylation. Therefore, transport of H2O2 out of mitochondria for removal in the cytosol may be a more likely defense mechanism [67], implying a more important role of catalase and other antioxidant enzymes outside of mitochondria. Despite the lower reactivity of H2O2, it is still reactive and can oxidize metal ions, particularly iron, to form the hydroxyl radical (•OH), which readily damages DNA, lipids, and proteins [41]. •OH is scavenged by metallothioneins I and II [69, 70] and glutatathione [71], indicating that these antioxidant proteins may be important defenses against byproducts of unaddressed mtROS. Other important antioxidant enzymes include glutamate-cysteine ligase (GCL), which is the rate-limiting step in glutathione synthesis, and glutathione reductase (GSR) and thioredoxin reductase (TRXR), which recycle glutathione and thioredoxin, respectively, to their reduced forms [41].
A ketogenic diet also has been shown to improve blood sugar control for patients with type 2 diabetes, at least in the short term. There is even more controversy when we consider the effect on cholesterol levels. A few studies show some patients have increase in cholesterol levels in the beginning, only to see cholesterol fall a few months later. However, there is no long-term research analyzing its effects over time on diabetes and high cholesterol.
My Wife was diagnosed with ALS (Lou Gehrig’s Disease) when she was 72 years old 4 years ago. The Rilutek (riluzole) did very little to help her. The medical team did even less. Her decline was rapid and devastating. Her arms weakened first, then her hands and legs. Last year, a family friend told us about Organic Herbal clinic and their successful ALS TREATMENT, we visited their website www. organicherbalclinic. com and ordered their ALS Formula, i am happy to report the treatment effectively treated and reversed her Amyotrophic Lateral Sclerosis (ALS), most of the symptoms stopped, she is able to walk and eat well, sleep well and exercise regularly., she is pretty active now and her attitude is extremely positive.

The oral glucose tolerance test (OGTT), or glucose tolerance test is a blood test used (not routinely however) to diagnose diabetes, and gestational diabetes. Information in regard to reliability of the oral glucose tolerance test is important, as some conditions (common cold), or food (caffeine), or lifestyle habits (smoking) may alter the results of the oral glucose tolerance test.


Metabolic syndrome between pregnancies increases the risk of recurrent preeclampsia, according to a retrospective cohort study of 197 women who had preeclampsia during their first pregnancy. Of the 197 women, 40 (20%) had metabolic syndrome between pregnancies. Of these 40 women, 18 (45%) had preeclampsia during their second pregnancy, compared with 27 (17%) of the 157 women without metabolic syndrome between pregnancies. The risk of recurrent preeclampsia increased with the number of components of the metabolic syndrome present. [68, 69]
NOTE:  Make sure to weigh your ingredients to ensure it rises properly and doesn’t get hallow and gummy.  Also, if you do weigh and grind your psyllium and still have a problem, try grinding the psyllium again.  We have a batch of psyllium that we ground and didn’t work.  Stay really wet.  So we ground it again and it works great!  Also, if your loaf looks nice and big but then deflates after removed from the oven, try reducing the baking powder to 3 teaspoons.
I’m giving a testimony about DR.MAGGI the great Herbalist, he has the cure to all manner of diseases, he cured my herpes simplex virus, though I went through different website I saw different testimonies about different spell casters and herbalist, I was like: ‘Many people’s have the herpes simplex virus cure why are people still suffering from it?’ I though of it, then I contact DR MAGGI via email, I didn’t believe him that much, I just wanted to give him a try, he replied my mail and Needed some Information about me, then I sent them to him, he prepared it (CURE) and sent it to me through Airfreight Online Courier Service for delivery, he gave my details to the Courier Office, they told me that 2-3 days I will receive the parcel and i took the medicine as prescribed by him and I went for check-up 2 week after finishing the medicine, I was tested herpes simplex virus negative, if you are herpes simplex virus patient do me a favor by you contacting him and I assure anyone who is suffering it,your problem will never remain the same again you will be cured.also DR MAGGI help my sister husband to cure his HIV/AIDS he was suffering from it for the past 3 years, After he {cure} my herpes simplex virus, then my sister heard about it, she went home to tell her husband about DR MAGGI then her husband email him and explain his problem to him, he also prepare herbal medicine and he use Airfreight courier service to sent him the herbal medicine and he instruct him on how he will be using it for 14 days, That on the 15 days of it, he should go and check his self in the hospital and he did as he was instructed by DR MAGGI to GOD be the glory he was cure of his HIV/AIDS which he was suffering from for the past 3 years thanks to these great man we will ever remain grateful to you sir indeed might work you did in our families. When you contact him, make sure you tell him that I refer you.. contact him via: Maggiherbalcenter@gmail.com or whats-app his telephone number +1(312)767-3460.or you can also text him on +1(662)967-1783 or you can also view his webs:drmaggiherbalcenter.webs.com……
If you need to lose weight, find an eating plan you can stick with. “Whatever results in lasting weight loss for you is the best approach for you,” Wright says. “If you make over-restrictive changes you can't maintain, as soon as you tire of that diet, you will fall back to what you did previously, gain weight, and raise your risk of type 2 diabetes.”

The primary problem in metabolic syndrome is insulin resistance. In the body's attempt to compensate for insulin resistance, extra insulin is produced, leading to elevated insulin levels. The elevated insulin levels can lead, directly or indirectly, to the characteristic metabolic abnormalities seen in these patients. Frequently, the insulin resistance will progress to overt type 2 diabetes, which further increases the risk of cardiovascular complications.
Metabolic syndrome is a cluster of metabolic risk factors that come together in a single individual. These metabolic factors include insulin resistance, hypertension (high blood pressure), cholesterol abnormalities, and an increased risk for blood clotting. Affected individuals are most often overweight or obese. An association between certain metabolic disorders and cardiovascular disease has been known since the 1940s.
Made this bread this morning Will use a little less water next time as along the bottom of the loaf about ½ an inch deep was a bit doughy & it did sink in the middle was also a darker colour than the one in the picture but is so yummy Have sliced it into peices & put 2 slices into bags in the freezer for when I have toast for breakfast Going to make another loaf tomorrow as my husband thought it was great So pleased to have finally found a bread recipe I can enjoy Thank u so much Really enjoy browsing on here
Clinical trials of various ketogenic agents have shown promising outcomes in AD. Recently, a case report was published describing a dramatic improvement in cognitive function in a patient consuming daily drinks of a ketone ester of beta-hydroxybutyrate-butanediol54. This corroborates evidence from animal studies of AD, which showed behavioural and anatomical improvements in AD mice treated with the same ketone ester55. Also, medical foods containing medium chain triglycerides can give an acute improvement in cognitive scores in AD patients 56 ,57. The effectiveness of this treatment was found to depend on the absence of a gene variant that has been associated to increased chance of AD, called APOE4. Finally, following a ketogenic diet for 6 weeks improved the symptoms of mild cognitive impairment58. It is still early days, but the use of ketogenic diets and exogenous ketones may help to improve the quality of life of patients with dementia and their caregivers.             
I can’t believe my genitial herpes and Hepatitis B is really cured, i never thought and believed that one day i will live on earth cured of this disease.i have been suffering of this deadly disease GENITAL herpes and Hepatitis B since 7years ago.Happiness is all i see now i never thought that i will live on earth before the year runs out this is a miracle A shot testimony on how i was cured for my Genital herpes and Hepatitis B Virus diseases by Dr MAGGI with his Herbal Root Herbs Medicine, Although this is almost too impossible to believe, but I am here to fulfill my promise to Dr MAGGI I am a survivor, I am a living proof of this medication, at first it sounded so fake, but my mum encouraged me to continue with the medication, within 3 days I notice the sours in my genitals were all dried up and my tongue stopped paining me, so i stopped taking my ARVS and focused on the herbal medication. I felted my body coming back to life, my skin, my face, no more body weakness and my mum kept praying for me, she was really happy when i was tested negative. This unbelievable transformation have also brought me closer to God, and thanks to Dr MAGG for his regular checkups, calls, sms and chats. I am CURED, I am CURED and I repeat I AM CURED! I have been a slave of Herpes for 3years but it took just 18 days for my cure! God Bless you Sir! contact him now for any kind of diseases problem on his mail (Maggiherbalcenter@gmail.com) contact him on +1[305]697-6952 or whatsapp or call his Africa branch +2348148487280, he is a herbal remedy to all sickness i have copied and sent the link of your contacts to a few Hepatitis B friends, please sir help them and God will increase you! thanks you again sir for putting a smile on my face again so i am posting to this forum saying if you are into similar situation or have any kind of disease problem you can as well contact him for help

Thank you for the terrific recipe. I must admit that this really turned out to be “oopsie bread” for me. Due to the expensive nature of the recipe (organic eggs, almond flour, grass fed butter) I really attempted to follow the recipe perfectly instead of going with my usual improvisational style. I also do not have a food processor however that did not impede anything… a hand mixer and a deft hand did the trick. I did add the optional xanthum gum and erythritol but not the cream of tartar. The batter filled my silicone loaf pan to the top, I smoothed it out and popped it into the oven. Then, to my horror, I saw the little pot of melted butter still on the stovetop. There was nothing to be done except cross my fingers and hope for the best.
Increasing dietary fiber, especially insoluble fiber from cereal and grains, is associated with a reduced risk of diabetes and has been shown to reduce fasting blood glucose and modestly lower HbA1c in people with type 2 diabetes (Martin, J Nutr 2008; Post,J Am Board Fam Med 2012). In people with type 1 diabetes, 50 grams of dietary fiber per day has been shown to significantly improve blood sugar control and reduce hypoglycemic events (Giacco, Diabetes Care 2000). The American Dietetic Association states that "diets providing 30 to 50 g fiber per day from whole food sources consistently produce lower serum glucose levels compared to a low-fiber diet. Fiber supplements providing doses of 10 to 29 g/day may have some benefit in terms of glycemic control." (Slavin, J Am Diet Assoc 2008). Although ConsumerLab.com has not tested fiber products, we have produced a webinar about that provides more information.
^ Klein MS, Buttchereit N, Miemczyk SP, Immervoll AK, Louis C, Wiedemann S, Junge W, Thaller G, Oefner PJ, Gronwald W (February 2012). "NMR metabolomic analysis of dairy cows reveals milk glycerophosphocholine to phosphocholine ratio as prognostic biomarker for risk of ketosis". Journal of Proteome Research. 11 (2): 1373–81. doi:10.1021/pr201017n. PMID 22098372.
Dr Akaka herbal medicine is a good remedy for Hiv/aids, I was a carrier of Hiv/aids and I saw a testimony on how Dr. Akaka cure Hiv/aids, I decided to contact Him, I contacted him and he guided me. I asked him for solutions and he started the remedies for my health. Thank God, now everything is fine, I’m cured by Dr. Akaka herbal medicine, I’m very thankful to Dr.Akaka, reach him on akakasolutionhome@gmail.com
I could go on for days about how a good diet can keep your blood sugar in control. To receive the most efficient information, set up a meeting with a dietician to look at your specific needs and you recent sugar readings. They can provide you with recipes and tools which make it easier for you to know exactly what you are putting into your body. 40 states in the United States require insurance companies to cover a meeting with a dietician for those with diabetes. Check with your insurance to see if this benefit is available for you.
This bread looks amazingly awesome and I will be trying it soon, but with a gluten free psyllium husk brand. I just wanted to point out that J Robb’s Psyllium Husk package declares the presence of WHEAT. Read the label listed on his website. Using his Psyllium Husk would make the bread NOT gluten free. It also states that it has a multitude of other allergens and possibly all of them are in a package at the same time. Just a heads up.

How, exactly, does our body take pyruvate (from glucose) or acetyl CoA (from fat) and generate so much ATP?  The answer lies in the beauty of the Krebs Cycle, which feeds into a process called the electron transport chain (or ETC), I alluded to above.  Since the adage ‘you can’t get something for nothing’ is as true in biochemistry as it appears to be in life, to get all that ATP (i.e., stored energy in the form of the phosphate bond), we need to give up something.  What the ETC does give up, as its name suggests, is electrons.  Through a series of redox reactions the ETC trades the stored energy held by electrons going from higher to lower energy states in exchange for the chemical energy stored in the bonds of the third phosphate group on an ATP molecule.

To get into ketosis without supplementation, you have to keep your insulin levels low. Supplementing with exogenous ketones can help get you into ketosis [17]. However, you won’t have achieved the same beneficial physiological changes as you would have from a well-formulated ketogenic diet or fasting. This is why we at Nutrita don’t recommend exogenous ketones as a substitute for a well-formulated ketogenic diet.

Maria, Maria. I really want this bread to work for me, but I just made my 4th attempt and it’s in the trash. I have read every comment about this bread, watched the video, I have all your recipe books and all the recipes come out great…but THIS bread is my nemesis! I don’t mind that it comes out purple, but my bread doesn’t rise like yours. It’s maybe 2-3″ tall, and it’s only porous on the top, while the bottom is soggy. Then, if I flip it over in the bread pan and bake it longer, to try to dry out the soggy part, the formerly soggy part turns porous and the previously porous part turns soggy. In other words, no matter what I do, the bottom half is disgusting. Is it the pan I’m using?? I have tried aluminized steel and stainless steel, both 9 x 5. I measure everything to the ounce or gram and run my psyllium husk through the coffee grinder a few times before weighing/adding it. I am really determined not to get a half soggy half bread-like purple brick out of this! Thoughts?
When lifestyle changes aren't enough, a child take prescription medicines to treat individual risk factors. So, kids with high blood pressure might be put on antihypertension drugs. Others with high LDL cholesterol might be prescribed statins or other lipid-lowering drugs. Children with high blood sugar, who are on the brink of developing diabetes, may get medicine to decrease insulin resistance.
i am tom kingsley i am so happy to share this testimony on how DR.SAM was able to heal me from Herpes Disease, well i was detected positive on 21st September 2015, and ever since i have been looking for a way to treat and cure this disease from me, but always i try ther was no solution,few weeks ago my aunt rosa introduce me to doctor SAM telling him all my problem he told me what we were to do, that he was going to send me a portion which i am going to take, and after seeing testimony of some people on how Dr sam was able to cure people from Herpes disease, i also heard about it on media when a young lady also gave her testimony about this same Dr sam, well left with no hope i message him and he sent me an herb portion that i will be taken., he told me to go back to the hospital for check up and after i have done that i should come and tell him the good news result, at first when i saw the message i was so shock and still did not believed i will be cured, well friend to make my story short i am cured from herpes now after many time of sorrow, i am Negative, and my sickness are gone, i thank God for leading me to this man….you can email him on samherbalhelp@gmail.com or you can also call,or wattssap him via +2349055464666 he can be of help to you on any problem like {1} HIV/AIDS {2CANCER {3}HERPES {4}DIABETES (5}HERPERTITIS B (6}HPV
Ok, My last question before I try it for the 5th time. Thank you for taking the time to answer!! I know you say grind it more, but here is my dilemma. You says yours weighs 90 grams for 10 tablespoons. So, i weighed mine out (I grind in a high power vitamix) my 10 tablespoons weight 115 grams…so mine is more dense than yours. I’m torn, should I actually grind less? Buy another brand? Maybe Frontier? Thanks for any help. I am so frustrated not having a bread sub for my grain free family 🙁 I tried protein bread but I have this awful aversion to cream cheese taste and can’t seem to get over it 🙁 Even if I could just get a baguette or roll to work out I’d be so happy! I get my hubby’s hopes up every time it bakes because it smells so good! Thanks again!
Hi Melissa, Are you beating the whole eggs? It needs to be egg whites only. Whole eggs will never form peaks. Adding a little cream of tartar helps, as well as making sure you start with a very clean bowl (preferably not plastic if you’re having issues). Having the egg whites at room temperature can be a little easier, too, though I usually don’t need to. Hope this answers your question!
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We can say that no species, including humans, could have survived for millions of years without the ability to withstand brief periods of hunger or starvation (Amen-Ra, 2006). These periods of fasting are themselves ketogenic (McCue, 2010) during which the concentrations of insulin and glucose decrease while that of glucagon increases in the attempt to maintain normal blood glucose levels. When the body passes from a condition of food abundance to one of deprivation (or else via VLCKD simulated deprivation), there is, with a slight delay, an increase in the concentration of free FAs as well as KB in the blood. Thus, from this point of view KD could be compared to caloric restriction for fasting. These manipulations of nutrients, both in quantity and quality, seem to not only act on blood glucose/KB level but also to promote changes in metabolic pathways and cellular signaling. How this kind of metabolic condition (ketosis) can affect satiety and hunger mechanisms is still a matter of debate.
Just like you! i read about doctor herbalist on the internet, Like you i had my doubts and was skeptical but unlike many i decided to place my destiny in my own hands by going further to contact and follow his instructions. These is not a testimony but the words of one who have felt the pains of being infected and affected with Herpes virus and get cured using natural roots and herbs after being in pains and abandoned for 4 years. I was taking my antiviral drug therapy same time praying to heaven and hoping i will be cured by any means which God answered using doctor excel herbal drink and a tree root branch after i have read about his wonderful herbs on YouTube videos posted by a survival. After writing him on Email Excelherbalcure@gmail.com I was amassed by the level of certainty he had by asking i return to do a confirmatory test after using his medicines. I used these medicines for the stipulated weeks and truly the result came out negative i was shocked and could not believe it, i immediately called doctor excel who told me to rejoice and pass the good news to my family and share my testimony with others and that’s why I’m doing this. Friends, I am a witness this day that you should contact Doctor excel for VIRAL infections like Herpes. call excel on +1 (859) 429 1007
Consistent with the mechanisms described above, changes in AMPK in response to a ketogenic or low-carbohydrate diet have been reported in several studies. In rodents, a ketogenic diet (Bio-Serv F3666) has increased AMPK activity in skeletal muscle [150] and AMPK phosphorylation in the liver [230], and a low-carbohydrate diet (18.5% of energy) supplemented with ketone esters (6% w/v) increased AMPK content in brown adipose [149]. In humans, a nonketogenic low-carbohydrate diet (% energy: 50 fat, 30 carbohydrate, and 20 protein) has increased AMPK phosphorylation in skeletal muscle [231].
In a separate post, I explained the difference between nutritional ketosis (NK) and diabetic ketoacidosis (DKA). If this distinction is not clear, I’d suggest giving this separate post a quick skim for a refresher.  DKA is a pathologic (i.e., harmful) state that results from the complete or near absence of insulin.  This occurs in the setting of type 1 diabetes or very end-stage type 2 diabetes, and often as the result of a physiologic insult (e.g., an infection) where the patient is not receiving sufficient insulin to bring glucose into his cells.  A person with a normal pancreas, regardless of how long he fasts (including the fellow I reference above who fasted for 382 days!) or how much he restricts carbohydrates, can not enter DKA because even a trace amount of insulin will keep B-OHB levels below about 7 or 8 mM, well below the threshold to develop the pathologic acid-base abnormalities associated with DKA. Let me reiterate, it is physiologically impossible to induce DKA in anyone that does not have T1D or very, very, very late-stage T2D with pancreatic “burnout.”
Maria – I have been looking at this recipe for years. I have bought everything needed over time, down to the kitchen scale but never baked it. For some reason baking bread made me nervous! Well tonight I bit the bullet and tried it out. It was so easy!! I followed your recipe to a T, measured everything…it came our perfectly! Thank you for all you do! The bread is delicious it’s been years since I’ve enjoyed a slice of bread with butter on it! (Kerry a Gold of course!)

Theoretically, supplying ketones during this period of compromised glucose metabolism could prevent the energy deficit and reduce the likelihood of long-term brain damage. This could be because ketones can act as an alternative, highly energy efficient substrate7. Additionally, the antioxidant, antiinflammatory33 and anti-apoptosis properties of ketones (i.e ketones prevent the opening of the mitochondrial permeability transition pore, which causes cell death66) could protect against neuronal loss and damage. 
My first try at this recipe –lower half was gummy. Crust tasted amazing to I’m eating the ends as toast. I’m too frugal to throw away 3 cups of almond flour, so I cubed up the rest of the loaf, put it in to bake at 350 for 30 minutes or so. Cubes are great on salad -taste like toasted almond/sesame. Now I’m making savory bread pudding with about 2 cups of the cubes (6 eggs, 3/4c almond milk, 1/4c cream, cooked bacon bits, shallots, basil and chives). Baking in muffin tins. Will be taking them for lunches.
The occurrence of mitohormesis is further supported by the potential for mtROS to simultaneously induce bioenergetic and antioxidant adaptations through a single signaling mediator. As discussed later in this review, this mediator is the transcription factor peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), and its role in simultaneously inducing bioenergetic and antioxidant adaptations has been demonstrated in several experimental models of mtROS production, including treatments with paraquat and H2O2. Paraquat is an herbicide that is reduced by the mtETC and subsequently initiates mtROS production by reacting with O2 to produce O2•− [74, 75], and H2O2 is a common form of mtROS. Treatment of a fibroblast cell line (10T1/2) with H2O2 has induced expression of both antioxidant enzymes (SOD1, SOD2, and GPx1) and proteins involved in mitochondrial oxidative phosphorylation, all in a manner largely dependent on PGC-1α [76]. Demonstrating the hormetic benefit of this response in a variety of brain cells, overexpression of PGC-1α protected against cell death induced by H2O2 or paraquat treatment, and this occurred in conjunction with changes in gene expression similar to those observed with the 10T1/2 cells [76]. Although the central role of PGC-1α in linking mitochondrial bioenergetics with antioxidant defense appears to not have been thoroughly investigated in vivo, some suggestive evidence does exist. In skeletal muscle of mice treated with paraquat, content of proteins involved in mitochondrial oxidative phosphorylation and uncoupling have been found to increase in conjunction with greater nuclear localization of PGC-1α [77]. Traditional antioxidant proteins were not measured, but, as will be discussed later, the increase in uncoupling proteins can be regarded as an indication of enhanced antioxidant defense based on the potential of these proteins to decrease mtROS production.
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