Health and wellness by Dr Corey Kirshner

Finding the Cause of Your Peripheral Neuropathy

September 28, 2016 / Conditions / By Corey Kirshner
Trying to explain what peripheral neuropathy is, and how finding the cause of your peripheral neuropathy is essential to your successful treatment, may seem daunting in the space of a blog post. At times it can be a very easy condition to address and fix, but more frequently it is very complex.

Peripheral neuropathy means the nerves outside of your spinal cord are damaged. Although often related to diseases like diabetes, the nerve damage ultimately comes from one of five things.

Five common causes of Peripheral Neuropathy:

1. Nerves are not getting enough nutrients (fuel) to stay healthy.

2. Nerves are not being activated, or used enough to stay healthy.

3. Nerves are being deprived of oxygen.

4. Nerves are being compressed, and from the point of compression on down, they are dying because of a lack of fuel, oxygen or activation.

5. Or, you are suffering from a combination of all of the above.

Depending upon the cause of your peripheral neuropathy, and which nerves are affected, you will eventually have symptoms like pain, tingling and numbness predominately in your feet, but it may spread to your hands as well. As nerves continue to die these symptoms will worsen and start to affect other tissue. The most commonly affected is the cerebellum, the part of your brain that controls eye movement, balance, and coordination of movement, so it is not coincidental that along with your peripheral neuropathy you may also have trouble balancing.

Try this test: stand in a relaxed manner, putting more weight on your left foot, then try to place your right foot on the floor directly in front of the left, touching the right heal to the left toe. Were you able to keep your balance? Now switch sides and try again? You should not wobble.

Pain is a normal, natural and essential sensation for your body to experience. It tells you something is wrong. Medications may truly give you relief from your pain symptoms, but relief only occurs while taking the medication; it masks symptoms for as long as you continue taking it. When you stop, you are still left with the underlying condition – your peripheral neuropathy. It has not been cured. And what’s worse, the entire time your symptoms and pain were being masked there is a good chance your nerves degenerated further. The purpose of medication is to change your brain chemistry NOT find the root cause of your symptoms. How will you ever regain healthy nerves if you don’t find which of the 5 causes of peripheral neuropathy you are suffering from?

Patient A and Patient B both suffered from peripheral neuropathy. Both had symptoms that were continuing to worsen. Patient A was 57 and Patient B was 62. Both were on Lyrica to minimize pain yet, their pain was slowly increasing, especially the burning foot pain at night.

Patient A suffered from diabetes and blood tests also revealed macrocytic anemia. Both conditions can deprive nerves of adequate fuel and oxygen. Knowing 2 of the causes of peripheral neuropathy are a lack of fuel (nutrients) and a lack of oxygen to the nerves, a fairly simple treatment plan was developed for Patient A. One which got his blood sugar under control and supported the efficient transport of oxygen rich blood. Within 4 months Patient A related that his peripheral neuropathy pain was gone, his use of Lyrica eliminated, and his blood sugar which was 160-180 with meds before treatment was reduced to 85-110 after treatment enabling him to decrease is diabetes medication by 75%.

Patient B, also diabetic, presented a more complex case. In addition to his diabetes, his initial examination showed he was suffering from loss of “wide diameter afferent neurons.” These nerves, when healthy, block pain. With this information treatment was directed to stabilize blood sugar and improve activation of these “wide diameter afferent nerves.” It was explained to Patient B that this treatment would take longer to see results. Five months into the care he related an 80% reduction of pain intensity and he was able to sleep at night with no pain.

Even though their peripheral neuropathy symptoms seemed the same, it took a careful individual assessment to find the underlying cause or causes in each case. Finding the cause of your peripheral neuropathy is the first step in a successful, drug free plan to improve nerve health and live a pain free life.

Why Are My Hands and Feet Always Cold?
September 28, 2016 / Conditions / By Corey Kirshner

Why Are My Hands and Feet Always Cold?

It’s a warm and slightly humid 82 degree end of summer kind of day. Bright sun, kids heading back to school, thoughts of reorganizing and cleaning out the house are pervasive as we move from one season to the next. If you look carefully the outer tips of leaves are starting to change, some have even begun to fall bringing with them thoughts of apple picking, football and pumpkins. A wonderful stirring of emotions until you remember this seasonal change brings with it a drop in temperature and the longing for spring when your hands and feet will be warm again. Unfortunately, some of us don’t even enjoy the reprieve of summer; we spend our days wondering “why are my hands and feet always cold?”

Contrary to popular belief cold hands and feet don’t just happen, they are a symptom of something not working optimally in your body that the warmest of mittens won’t fix. Although there can be a number of CAUSES for your cold hands and feet, it’s important not to fall too quickly into the trap of focusing on one single thing as the culprit.

Possible causes of cold hands and feet:

Anemia and other nutritional deficiencies

Autoimmune diseases like Raynaud’s and Hashimoto’s
Over active sympathetic nerves
Hormonal imbalances
Thyroid Dysfunction
Chances are you have been researching your condition and understand my caution when reading the above list. For those new to this information let me explain. All of the conditions listed have the ability to cause cold hands and feet on their own BUT they are most often intertwined with one another. We refer to this as a “web of physiologic dysfunction.” For instance, thyroid dysfunction occurs in approximately 30% of women, some will have anemia and cold hands and feet, or the autoimmune condition known as Raynaud’s and an inability to lose weight, others may be experiencing digestive disorders and depression along with their cold hands and feet. So, again it is essential to consider all the possible culprits.

Let’s look at some of the possibilities more closely starting with thyroid conditions.

As mentioned, 30% of women in the US suffer from thyroid related issues. Your thyroid gland controls your metabolism. Metabolism is your body’s process for turning food into energy. If your thyroid is sluggish your metabolism slows down and so do all of the systems of your body that depend upon it. Cold hands and feet can easily be attributed to poor blood flow to peripheral nerves as a result of faulty metabolism. Other metabolic break downs may appear as hair loss, weight gain, depression, fatigue and digestive disorders.

80% of thyroid related issues actually stem from an autoimmune condition call Hashimoto’s. What does that mean for you? Your thyroid symptoms, fatigue, depression, hair loss, dry skin, digestive disorders and yes, cold hands and feet are secondary to an autoimmune condition. Meaning you generally won’t have one without the other. The web of physiologic dysfunction is in play here. If your thyroid condition is treated without considering the autoimmune component or vice versa there is a high probability you will continue to suffer and allow the underlying cause to wreak havoc on your body.

Anemia, hormonal imbalances and nerve issues, all of which may be related to metabolic breakdown, are also listed above as possible culprits of your cold hands and feet. But as you are learning, these may be the primary problem causing your symptoms OR the secondary problem; remember the role the web of physiologic dysfunction plays in your health. The relationship of anemia in thyroid sufferers is well documented, with some studies claiming as many as 43% of hypothyroid patients having some type of anemia.

In reality you are suffering from two things: the SYMPTOMS – cold hands and feet, and the underlying CAUSES of your condition.

The biggest pitfalls in your care will be treating the symptoms as the problem, and focusing only on one possible cause. Avoid these pitfalls and stop asking “Why are my hands and feet always cold?” Get proper testing, including a complete thyroid panel (not just TSH) with thyroid antibodies, check Vitamin D levels, as low Vitamin D is a precursor for many diseases including autoimmune conditions, and when indicated, test for intestinal permeability, a condition that will cause significant nutritional deficits.

Wouldn’t it be a nice change to enjoy a mug of warm apple cider because of the sweet, spicy dance it performs on your tongue instead of holding onto it for dear life as your hand warmer?

Why Can’t I Eat Anything Without Feeling Sick?
September 28, 2016 / Conditions / By Corey Kirshner
One of the most commonly asked questions among IBS, Crohn’s & Colitis patients is “Why can’t I eat anything without feeling sick?” Typically when people are intolerant to may foods they will direct their attention to the “what” question. “What can I eat? What will calm down the reaction? What do I take to settle my stomach?” Answering the “what” question will lead to many “solutions” but will not uncover the underlying cause. “What” solutions are many: restrict your diet, take pills and acid blockers, get tested for food allergies. Or, you can start asking Why you can’t eat anything without feeling sick.

By asking why you can’t eat anything without feeling sick , you are seeking the root cause of your condition, not just a resolution to the effects or symptoms from your condition. Although there are other possible reasons you may be reacting to everything you eat, one of the most common causes is a condition called Intestinal Permeability, or Leaky Gut. Your digestive tract begins with your mouth and ends with, well, your other end. Each part of the system has a specific job, from ingesting food to excreting it, the system is finely tuned to keep your body functioning properly. The job of the small intestine, where Leaky Gut can occur is to breakdown the proteins, fats and carbohydrates from the foods you eat before they enter your blood stream to nourish all the cells of your body. A healthy small intestine is lined with densely packed cells that act as a filter for the broken down particles. The space between these cells are referred to as junctions. A healthy intestine will have tight junctions or a very fine filter. Like the screens in your house, the junctions create a barrier that are meant to let the good stuff in while keeping the bad stuff out. Large undigested particles of food, parasites, and bacteria are all able to pass through the weakened junctions of a leaky gut which alerts the body to a foreign invader causing an inflammatory reaction.

Systemic inflammatory reactions related to Intestinal Permeability:

Nonspecific joint pain
Brain fog
Fatigue
Skin issues
Bloating
Constipation
Diarrhea
Without fixing this barrier, you will develop more food intolerances and more systemic inflammatory reactions.

Going back to the most important question-Why? Why would you have Intestinal Permeability? This question has many answers. Foods sensitivities, low Vitamin D, intestinal parasites, medications, stress, and hyperthyroid or hypothyroid are all known culprits. From these culprits your barrier system will be affected in stages, starting with localized inflammation of the intestinal lining. As the lining continues to degrade your whole immune system will join the battle and, even though the damage is confined to the gut, the whole body immune/inflammatory reaction may cause symptoms anywhere in the body. Brain fog, skin conditions like acne or eczema, headaches, joint pain, and of course food sensitivities are all inflammatory reactions to Leaky Gut. As leaky gut progresses even further you will develop an accumulation of lipopolysaccharides locally in the gut, which is basically an overgrowth of bad bacteria or sludge on the intestinal wall which further affects the inflammatory process and inhibits digestion, creating a state of malnutrition.

By allowing the condition to persist you are seriously hindering any chance of regaining health. There are tests available to determine if you have Intestinal Permeability and what type you may have. Uncovering this roadblock will help to answer the question “Why can’t I eat anything without feeling sick?”

Dr. Kirshner holds Free Workshops where you can learn more about your condition and how to control it without medication.

Top health topics on aging and health hacks 3-20-2018

View
Eggplant and apple cider vinegar for skin cancer
View
Signs of the preactive/ active phase of dying and medications for terminally ill
View
Apple cider vinegar kills parasites, cleansing to the liver and prevents stroke
View
Philippines Coconut Wine -Tuba
View
DMSO, hydrogen peroxide and Vit C fight cancer cells
View
Nitric Oxide Dump Exercise with nose breathing to lower blood pressure and thin blood
View
Home page / Archives
View
MEDICATIONS TO AVOID that worse PD (Parkinson’s disease)
View
Can Gout be cured permanently?
View
Non pasteurized beers have more health benefits
View
Answers to your health questions from science and cultural healing ways
View
Iron and sweet wormwood herb kill breast cancer cells in 16hrs
View
Fatigue and Red (bloodshot) eyes from WebMD
View
Vagus nerve stimulation thru breathing, laughs and yoga
View
Can balsamic vinegar help with gout?
View
Fungus on tobacco, wheat and other plants
View
Anti-aging and Parkinson/Alzheimer’s prevention: Enzymes and apple cider vinegar
View
Answers to your health questions from science and cultural healing ways
View
What’s a good analogy to explain the immune system?
View
Soluble fiber encapsulates bad fats and sugar out of your body
View
Sovaldi , for Hepatitis C, is $483 in India and $84,000 in the USA
View
Increase the body’s oxygen carrying capacity with exercise, EPO and whole foods
View
Ultrasound kills bacteria , frequency and music killing cancer cells
View
Detox your lungs from air pollution and metal toxins and for early lung cancer
View
Iodine prevents cancer growth; up avocado and reduce caffeine intake to prevent Thyroid cancer
View
Healthcare C-suite lacks diversity
View
16 Tips On How To Treat HPV Naturally And Effectively At Home
View
How important is the thymus gland in keeping your body free from diseases?
View
Avoid chronic bronchitis with green apple, onions, garlic, vinegar and rest
View
Parasites and their effects on your immune system
View
Dopamine pathways and Parkinson
View
Parkinson and Exercises
View
2
Shark oil for your skin, wound healing and overall health
View
2
Iron and sweet wormwood herb kill breast cancer cells in 16hrs
View
2
Lung cancer in the Philippines
View
2
When will Souvenaid become available in Canada and US to treat Alzheimer’s Disease?
View
2
Good fats, SCFA – short chain fatty acids
View
2
Stop aging of your face with DIY Vitamin C serum by wellnessmama
View
2
Anabolic and catabolic process, hormones and exercise
View
2
What could cause an low basophil count?
View
2
24-hr lip stain for powerful lips
View
1
Menu for the healthy plus kitchen tips
View
1
More nitrate-reducing bacteria in saliva causes Migraine
View
1
Your complete DNA sequence will help shape the future of medicine
View
1
Restore your vision naturally y Dr. Mercola
View
1
Wrinkles lessen in 4 months of Jeunesse Luminesce use
View
1
Gout, Dementia, Chelation Therapy
View
1
Massage oil of fresh ginger and coconut oil relieves joint pain
View
1
Boron fights radiation by Dr Mercola
View
1
Eat protein-rich food when drinking alcohol to protect your stomach
View
1
Vitamin B and Pineapple for nerve damage by Dr E. Kane
View
1
Mullein herb for lung and breast health – COPD signs, symptoms and diagnosis
View
1
How many hours does it take normally for the stomach to empty totally after a good meal. Is it a good eating habit not to eat during this…
View
1
Cancer statistics
View
1
Liver cancer , China has 50% of worldwide cases, Molds in food
View
1
IRS-1 protein in blood, indicative of Alzheimer
View
1
Joint pain gone with Anti-inflammatory yellow powder, UltraX360
View
1
When to see a dermatologist or doctor
View
1
Shingles Natural Treatments
View
1
Levenson Self-Report Psychopathy Scale, a test of sociopathy
View
1
How quickly do different cells in the body replace themselves?
View
1
Foods to eat and avoid when you have Gout and leg pains
View
1
What are the benefits of eating chicken soup during pregnancy?
View
1
Neck pain and MTHFR gene , folate , methionine
View
1
Nitric Oxide for strong blood vessels’ cells , up with exercise, melons, cucumber, Vit C, E, amino acid – L-arginine, L-citrulline
View
1
Roman Coriander, Fennel flower or Black Cumin Seed Oil as an anti-tumor, anti-gastritis and anti-convulsant oil
View
1
Slimy veggies, saluyot and okra fight cancer
View
1
Alcohol, virus, sugar and fats lead to fatty liver
View
1
Lung cancer and heavy metal toxins
View
1
Hair Loss/Weight Loss, herbs for allergies, drug side-effects, herbs with caution, chemo Q&A
View
1
Grow the Feeling and the Essence of Argentine Tango
View
1
Anti-aging Vitamin B3, Niacin
View
1
Dr Mercola’s book – Fat for Fuel
View
1
Yoga and behavioral memory interventions for the aging brain
View
1
Fasting, sun bathing ,Vit C, Lysine, turmeric, green tea, carrots and raw food diet to reduce tumor size
View
1
Does drinking warm water reduce cholesterol?
View
1
Paul Ryan and Mitch McConnell implicated in Russia-Trump
View
1
Non pasteurized beers have more health benefits
View
1
Inclined Bed Therapy
View
1
Link between liver disease and heart problems
View
1
Cardio-based body weight exercises
View
1
Why is the Quora community so anti-Donald Trump?
View
1
How to replace our anti-hypertensive medication
View
1
Levenson Self-Report Psychopathy Scale, a test of sociopathy
View
1
Best health topics on How To and tips about our health
View
1
Countdown to April 14 March for Science
View
1
Free trip to Africa on March 18-22 , qualify by Dec 31
View
1
Mike Pence involvement in Russia scandal
View
1
Reducing belly fat
View
1
I’m 36 years old, and my SGPT level is 131. Is this serious? How can I reduce my SGPT level in a week?
View
1
Baking soda for mosquito bites
View
1
Association of Coffee Consumption With Total and Cause-Specific Mortality Among Nonwhite Populations
View
1
Men’s health
View
1
Andrew McCabe is a patriot
View
1
Why life expectancy in the Philippines decreased?
View
1
Stephen Colbert Monologue | 8/3/2017 The F.B.I.’s Trump-Russia Investigation
View
1
We do not want to die with no one beside us
View
1
Metabolism Myths
View
1
Carbon monoxide poisoning and Dementia
View
1
5x more antioxidants in Okinawan diet of sweet potatoes and low calorie diet
View
1
Prevention mag: Alzheimer’s disease
View
1
Gut Microbes May Talk to the Brain Through Cortisol
View
1
Thyme herb for toe fungus (guava and comfrey leaves and others)
View
1
Top aging and health hacks 3-16-2018
View
1
Signs of the preactive/ active phase of dying and medications for terminally ill
View
1
Narrative Medicine
View
1
Yohimbine and sleep apnea
View
1
What is ‘dry drowning?’
View
1
Prostate flush and masturbation
View
1
Constipation, kidney stones and sedentary
View
1
In-home caregivers can prevent re-admission and an important care team member
View
1
Top posts
View
1
Zinc and lemongrass for skin health issues
View
1
NAC, activated charcoal , sleep and parasites
View
1
Calcium, magnesium, Vitamin D3 and K2 and Omega-3s cut risk of cancer
View
1
Australia has announced the new skilled occupation list for the immigration 2018
View
1
Stroke Recovery Improved by Sensory Deprivation
View
1
MIND Diet
View
1
Inflammation Linked to Chemo Brain
View
1
Nervous system puts the brakes on inflammation
View
1
New York Times Opinions 3-15-2018
View
1
Washington Post opinions 3-15-2018
View
1
John Oliver: Bernie Sander called it God Forbid
View
1
How to replace our anti-hypertensive medication
View
1
Leg cramps, heart muscles, magnesium and CQ10

How To Heal Your Metabolism , reset your hormones and make you feel young

How To Heal Your Metabolism

How to Heal Your Metabolism

Lately, as many of you know I have been deep in reading and researching about the systems of the body, healing the body, nutrients, foods that heal and how they are all related in increasing metabolic function.  I think we can agree that we would all like to increase our metabolism…right?  As we get older we are led to believe that our metabolism will just naturally slow down.  We will have to work harder and eat less just to stay thin and feel good about ourselves.  Do these statements ring true to you?  They certainly did for me…of course, until now.

Here are ELEVEN things that will help increase cellular respiration and help heal your metabolism.

  1. Stop dieting
  2. Reduce all other toxins
  3. Get more Sleep
  4. Get more Sunlight
  5. Decrease polyunsaturated fats (PUFA) in meats
  6. Decrease phytoestrogens (soy)
  7. Increase saturated fats in coconut oil
  8. Eat the right types of carbohydrates (sugars) in ripe fruits, root vegetables
  9. Eat the right type of protein in eggs and white fish
  10. Increasing Carbon dioxide (C02) by eating baking soda or carbonated water

You see, for many years, I believed the only way that I could increase my metabolic expenditure (increase calories burned) was to add more muscle to my body and/or to exert more energy through increased exercise load and intensity.  However, there is actually a third way to increase your metabolism.  One that is not discussed very often, either because people do not know about it or they just do not understand it.  Are you wondering what it is?  Oh, I bet you are…

Over the last few years of my studies, I have begun to look at the body and its functions very differently.  I have realized that the health of our metabolism is more than just how much we move and how much muscle we have; a healthy metabolism is about what is happening in every cell of our body and the actual respiration of every cell of our body.  Thus, if we can increase cellular respiration we can increase metabolic function.

First, what is cellular respiration?

Cellular respiration is the set of the metabolic reactions and processes that take place in the cells of organisms to convert biochemical energy from nutrients into adenosine triphosphate (ATP), and then release waste products.

Basically, it is what happens when glucose (sugar) enters the cells and converts to usable energy.  Without getting too scientific, it’s the most efficient way for cells to harvest energy stored in food.

Cellular respiration has three main stages: glycolysis, the Kreb’s cycle, and the electron transport chain.  For all the geeks, here is a basic explanation of each, for everyone else, skip ahead…

  1. Glycolysis is the metabolic process occurring in the cytosol of your cells that converts glucose (sugar) into two pyruvate molecules.  Glycolysis is an anaerobic (does not require oxygen) reaction that has an end production of 2 ATP (ATP is usable energy) molecules.
  2. Kreb’s Cycle (Citric Acid Cycle) is an aerobic (requires oxygen) reaction that occurs in the mitochondria of every cell in your body.  The mitochondria are referred to as the cell’s power plant because they produce most of the cells supply of ATP (energy). Once oxygen is present, Acetyl Co A is produced from the two pyruvate molecules.  Through an 8-step process 6 NADH, 2 FADH2, and 2 ATP are formed (yes, I know you have no idea what this means…but keep reading, it will all make sense soon).
  3. 3. Electron Transport Chain (ETC) is also an aerobic reaction occurring in the mitochondria.  The ETC transports electrons from donors (like NADH and FADH2) to acceptors (like Oxygen).   When working properly the Kreb’s cycle and the ETC produce most of the cells energy.  The end result is an additional 34 ATP.  As you can see we need adequate amount of glucose, oxygen and a healthy mitochondria to produce sufficient amounts of energy…without these our cells become inefficient and eventually die.

Have I lost you with all this scientific jargon?  Stick with me; things will start to come together soon…

What I want you to see is when everything is working optimally and our cells are getting adequate glucose and oxygen we produce lots of energy (increased cellular respiration).  With increased cellular respiration our metabolism increases.  A great running metabolism means we are meeting our body’s energy needs, we are repairing tissue, we are detoxing properly, we have proper hormone function, we have good energy, we feel happy and life is good.

Did you ever have a friend when you were young who was thin, didn’t workout and could eat whatever she wanted and never gain a pound?  You know, that friend you hated… we will call her Britch.   Britch had great cellular respiration.  It is not the amount of muscle she had or the amount of exercise or activity she did that kept her thin.  Her increased metabolic function came from great cellular respiration.  However, if Britch continued to live her crappy-eating, non-exercising lifestyle her cells would become damaged and her lifestyle would catch up to her.

Many of us would attribute this phenomenon to great genes.   This is partially true since our mitochondria has its own set of DNA.   However, we can help or harm the health of our cellular respiration through the foods we eat, the lifestyles we choose and the decisions we make.  So even if you were not born with great mitochondrial genes you can still improve OR worsen your cells energy production.

  1. Decrease polyunsaturated fats (PUFA).  As I have discussed before PUFAs are highly unstable and oxidize easily in the body.  PUFAs cause mitochondrial damage and reduce respiration.  PUFAs also bind to the same protein receptors that transport your thyroid hormone, reducing thyroid usage…which, once again, has an adverse effect on your cells respiration.  Some examples of PUFA’s are vegetable oils, corn oils, seed oils, nut oils, fish oils, most nuts and seeds and most conventional meats.
  2. Decrease phytoestrogens (soy). An increased level of phytoestrogens increases free fatty acids (FFA) in the body.  FFA acids are known to inhibit the thyroid function and disrupt glucose metabolism.  Soy, like PUFAs, lowers cellular respiration.
  3. Increase saturated fats. Yes, you heard me.  Increasing the right types of saturated fats like coconut oil, organic butter or ghee, cocoa butter, raw organic dairy, and grass fed meats can be very beneficial for your cells.  Saturated fats are stable. Unlike PUFAs, saturated fats bind to proteins in the correct way.  They are used properly and do not break down causing damage to mitochondria genes (DNA).
  4. Eat the right types of carbohydrates (sugars). I know everyone is scared of the words carbohydrate and sugar these days.  You would think by telling you to consume them, it is like telling you to go jump off a bridge.  We must understand not all carbohydrates (sugars) are created equal.  When I say the right types of carbs or sugars, I am referring to ripe fruits, root vegetables, organic raw dairy, pulp free OJ and some low starch above ground vegetables.  I am not referring to processed cookies, crackers, grains, breads and candies.   Sugar is the bodies preferred source of energy.  When we use the right sugars to fuel our cells they produce the most energy by using the least amount of our own bodies resources.  When we use a less optimal fuel (like protein or fat) our body uses more resources to produce less energy.
  5. Eat the right type of protein. Consuming easily digestible proteins like organic beef broth, gelatin, white fish, eggs, dairy and shellfish help support the liver and thyroid.  Increase thyroid hormone increases mitochondria respiration and increases CO2 production.
  6. Increasing Carbon dioxide (C02). C02 helps increase cellular respiration.  You can increase your C02 levels by living at high altitudes (Denver, you are all set), bag breathing, ingesting or bathing in baking soda and increasing your intake of carbonated water.
  7. The right exercise.  Stressful exercise increases mitochondrial damage.  Long duration cardio is incredibly stressful to the body.  Endurance athletes, although fit, have decreased cellular function, you can see this in their very low pulse and low body temperature.  According to Dr. Ray Peat “concentric” weight training is actually restorative to the cells mitochondria.  This means lifting with a load and relaxing without a load.  Burst training (short burst of exercise followed by rest) is also supportive of a healthy metabolism.
  8. Get more Sunlight. According to Dr. Ray Peat, “It turns out that day light 
stimulates our ability to use oxygen for energy production, and
 protects our tissues from some of the free-radical toxins that are
 produced by normal metabolism, by stress, or by radiation.”   This does not mean lay in the sun for 10 hours/day.  Refer to my blog on Vitamin D to help decide how much sun you need.
  9. Get more Sleep. Getting restorative sleep helps with proper cellular function.  This can mean anywhere from 6- 10 hours depending on the person.  Deep sleep is better than more sleep.  Best hours for sleeping are between the hours of 10:30PM -6:30AM.  When the body is at rest its primary energy source should be fat.  Burning fat while sleeping is far less harmful to the cells than oxidizing it while working out.  Remember to optimize energy production sugars should be used while awake and fats should be used while asleep.
  10. Stop dieting. Dieting, starvation, and detox programs may all help you lose weight fast and help you feel better in the short run.  However, long term they are all doing the same thing…they damage your mitochondria and decrease cellular respiration.  Have you ever wondered why ever time you “diet” it gets a little harder to lose weight?  It’s because “dieting”deprives our cells of proper energy and nutrients, damaging our cells and decreasing metabolism.
  11. Reduce all other toxins.  Remove as many toxins from your life as possible.  This includes processed foods, trans-fats, high fructose corn syrup, additives, preservatives, carrageenan, hormones, anti-biotics, drugs, alcohol, environmental toxins, fluoride, pesticides, herbicides, mercury, radiation, etc.  All toxins will disrupt and interfere with proper cell function.  All toxins will lower cellular respiration.

Okay, you got all that?  Yes, I know this is a lot to take in.  And yes, I know some of you may think I am crazy.  This is totally okay with me.  However, what you should know is everything I write about is based on the physiology of the human body, scientific research and my own self-experimentation.   I am not here to tell you what you should or should not do.  My intentions for giving you this information is to only share with you what I am learning, and how it is helping not only myself, but also many of my clients.

Please understand the recommendations I am giving are not person specific.  Every person is different, is at a different state of health and has different needs.  You must also understand that healing the body on a cellular level takes time, a real commitment to wanting to get better and a belief that you are doing the right thing.  There is so much misinformation on health and nutrition out there, it is hard to know what to believe anymore.  In fact, you should question everything you learn, including me.  It is important that you investigate on your own, find out what works for you, ask lots questions, and get help from a professional if you feel you need it.  For more information on how to heal your metabolism…Buy The BOOK.

Happy healing!

Your Optimal Health Coach,

Kate

“Disclaimer:  I am an exercise physiologist, personal trainer, nutritional and lifestyle coach, not a medical doctor.  I do not diagnose, prescribe for, treat or claim to prevent, mitigate or cure any human disease or physical problem. I do not provide diagnosis, care treatment or rehabilitation of individuals, nor apply medical, mental health or human development principles.  I do not prescribe prescription drugs nor do I tell you to discontinue them.  I provide physical and dietary suggestions to improve health and wellness and to nourish and support normal function and structure of the body.  If you suspect any disease please consult your physician.”

References:

  1. Mitochondria and Mortality.  Dr. Ray Peat
  2. Energy structure and carbon dioxide: A realistic view of the organism. Dr. Ray Peat
  3. Using Sunlight to Sustain Life.  Dr. Ray Peat
  4. The acute phase response and exercise: the ultra marathon as prototype exercise. Clin J Sport Med. 2001 Jan;11(1):38-43.
  5. Systemic inflammatory response to exhaustive exercise. Cytokine kinetics.
Suzuki K, Nakaji S, Yamada M, Totsuka M, Sato K, Sugawara K.  Exerc Immunol Rev. 2002;8:6-48.
  6. Inhibition of NADH-linked mitochondrial respiration by 4-hydroxy-2-nonenal.
Humphries KM, Yoo Y, Szweda LI.  Biochemistry. 1998 Jan 13;37(2):552-7.
  7. 4-Hydroxy-2(E)-nonenal inhibits CNS mitochondrial respiration at multiple sites.
Picklo MJ, Amarnath V, McIntyre JO, Graham DG, Montine TJ.  J Neurochem. 1999 Apr;72(4):1617-24.
  8. Effect of high plasma free fatty acids on the free radical formation of myocardial mitochondria isolated from ischemic dog hearts.
Kamikawa T, Yamazaki N.  Jpn Heart J. 1981 Nov;22(6):939-49.
  9. Acrolein inhibits respiration in isolated brain mitochondria.
Picklo MJ, Montine TJ.  Biochim Biophys Acta. 2001 Feb 14;1535(2):145-52
  10. Acrolein, a product of lipid peroxidation, inhibits glucose and glutamate uptake in primary neuronal cultures.
Lovell MA, Xie C, Markesbery WR.  Free Radic Biol Med. 2000 Oct 15;29(8):714-20.
  11. Thyroid hormone action in mitochondria.  C Wrutniak-Cabello, F Casas and G Cabello UMR Différenciation Cellulaire et Croissance (INRA, Université Montpellier II, ENSAM), Unité d’Endocrinologie Cellulaire, INRA, 2 Place Viala, 34060 Montpellier Cedex 1, France

How you can use your health history form to find holistic cures with a CAM doctor

A complimentary alternative or medical doctor can help you find holistic healing ways. Knowing details of your health history will allow your health care professionals and you determine the course of action toward a healthier you.

Your determination to optimize your current health and your environment will have a greater impact on your success to achieving a healthier you.

If I become your health coach, you have to work with me to motivate yourself to wake up each day with the goal of achieving maximum health.

Examine the air your breath, the water or liquid drink you take, the time you sleep and for how long, your stress level, the texture of your skin, your eyes and your vowel.

For quality supplementation to reset your gene expression to a younger you with AGELOC family of products, visit

http://www.clubalthea.pxproducts.com

This slideshow requires JavaScript.

This slideshow requires JavaScript.

Knowing more about our brain for longevity

Image shows the bbb.

A RECIPE TO MAKE A HUMAN BLOOD-BRAIN BARRIER

Researchers have defined a process that can help to create more realistic human blood-brain barriers in a dish. READ MORE…

Image shows a visualization of brainwaves.

BURSTS OF BETA WAVES, NOT SUSTAINED RHYTHMS, FILTER SENSORY PROCESSING IN BRAIN

In both human and animal subject, bursts of beta wave activity in the brain help to filter distraction in order to process different sensations, a new study reports. READ MORE…

a brain

BRAIN IMAGING REVEALS ADHD AS A COLLECTION OF DIFFERENT DISORDERS

A new study sheds light on ADHD, reporting teens with the disorder fit into one of three specific subgroups with distinct brain impairments and no common abnormalities between them. READ MORE…

Image shows neurons.

HIGHER ESTROGEN LEVELS LINKED TO INCREASED ALCOHOL SENSITIVITY IN BRAIN’S REWARD CENTER

Neurons in the ventral tegmental area, an area of the brain considered to be the reward center, fire more rapidly to alcohol when estrogen levels are elevated, a new study reports. The study may shed light on how alcohol addiction develops in some women. READ MORE…
Image shows the selective response of a subplate neuron.

SOURCE OF EARLY BRAIN ACTIVITY IDENTIFIED

A new study reveals a mechanism that may explain the link between sound input and cognitive function in the developing brain. READ MORE…
Image shows a section of the optic tectum.

ROLE OF THYROID HORMONE IN BRAIN DEVELOPMENT

Researchers report a thyroid hormone is critical for the earliest stages of brain development. READ MORE…
Image shows neurons.

BLAME TIRED BRAIN CELLS FOR MENTAL LAPSES AFTER POOR SLEEP

UCLA researchers report sleep deprivation prevents neurons from correctly connecting with each other, resulting in temporary cognitive lapses in visual perception and memory. READ MORE…
Image shows an Alzheimer's brain.

HIGHER BRAIN GLUCOSE LEVELS MAY MEAN MORE SEVERE ALZHEIMER’S

A new NIH study reveals abnormalities in brain glucose metabolism could be linked to the severity of Alzheimer’s pathology. READ MORE…
Image shows people talking.

BRAIN TREATS DIALECT AS LANGUAGE

A new study reports the brain treats language and different dialects in the same way. READ MORE…
Image shows a lady sitting next to a monitor undergoing rTMS.

EXPERIMENTAL BRAIN TECHNOLOGY CAN REWIND ALZHEIMER’S DISEASE

Researchers report repetitive transcranial magnetic stimulation can help to reverse some of the signs of Alzheimer’s disease. So long as patients receive the treatments, cognitive decline appears to halt and, in some cases, cognitive abilities improve. READ MORE…

WHY OUR BRAINS NEED SLEEP, AND WHAT HAPPENS IF WE DON’T GET ENOUGH

From consolidating memories to cleaning out toxins in the brain that accumulate during waking hours, researchers explore why sleep is so important and what happens when we don’t get enough. READ MORE…

a brain

BRAIN ACTIVITY IS INHERITED: FINDINGS MAY INFORM TREATMENT FOR ADHD AND AUTISM

Machine learning study reveals that, much like genetics, brain connectivity patterns are passed down from parents to children.  READ MORE…
Image shows a brain.

HERE’S WHAT WE THINK ALZHEIMER’S DOES TO THE BRAIN

A new paper explores different findings about the development of Alzheimer’s and considers how personalized treatments may help combat this complex disease. READ MORE…
a woman sleeping

SLEEPING THROUGH SNORING: NEURONS THAT ROUSE BRAIN TO BREATH IDENTIFIED

Researchers have identified a mechanism that helps rouse the brains of mice suffering from simulated sleep apnea. The findings could help develop new treatments for people with obstructive sleep apnea and provide new insights into SIDS. READ MORE…
brain and neurons

BRAIN’S ALERTNESS CIRCUITRY CONSERVED THROUGH EVOLUTION

Optogenetics research reveals brain circuits critical for alertness. READ MORE…
Image shows DNA.

BLOOD CLOTTING PROTEIN PREVENTS REPAIR IN THE BRAIN

A new study sheds light on demylination diseases like Multiple Sclerosis. Researchers discovered a blood clotting protein can leak into the central nervous system and prevent myelin production. READ MORE…
neurons

ELECTRON MICROSCOPY UNCOVERS UNEXPECTED CONNECTIONS IN FRUIT FLY BRAIN

Microscopy technology allows researchers to discover new connections in brain areas associated with memory and learning in fruit flies. READ MORE…
neuron

HOW NEWBORN NEURONS FIND THEIR PROPER PLACE IN THE ADULT BRAIN

CSHL researchers document how neuroblasts make their journey through the rostral migratory stream to their target destination in the olfactory bulb. READ MORE…
neurons

TOO MANY BRAIN CONNECTIONS MAY BE AT THE ROOT OF AUTISM

Researchers report too many connections form between neurons in the cerebellum and learning difficulties are expressed in mice who lack the RNF8 gene. READ MORE…

MIDDLE AGE INFLAMMATION LINKED TO BRAIN SHRINKAGE DECADES LATER

According to a new study, people who have inflammation biomarkers in their blood during middle age are more likely to have increased brain shrinkage as they grow older. Researchers report the brain cell loss associated with inflammation was most prevalent in areas affected in Alzheimer’s disease. READ MORE…
Image shows neurons.

HOW DO ADULT BRAIN CIRCUITS REGULATE NEW NEURON PRODUCTION?

UNC researchers have identified a brain circuit that runs from near the front of the brain to the hippocampus that helps to control neurogenesis. READ MORE…
Image shows a diagram of neurons.

AUTISM TREATMENTS MAY RESTORE BRAIN CONNECTIONS

Researchers report they have identified potential treatments that could restore brain function in people on the autism spectrum who lack a gene critical for neural connections. READ MORE…

neurons

MATURITY MOLECULE HELPS ADOLESCENT BRAIN GROW UP

Mice lacking a gene called laminin alpha 5 suffer defects in synaptic maturation during teen brain development, leading to fewer synapses in adulthood. This may contribute to neuropsychological conditions, such as Schizophrenia, which can appear during later adolescence.READ MORE…

The image shows brains as the feet of musical notes.

NEUROSCIENCE OF MUSIC – HOW MUSIC ENHANCES LEARNING THROUGH NEUROPLASTICITY

Neuroscience research into the neuroscience of music shows that musicians’ brains may be primed to distinguish meaningful sensory information from noise.  READ MORE…

THOUGHT CONTROL OF PROSTHETIC LIMBS FUNDED BY DARPA

Thought control of prosthetic limbs via brain-controlled interfaces will be tested and developed with funding from DARPA. Human subjects will test neural interface systems used to control prosthetic limbs.  READ MORE…

GUT BACTERIA CAN AFFECT ONSET OF MULTIPLE SCLEROSIS

Gut bacteria, previously considered benign, has the ability to alter the immune system of mice enough to affect the rate of Multiple Sclerosis occurance.  READ MORE…
article placeholder

NEUROBIOLOGY RESEARCH FINDS GABA INTERFERES WITH MEMORY OF NEUROFIBROMATOSIS TYPE 1 PATIENTS

Neurobiology research from UCLA indicates the possibility of GABA interfering with working memory in patients with neurofibromatosis type 1, or NF1. READ MORE…

3 BLIND MICE COULD SEE? IPRGCS HELP RODS AND CONES WITH IMAGE FORMATION

Mice without rods and cones were able to use ipRGCs to detect light and possibly form low acuity images. READ MORE…

RESEARCH SHOWS SIRT1 ENHANCES SYNAPTIC PLASTICITY AND MEMORY

Researchers at MIT have discovered that Sirtuin1, a protein encoded by the SIRT1 gene, promotes synaptic plasticity and boosts memory. READ MORE…

CHEMICAL P7C3 GROWS NEW NEURONS AND IMPROVES LEARNING

Scientists find the chemical P7C3 grows new neuronal growth within the dentate gyrus and improves learning and memory. READ MORE…

AUTISM RESEARCH: MISOPROSTOL INTERFERES WITH NEURONAL CELL FUNCTION

Neuroscience research on Autism has shown how misoprostol interferes with neuronal cell function.  READ MORE…

NATURAL MECHANISM THAT CONTROLS COCAINE USE DISCOVERED

A natural mechanism that controls cocaine use was discovered by Scripps Research scientists. READ MORE…

SCIENTISTS PREDICT YOUR BEHAVIORS BETTER THAN YOU

Scientists predict your behavior better than you according to new neuroscience research. READ MORE…
article placeholder

COFFEE AND NIGHTTIME JOBS DON’T MIX, STUDY FINDS

Night-shift workers should avoid drinking coffee if they wish to improve their sleep, according to research published in the journal Sleep Medicine. READ MORE…

article placeholder

NEW GUIDELINES IDENTIFY BEST TREATMENTS TO HELP ALS PATIENTS LIVE LONGER, EASIER

ST. PAUL, Minn. – New guidelines from the American Academy of Neurology identify the most effective treatments for amyotrophic lateral sclerosis (ALS), often caREAD MORE…

NEUROBIOLOGICAL MARKERS FOR DEPRESSION

Neuroscience researchers suggest that utilizing fMRI studies could help to provide biomarkers for the diagnosis of depression. A recent fMRI study of patients with depression showed marked abnormal activations in the medial prefronal cortex. Researchers believe that by identifying the neurobiological markers for depression, psychiatrists can tailor medications and therapies to suit the needs of individual patients. READ MORE…

NERVE CELL REGENERATION IN HIPPOCAMPUS CAN PREVENT MEMORY LOSS

New research released from the University of Florida suggests the production of new nerve cells within the Hippocampus could prevent memory loss and assist in improving memory. READ MORE…

OLDER CORPUS COLLOSUM CROSSTALK SLOWS RESPONSE TIMES

This research shows that the loss of connections in the corpus collosum could be partly responsible for slower response times seen in older animals and humans due to too much crosstalk and confusion between the brain hemispheres. READ MORE…

SINGLE NEURONS AND DENDRITES CAN DETECT DIFFERENT INPUT SEQUENCES

UCL neuroscientists have shown that a single neuron, and even a single dendrite, can respond differently to unique sequences of input. READ MORE…

PERFORANT PATH IDENTIFIED IN HUMANS – EARLY ID OF ALZHEIMER’S POSSIBLE

UC Irvine researchers have identified the perforant path in humans with the diffusion tensor imaging technique. READ MORE…

REGENERATION OF NERVE CONNECTIONS AFTER SPINAL CORD INJURY – PTEN DELETION

Deleting the enzyme PTEN allowed neurology researchers to regenerate corticospinal tract neurons after spinal cord injuries in rodents. READ MORE…

ARTIFICIAL BEE EYES SHOW WORLD FROM BEE’S POINT OF VIEW

Researchers have developed a camera system that mimics the bee eye. The artificial bee eyes allow the researchers to take images that are believed to be similar to the bee’s viewpoint. READ MORE…

MEMORIES WITH EMOTIONAL CONTENT FORM EVEN WHEN AMYGDALA IS DAMAGED

A new study from researchers at UCLA indicates that new memories with emotional content can be formed even if the amygdala is damaged. Researchers believe that other areas compensated for the damaged amygdala, and aided learning and memory. READ MORE…

NEUROGLOBIN COULD BE KEY TO PREVENTING ALZHEIMER’S DISEASE

Research scientists from UC Davis and the University of Auckland have discovered that neuroglobin might be key to preventing Alzheimer’s disease. Neuroglobin can prevent apoptosis in response to nautral stress.  READ MORE…

HARD TO CATCH UP ON SLEEP LOSS STUDY FINDS

Sleeping in on the weekends may not allow you to recover from the sleep lost during the work week according to a recent sleep study. READ MORE…

A library aisle is shown.

EARLY EDUCATION FIGHTS DEMENTIA

Brain research reveals a correlation between amount of education and dementia.READ MORE…

N

FIRST DIRECT EVIDENCE THAT ADHD IS A GENETIC DISORDER FOUND

Neuroscience researchers from Cardiff University have found the first direct evidence that ADHD is a genetic disorder. READ MORE…

EARLY LIFE STRESSES COULD HAVE LASTING EFFECTS ON GAD1 GENE

Neuroscience research published in September’s Journal of Neuroscience suggests early life stresses may modify the GAD1 gene, which controls the production of GABA. Through their research on rats, researchers were able to note that those who experienced a lack of affection showed an obstruction within the DNA which controls the GAD1 gene. As it is believed that GABA deficits might be apparent within schizophrenic patients, researchers propose that the modification of GAD1 might determine a child’s predisposition to mental illness. READ MORE…

CHANGING RIGHT HANDERS TO LEFT HANDERS

Neuroscientists at UC Berkeley have discovered that stimulation of a certain area of the brain can cause a change in which hand a person favors to perform a task. Using transcranial magnetic stimulation on right handed test subjects, researchers discovered that stimulating the posterior parietal cortex on the left side caused an increase in the use of the left hand. Researchers suggested this finding might be useful in discovering methods to help patients overcome learned limb disuse. READ MORE…

GAMERS HAVE ADVANTAGE IN PERFORMING VISUOMOTOR TASKS

A study published in October’s Cortex has shown young people who regularly play video games have an advantage in performing tasks which require visuomotor skills. The study also found that gamers show increased activity in the prefrontal cortex when asked to perform visuomotor tasks. By contrast, non-gamers had more reliant use of the parietal cortex, an area which involves hand-eye coordination, when performing visuomotor tasks. READ MORE…

CAN CAREER CHOICES INFLUENCE DEMENTIA?

Correlating data from 588 patients diagnosed with frontotemporal lobe degeneration (FTLD), researchers found that subjects with professions which related highly for verbal skills had greater tissue loss on the right hand side of the brain. By contrast, those whose professions required less aptitude for verbal skills, for example flight engineers, had more tissue damage to the left hand side of the brain. READ MORE…

DISABLING THE RGS14 GENE MAKES MICE SMARTER

Researchers have discovered that disabling the RGS14 gene in mice can make them smarter. When the RGS14 gene was disabled within the CA2 region of the hippocampus, researchers found that mice were better able to remember objects they had explored and learn to navigate mazes better than regular mice.  READ MORE…

INTROSPECTIVE PEOPLE HAVE LARGER PREFRONTAL CORTEX

Neuroscience researchers have discovered the anterior prefrontal cortex appears to be larger in people with strong introspective abilities. Additionally, the structure of white matter within this area of the brain is also linked to the process of introspection. READ MORE…

PHYSICALLY FIT CHILDREN HAVE BIGGER HIPPOCAMPAL VOLUME

Neuroscientists have reported they have found an association between physical fitness and brain development in children. The report suggests children who are physically fitter tend to have larger hippocampi and perform better in memory based tests than their less fit counterparts.  READ MORE…

DECREASED NEURAL INHIBITION MAKES DECISION MAKING HARDER FOR THE ANXIOUS

New psychology research from CU-Boulder suggests that “neural inhibition” is a critical component in our ability to make choices. Psychologists have proposed people who suffer from anxiety could have decreased neuronal inhibition, which makes it more difficult to make important decisions. READ MORE…

NEW MOLECULAR PATHWAY UNDERLYING PARKINSON’S DISEASE IDENTIFIED

Neuroscience researchers have identified a new molecular pathway underlying Parkinson’s disease. The pathway involves polyamines, which were discovered to be responsible for increased build-up of other toxic proteins in neurons. The research also suggests polyamine lowering drugs could have a protective effect from Parkinson’s disease.  READ MORE…

TWO STEPS DURING LTP REMODEL INTERNAL SKELETON OF DENDRITIC SPINES

Neuroscience researchers have discovered how a structural component within neurons performs coordinated movements when connections are strengthened. Researchers also distinguished two separate steps during long term potentiation which are involved in remodeling the internal “skeletons” of dendritic spines. The research could be influential in providing further understanding of many neurological, cognitive and neurodegenerative diseases. READ MORE…

Oxidative Stress, Inflammation, Thyroid and Anti-oxidant

Why is it harder for older people to lose weight? Is inflammed thyroid the culprit?

It can be anything from stress and hormones to poor nutrition, food sensitivities, bacteria in your gut, or toxins in your liver. It could even be the result of an event that happened decades ago that’s causing unhealthy coping patterns or emotional stress.

Although you may think you are past those things, they could still be triggering a reaction in your body and making you sick. In fact, they could be disrupting the thyroid hormones that virtually every cell in the body needs to work properly!

When something triggers a disruption in your thyroid hormone, everything can go awry, from your GI tract to your liver and kidney function. You may experience all kinds of symptoms: gas and bloating, unexplained weight gain, mood swings, rashes, fatigue, aches and pains, and so many others.

How do you balance reactive oxygen species and anti-oxidant species? Whole foods, less inflammed body, rest and sleep, exercise, sunshine and anti-oxidants. AgeLOC is one of its class in my opinion in helping our aging mechanism from oxidation, inflammation and aging.

Connie

Email motherhealth@gmail.com or order AgeLOC to help your aging mechanisms at:

https://www.nuskin.com/content/nuskin/en_US/signup/customer.html

sponsor connie USW9578356

agelok youth 2agelok youth


Inflammation and oxidative stress (OS) are closely related processes, as well exemplified in obesity and cardiovascular diseases. OS is also related to hormonal derangement in a reciprocal way. Among the various hormonal influences that operate on the antioxidant balance, thyroid hormones play particularly important roles, since both hyperthyroidism and hypothyroidism have been shown to be associated with OS in animals and humans. In this context, the nonthyroidal illness syndrome (NTIS) that typically manifests as reduced conversion of thyroxine (T4) to triiodothyronine (T3) in different acute and chronic systemic conditions is still a debated topic. The pathophysiological mechanisms of this syndrome are reviewed, together with the roles of deiodinases, the enzymes responsible for the conversion of T4 to T3, in both physiological and pathological situations. The presence of OS indexes in NTIS supports the hypothesis that it represents a condition of hypothyroidism at the tissue level and not only an adaptive mechanism to diseases.

Balance of Reactive oxygen species and Anti-oxidant defenses

Oxidative stress (OS) is defined as an unbalance between the production of prooxidant substances and antioxidant defenses.

The most important prooxidants are the reactive oxygen species (ROS) and reactive nitrogen species (RNS) [1]. The ROS family includes superoxide anion, hydroxyl radical, hydrogen peroxide, and hypochlorous acid. The first three substances are produced in vivo mainly by the mitochondrial respiratory chain during the oxidative metabolism of energetic substrates [2, 3]. They are regulators of redox-sensitive pathways involved in cellular homeostasis [4] and influence some transcription factors, in addition to the endogenous antioxidant pool [4–7].

RNS are peroxynitrite, produced by the reaction of nitric oxide (NO) with superoxide, and nitrosoperoxycarbonate, formed by the reaction of peroxynitrite with carbon dioxide. ROS and RNS are considered important pathogenetic factors in different diseases [8]. Among them, a particular pathogenetic role is played by the free radicals, that is, superoxide anion and hydroxyl radical, that are molecules characterized by high chemical reactivity due to a single unpaired electron in the external orbital.

In some cell types, such as leukocytes, endothelial and mesangial cells, fibroblasts, thyrocytes, oocytes, Leydig cells, and adipocytes, ROS generation could play functional roles [9]. Dual oxidases (DUOX), enzymes crucial for hydrogen peroxide generation, are essential for thyroid peroxidase- (TPO-) catalyzed hormone synthesis [10]. Two oxidases of such family are present in thyroid (DUOX1 and DUOX2). They work in conjunction with DUOXA1 and DUOXA2, which are maturation factors that allow DUOX enzymes to translocate to the follicular cell membrane and exert their enzymatic activity [10]. In addition, NADPH oxidase 4 (NOX4) [11] is a new intracellular ROS generating system recently described in the human thyroid gland.

An increased ROS production by the respiratory chain resulting from the rise of the energetic demand or substrate availability [12], as occurs in obesity, or mitochondrial dysfunction or impairment, can produce cell damage and contribute to the pathophysiology of different diseases, such as inflammatory (e.g., rheumatoid arthritis) and cardiovascular (e.g., myocardial infarction) diseases [2].

A pathophysiological role of ROS has been also suggested in diabetes mellitus, in which oxidation accompanies glycation in vivoand the antioxidant capacity is decreased, resulting in increased susceptibility to oxidative stress [13].

Different defensive mechanisms that protect against the free radical damage have been characterized in various cellular localizations, including the endoplasmic reticulum, mitochondria, plasma membrane, peroxisomes, and cytosol [2]. Enzymes such as superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), and transition-metal binding proteins, such as transferrin, ferritin, and ceruloplasmin, prevent the production of or rapidly inactivate free radicals. SOD accelerates the dismutation process of superoxide anion in hydrogen peroxide and molecular oxygen that normally occurs with a rate constant 104-fold lower. CAT detoxifies hydrogen peroxide by transforming it in water and molecular oxygen.

GPx also participates in hydrogen peroxide detoxification when hydrogen peroxide levels are high. In addition, GPx detoxifies lipid peroxides by transforming them in the corresponding alcohols. “Scavengers” molecules, including both water-soluble, such as albumin, bilirubin, ascorbic acid, urates and thiols, and liposoluble, such as Vitamin E and coenzyme Q10 (CoQ10), substances interrupt the lipid-peroxidation chain by reacting with and neutralizing the intermediate radicals.

The high diffusion rate of scavengers, particularly the liposoluble ones in biological membranes, allows them to intercept radicals and transform them into more stable molecules, thus stopping the radical chain. Sometimes scavengers can be regenerated.

A third defensive mechanism uses processes which remove the molecules damaged by the oxidative attack, allowing the reconstitution of normal structures (e.g., specific phospholipases remove the peroxidized fatty acids, making the enzymatic reacylation of damaged molecules possible) [2].

The production of ROS and RNS can occur at the cellular level in response to metabolic overload caused by the overabundance of macronutrients. In addition, mitochondrial dysfunction and endothelial reticulum stress contribute to adipose tissue metabolic derangement in obese patients [14, 15]. ROS generation is further maintained by an inflammatory response, feeding a vicious circle. This picture is worse in pre- and postpubertal children, because puberty alters some inflammatory markers associated with endothelial dysfunction (adipocytokine levels, OS, and insulin sensitivity).

Recent findings suggest that mitochondrial reactive species are signalling molecules that mediate the production of proinflammatory cytokines, thus connecting OS and inflammation. This topic has been extensively studied in cardiovascular diseases [16].

However, besides inflammation, OS can be related to hormonal derangement in a reciprocal way. Some hormones influence antioxidant levels; on the other hand, OS can modify synthesis, activity, and metabolism of hormones. Therefore, OS is related to both systemic inflammation and hormonal derangement. In particular, thyroid hormones play important roles in antioxidant modulation, as demonstrated in different in vitro and in vivo studies. Reduced glutathione (GSH) is an important cofactor of both antioxidant enzymes and deiodinases, the enzymes responsible for the conversion of thyroxine (T4) to triiodothyronine (T3).

Moreover, plasma levels of small antioxidant molecules, such as Vitamin E and CoQ10, and thyroid hormones are closely related to each other [2, 17]. Both hyperthyroidism and hypothyroidism have been shown to be associated with OS and special cases are the autoimmune thyroiditis or the functional picture of low-T3 syndrome, observed in acute and chronic nonthyroidal illness syndrome (NTIS) [17–19]. It is still debated whether NTIS represents an adaptive response or a real hypothyroidism at the tissue level. Therefore, studies on OS in NTIS are important to gain knowledge about the pathophysiology of the syndrome itself.

In this review, we firstly examine the relationships between OS and inflammation. Then, we present available data on thyroid hormones and antioxidant regulation. Finally, we report the results of investigations on the relationships between inflammatory mediators and OS in NTIS, in the attempt of hypothesizing a reciprocal influence between tissue hypothyroidism (as primary cause or secondary to inflammation) and OS. Thus, the aim of our review is to discuss and clarify the relationships between thyroid hormones and parameters of OS in the context of the inflammatory diseases.

2. Oxidative Stress and Inflammation

Different mediators produced by the adipose tissue may potentially cause an increase of systemic and local ROS and RNS. Thus, the dysregulation of signalling pathway originating in adipocytes, as observed in obese patients, can induce and perpetuate inflammation and OS. Recent studies clearly indicate that the adipose tissue can be considered as an endocrine organ producing different proteins (adipokines) with wide biologic activities. In addition, after maturation from the stage of preadipocytes, the adipocytes gain functions similar to those of macrophages, including the ability to be activated by components of the bacterial wall and to synthesize and secrete cytokines [20]. Moreover, during the periods in which weight gain or loss occurs, the cellular composition of the adipose tissue dynamically changes, showing variations in the levels of various cell types represented in the tissue, in particular vascular and immune cells.

The levels of the latter, in particular the macrophages, importantly increase in obese patients.

The macrophages seem to play important roles in the pathogenesis of insulin resistance associated with obesity, through the production of Monocyte Chemoattractant Protein-1 (MCP-1) and the modulation of the spreading and the growth of the adipose tissue itself [21]. Monocytes mobilized and attracted by MCP-1, together with neutrophils and lymphocytes T present in the adipose tissue, originate an inflammatory response that is reinforced by the stimulation of the synthesis and secretion of tumor necrosis factor (TNF) by macrophages, in turn induced by the increased production of free fatty acids (FFAs) by adipocytes. In addition, a two-way interaction between adipocytes and macrophages seems to develop, by which the macrophages stimulate the expression and release of MCP-1 from the adipocytes through ROS production.

By this way a vicious circle is established, which may promote a chronic inflammatory status gradually more and more intense, typical of obesity and its complications. Finally, the macrophages regulate the remodelling of the adipose tissue when a chronic positive energetic balance ensues. Different pathways are activated in adipocytes depending on whether subtype M1 or M2 macrophages are stimulated, that regulate adipocyte proliferation, growth, and survival. The induced changes are responsible for the appearance of a hypertrophic or hyperplastic obesity. In case of the prevalence the M1 proinflammatory macrophagic subtype, the reduced survival and proliferation of the preadipocytes will cause an inadequate adipocyte reserve; consequently, the energetic backlog, through an excessive hypertrophy, will produce a dysfunctional adipose tissue, which will perpetuate the inflammatory process and, in the long term, produce insulin resistance. Conversely, if the M2 macrophagic subtype is prevalent, the functional pool of preadipocytes will be favoured. They will differentiate into adipocytes, contributing to the formation of an adequate hyperplastic adipose tissue with preserved cell functions and insulin sensitivity [22].

Therefore, obesity is associated with increased secretion of proinflammatory hormones and cytokines (leptin, resistin, TNF-α, and interleukin- (IL-) 6) and decreased release of adipokines that downregulate inflammation (adiponectin, IL-10). Recent studies [23] show that not only the amount but also the kind of adipose tissue, as well as the kinds of fats in the diet, influence in different ways this chronic inflammatory state.

Many other mechanisms reviewed by Siti et al. [16] reinforce the link between OS and inflammation. Among these, there is the overexpression of endothelin that induces ROS production in endothelial cells by increasing NADPH oxidase activity [24]; on the other hand, OS causes an increase in angiotensin converting enzyme [25], creating a loop with the previously cited mechanism. Another important mechanism is the OS-induced Ca2+ influx, responsible for inflammatory processes [26].

In diabetes, the chronic inflammation, the increase in FFA levels, and the overactivation of the renin-angiotensin system contribute to insulin resistance via OS [27]. TNF-α, an important mediator of inflammation, interferes with insulin signals through the activation of the PI3-kinase pathway in endothelial cells [28]. A systemic lipid infusion, that induces acute elevation of plasma FFA levels, causes the activation of the NF-kB pathway, OS, and impairment of endothelium-dependent vasodilatation. In addition, insulin effects on vasodilatation, NO production, and muscle capillary recruitment are blunted by the lipid infusion [29–32]. Regarding this subject, we have shown that a naturally enriched antioxidant diet is capable of improving insulin sensitivity and metformin effects in adult obese patients [33].

Other studies confirmed the link between OS, vascular inflammation, and hypertension-associated vascular changes [34]. Moreover, it is well known that oxidized LDL have a key role in the initiation and progression of the atheromatous plaque [16, 35]; a main role has been recently attributed to the lectin-like oxidized LDL receptor-1 (LOX-1), which is upregulated by the exposure to inflammatory stimuli [36]. The role of the renin-angiotensin system in OS-related injury of endothelial cells has been recently reviewed [37]. Elegant studies conducted in experimental animal models, such as the ApoE knock-out mouse, confirmed an oxidant/antioxidant unbalance in the atherosclerotic process [38–40]. A large number of studies have been published on this topic, which, however, is not among the subjects of the present review. Nevertheless, they overall confirm the association between inflammation and OS.

3. The Role of Thyroid Hormones in Antioxidant Regulation

The role of thyroid in the regulation of the antioxidant systems has been recently reviewed in the context of the reproductive endocrinology [41]. It is well known that thyroid function influences the ovarian activity. ROS play physiological roles in the ovary and hypothyroidism, or a low-T3 syndrome, can induce ovarian dysfunction by interfering with the antioxidant systems.

OS has been shown to be associated with both hyperthyroidism and hypothyroidism [42]. However, the mechanisms by which OS is generated in these two clinical conditions are different: increased ROS production in hyperthyroidism and low availability of antioxidants in hypothyroidism.

Some complications of hyperthyroidism in target tissues are caused by OS [43]. Thyroid hormones per secan act as oxidants and produce DNA damage (contrasted by CAT), probably through the phenolic group, which is similar to that of steroidal estrogens [44]. Many other mechanisms, as previously reviewed [45], can be involved, in particular the enhanced Nitric Oxide Synthase (NOS) gene expression with NO overproduction and the activation of hepatic NF-kB with the consequent increase in cytokines levels which induces ROS production. On the other hand, other mechanisms regulated by thyroid hormones carry out a fine regulation of the oxidative status via autoloop feedback. Among them, we underline the role of Uncoupling Protein- (UCP-) 2 and Uncoupling Protein-3. Data obtained in plants and animals indicate that these molecules have antioxidant activity [46–48]. However, only T3 seems to regulate UCP, whereas no effect is exerted by T4 [49, 50]. An opposite effect is induced by estrogens, which increase ROS production by repressing UCP [51].

The increased turnover of mitochondrial proteins and mitoptosis also participate in the regulation of the oxidative status, by removing the mitochondria damaged by OS [52]. These processes are regulated by peroxisome proliferator-activated receptor gamma coactivator-1, which in turn is upregulated by T3administration [53].

Thyroid hormones influence lipid composition of rat tissues and consequently the susceptibility to OS.

However, the response is tissue-specific, and discrepant effects of T3 and T4 have been reported. In rat liver, T3-induced hyperthyroidism was found to be associated with altered lipid-peroxidation indexes, including elevated levels of thiobarbituric reactive substances (TBARS) and lipid hydroperoxides that are byproducts of lipid peroxidation [45, 53–55]. On the contrary, no changes in TBARS production were found in homogenized livers from rats made hyperthyroid by administration of T4 over a 4-week period [56]. No significant changes of TBARS or lipid hydroperoxides were observed in testes of hyperthyroid adult rats as well; however, hyperthyroidism promoted protein oxidation in testes, as indicated by the enhanced content of protein-bound carbonyls [57]. In addition, it should be emphasized that the effects of hyperthyroidism on the activity of antioxidant enzymes, including Mn- or Cu,Zn-SOD, CAT, and GPx, depend on the tissue investigated, with T3 and T4 having differentiated effects [58].

At the systemic level, hyperthyroidism has been associated with reduced circulating levels of alpha-tocopherol [59, 60] and CoQ10 [60, 61] in humans. CoQ10 showed a trend toward higher levels in hypothyroidism [61]. Thus, it seems to be a sensitive index of tissue effect induced by thyroid hormones in situations in which drug interference, such as treatment with amiodarone [62], or systemic illness inducing low-T3 conditions [63] complicate the interpretation of thyroid hormone levels.

On the other side, data on hypothyroidism and OS in humans are conflicting. In a group of patients with primary hypothyroidism, Baskol et al. [64] found high plasma levels of malondialdehyde (MDA), an OS marker that is formed by lipid peroxidation, and NO, low activity of paraoxonase- (PON-) 1, an enzyme synthetized in the liver with antioxidant properties, and SOD levels not significantly different from those of controls. Interestingly, the treatment with thyroid hormones decreased MDA levels and increased PON-1 activity, even though values similar to those observed in controls were not reached [64]. They hypothesized that in patients with hypothyroidism the prooxidant environment could play a role in the development of atherosclerosis. Elevated MDA levels were also shown in subclinical hypothyroidism [65]. In this setting, the increased OS was attributed primarily not only to the decrease in antioxidants levels, but also to altered lipid metabolism, since a significant correlation among MDA and LDL-cholesterol, total cholesterol, and triglyceride levels was found. Total antioxidant status (TAS) was similar in overt hypothyroidism, subclinical hypothyroidism, and controls.

Excess TSH is known to directly produce OS [66]. Other studies confirmed the lipid peroxidation both in overt hypothyroidism and in subclinical hypothyroidism [67] as indicated by MDA elevation; protein oxidation has been reported as well, with elevation of protein carbonyls [67]. In this study, the correlation analysis suggested that both the TSH increase and the MDA elevation contribute to protein damage. Finally, different studies reported NO elevation [68, 69].

Data on other parameters are more conflicting. As far as PON-1 is concerned, a decreased activity of this enzyme was observed both in hypothyroidism and in hyperthyroidism [70], whereas no significant differences with respect to controls were shown in other studies [68]. Increased levels of TBARS, but also antioxidants, such as SOD, CAT, and Vitamin E, have been also reported [71]. All these parameters correlated with T3 and the correlation between T3 and CAT remained significant also when corrected for total cholesterol. TBARS elevation was shown in both overt hypothyroidism and subclinical hypothyroidism [69, 72], but these findings were not confirmed in other studies [68, 73].

Another matter of discussion is whether OS is related to hypothyroidism per se or to lipid profile alterations caused by thyroid disfunction, as reported above. Indeed, Santi et al. [74] reported OS in subclinical hypothyroidism, as shown by reduced arylesterase and increased TBARS and CAT, but they attributed this pattern to hypercholesterolemia.

We showed low total antioxidant capacity (TAC) levels in hypothyroid patients [75] and increased CoQ10plasma levels in secondary hypothyroidism. This latter finding is mainly to be put in correlation with the metabolic role of CoQ10 in the mitochondrial respiratory chain and its consequent reduced cell use in hypothyroid patients. In secondary hypothyroidism, the picture is complicated by concomitant alterations of other pituitary-dependent axes, which can have opposite effect on CoQ10 plasma levels. Acromegaly and hypoadrenalism are characterized by low CoQ10 plasma concentrations; however, when they are associated with hypothyroidism, this latter has a predominant effect [75, 76].

New perspectives concern DUOX, DUOXA, and NOX4. Cases of hypothyroidism due to mutation of DUOX or DUOXA genes have been reported in the literature [10, 11]. In addition, alterations of NOX4 could be associated with thyroid cancer (via activation by H-Ras oncogene) and Hashimoto’s thyroiditis, in which the increased extracellular expression of this enzyme raises Intercellular Adhesion Molecule-1 (ICAM-1) expression and cytokine release [77, 78].

Finally, another study conducted on patients affected by subclinical hypothyroidism secondary to Hashimoto’s thyroiditis did not show any difference in endogenous MDA levels between hypothyroid patients and controls; however, MDA induction by the prooxidant 2,2′-azobis-(2-amidinopropane) hydrochloride was markedly augmented in hypothyroid patients. This response in serum was not accompanied by a similar pattern in the LDL fraction: in fact, copper-induced MDA production did not differ in patients affected by subclinical hypothyroidism with respect to controls, whereas it was significantly different from controls in patients with overt hypothyroidism [79]. Studies on patients with thyroiditis should be, however, interpreted with caution, in that both tissue inflammation and systemic inflammation are present in this autoimmune disorder.

The experimental procedures by which hypothyroidism is induced affect the OS findings. Hypothyroidism obtained by surgical thyroid resection in rats was associated with decreased OS in heart [80] and kidney [81]. On the contrary, drug-induced hypothyroidism was associated with increased lipid peroxidation in amygdala [82] and hippocampus in rats [82, 83]. Other cerebral areas, including the cerebellum, remained unaffected [84]. The latter findings, however, were not confirmed in other studies [82, 83]. Similarly, cell damage in various organs, including heart, spleen, liver, lung, and kidney, has been found in animals following methimazole treatment, but not after thyroidectomy [84]. Some studies, however, indicate that the organ damage is not consequent to the hypothyroidism per se, but to the drug itself [85, 86].

In the latest years, the attention has been concentrated on the damage induced by OS in certain organs, including liver, bone, skeletal muscle, and particularly the heart [53]. The metabolism of cardiomyocytes depends on serum T3, in that these cells lack a significant deiodinase activity [87]. Increased, decreased, or unmodified levels of total SOD, Mn-SOD, Cu,Zn-SOD, GPx, GSH, or Vitamin E have been reported in cardiomyocytes in response to hypothyroidism [88]. Unchanged or decreased levels of various other antioxidant molecules or parameters, such CoQ9, CoQ10, and TAC, have been also reported. These findings indicate that the evaluation of a single OS parameter is not a reliable index of the cellular oxidative status and the evaluation of TAC depends on the measurement method used.

OS has been also involved in the pathophysiology of schizophrenia. In fact, higher plasma levels of MDA and total plasma peroxides have been found in schizophrenic patients with respect to control subjects, which showed a significant correlation with T3 levels [89].

The thyroid itself can be damaged by OS, which occurs in case of iodine excess. This topic has been studied both in vitro and in animals fed with a diet rich in iodide [90, 91]. Iodide has a stimulatory action of on hydrogen peroxide generation in thyroid slices and induces thyroid cell apoptosis at high concentrations [92].

Vitamin E has been shown to be protective against the tissue damage induced by peroxyl radicals, mainly not only by preserving the polyunsaturated fatty acids in biological membranes, but also by reducing the activity of NADPH oxidase [53].

4. The Model of Low-T3 Syndrome

Low-T3 syndrome is a condition characterized by a reduced peripheral conversion of T4 to T3 in the presence of normal thyroid hormone secretion. It occurs in a variety of nonthyroidal illness (NTI) and is defined as nonthyroidal illness syndrome (NTIS). The most important acute conditions in which the low-T3syndrome occurs include starvation and eating disorders and critical illness. During starvation (especially carbohydrate deprivation) and nonthyroid illness, deiodination of T4 to T3 is rapidly inhibited, causing the low-T3 syndrome. As the illness progresses to more and more severe stages, a more complex syndrome with low-T3 and T4 ensues. In critical illness, many other changes of the pituitary-thyroid axis have been shown, including attenuated response to TRH, low tissue uptake of thyroid hormones, and altered thyroid hormone metabolism. A low-T3 syndrome caused by the reduced peripheral conversion from the prohormone T4 is also observed in different chronic diseases, including chronic kidney disease, liver failure, and chronic inflammatory diseases.

A component of NTIS can be related to cachexia, which is common in chronic systemic inflammation, renal failure, and heart failure. This field has been widely investigated in cancer patients. Cachexia represents a hypermetabolic wasting syndrome with progressive depletion of adipose tissue and skeletal muscle mass, often accompanied by anorexia [93]. Among the mediators of cachexia in cancer patients there are several cytokines and hormones also involved in the pathophysiology of NTIS. They are produced by tumour cells or macrophages surrounding them, as expression of the interaction between the neoplasia and the host environment. The most important are TNF-α, IL-1, IL-6, interferon- (IFN-) γ, proteolysis-inducing factor (PIF), angiotensin II, and myostatin, a member of the transforming growth factor-β superfamily. Interestingly, the signal transduction pathways of many of these substances involve NF-kB, the activity of which is in turn related to ROS levels. In fact, it has been shown that hydrogen peroxide, PIF, and angiotensin II activate NF-kB in myotubes [94] and the treatment of myotubes exposed to TNF-α, PIF, or angiotensin II with antioxidants reduces the NF-kB binding to DNA [94, 95]. In addition, it has been reported that the treatment of MAC16 colon-tumour bearing mice with Vitamin E reduces protein degradation in skeletal muscle [95]. Finally, some cytokines, including TNF-α, IL-1, IL-6, and IFN-γ, mimic leptin signalling, inducing central suppression of appetite [96].

The condition of NTIS is considered as an adaptive response rather than true hypothyroidism. Thyroid replacement therapy is not usually required, but this topic is still debated, since indirect signs of true hypothyroidism at tissue level have been shown. Some molecular mechanisms of NTIS are known, but more studies are necessary to further elucidate its pathogenesis. Indeed, it is probable that a full understanding of the pathophysiological mechanisms at the tissue level will allow the identification of patients who would benefit from replacement therapy. Our discussion will focus on the roles of cytokines and OS in the pathophysiology of NTIS.

The roles of cytokines as key molecules involved in coordinating the hormone, immune, and inflammatory responses to a variety of stressful stimuli are well known [18]. In a series of septic patients studied shortly after admission to the ICU, total T4 (tT4), free T4 (fT4), total T3 (tT3), and TSH plasma concentrations were depressed, and plasma levels of IL-1β, sIL-2 receptor, and TNF-α were elevated [97], indicating the establishment of central TSH suppression. The hypothalamic-pituitary-adrenal axis was activated as expected. Continuous infusion of IL-1 in rats causes reduction of TSH, free T3 (fT3), and fT4 plasma levels. Higher doses of IL-1 induced a febrile reaction and suppression of food intake, with a cascade of events altering thyroid hormone economy [98]. However, IL-1 did not decrease the hepatic 5′-deiodinase activity that, on the contrary, is typically reduced in NTIS.

TNF is another proinflammatory cytokine that is thought to be involved in many of the alterations associated with NTIS. Infusion of rTNF in man decreases serum T3 and TSH and increases reverse-T3(rT3) [99]. These findings suggest that TNF could be involved in the IL-6-mediated suppression of the hypothalamic-pituitary axis. However, the involvement of TNF in NTIS pathophysiology was not confirmed in other studies, in which the effects of endotoxin on thyroid hormones in humans were not counteracted by TNF-α blockade through specific IgG fusion proteins [100]. TNF-α was found in in vitrostudies to activate NF-kB [101], which in turn inhibits T3-induced expression of deiodinase 1 (D1).

An important pathophysiological role in NTIS has been attributed to IL-6, which is often elevated in serum of NTIS patients [102] in an inversely proportional manner with respect to T3 levels [103]. Short term infusion of rIL-6 to healthy volunteers [104] suppressed TSH secretion, whereas daily injections over a 6-week period only slightly decreased T3 levels and transiently increased rT3 and fT4 concentrations.

Deiodinases are dimeric selenoproteins that catalyze the stereospecific removal of iodine atoms from the prohormone T4, generating the active and inactive isomers of both T3 and diiodothyronine (T2). Different isoforms are expressed with tissue specificity: D1 and D2, via the deiodination of the outer ring, convert T4to active T3; D3, via the inner ring deiodination, converts T4 to inactive metabolites: rT3 and 3,3′-T2 [105, 106]. Phylogenetic analysis suggests that D1 is the oldest vertebrate deiodinase, while D2 is the most recent one; this is in agreement with the key role of D2 as the most specialized and finely regulated member of this enzyme family [106].

Deiodinases play pivotal roles in the regulation of the intracellular levels of active thyroid hormones [107]. D2 is located in the endoplasmic reticulum and plays the primary role in the conversion of T4 to T3. D1 has lower affinities for the substrates with respect to D2 and seems to be mainly a scavenger enzyme, involved in iodine recycling. Furthermore, the balance between D2 and D3 activities seems to be an important factor in determining the amount of T3 available to bind the nuclear receptors. Different mechanisms regulate the expression of deiodinase genes (DIO1, DIO2, and DIO3), first of all the levels of thyroid hormones: hyperthyroidism suppresses D2 activity and DIO2 expression, whereas hypothyroidism exerts the opposite effects [108]. The ubiquitination of the enzymes, which can be reversible to assure the appropriate protein homeostasis, is a mechanism of finer regulation of deiodinase activity [109].

D2 plays important roles in the regulation of the energetic balance as well. It has been shown that animal exposure to low temperatures activates D2 in brown adipose tissue through catecholamine-induced cAMP production. The resulting increase in T3 levels induces thermogenic genes, including UCP-1 [110]. In addition, DIO2 expression is upregulated by bile acids in the brown adipose tissue of mice through the increase in cAMP levels. When fed with a high fat diet supplemented with bile acids, the animals do not gain weight, showing a resistance to diet-induced obesity, and this effect is absent in D2 knock-out animals [111, 112].

Recent studies on the effects of IL-6 on both endogenous cofactor-mediated and dithiothreitol-stimulated deiodinase activity in human cell lines [112] have shown that T3 generation by D1 and D2 is suppressed by IL-6, despite an increase in expression of deiodinases. The inhibitory action of IL-6 is prevented by the addition of N-acetyl-cysteine (NAC), an antioxidant that restores intracellular GSH concentrations, suggesting the involvement of prooxidant substances in IL-6-induced effects.

Finally, the interaction between the complex network of cytokines and the hypothalamic-pituitary-thyroid axis probably plays pathogenetic roles in NTIS, even though it is not possible to build a simplistic model [18]. Also the role of cytokines in eating disorders and related thyroid hormone alterations has been recently reviewed [113].

Different conditions in which NTIS develops are associated with OS, due to augmented production ROS or RNS [114]. Since thyroid hormones, as above discussed, increase ROS generation, low-T3 could be viewed as a compensatory mechanism. In fact, low-T3 concentrations would be associated with decreased metabolic rate that would reduce further radical generation. Cytosolic thiols, particularly GSH, and Thioredoxin (Trx), which are also deiodinase cofactors, contribute to the maintaining of a reducing intracellular environment. Thus, their depletion, consequent to their buffering effect on radical propagation, could interfere with the conversion of T4 to T3 [115]. The nuclear sequestration of SECIS binding protein 2 (SBP2), which reduces the incorporation of selenocysteine residues in the selenoproteins [116], might be another mechanism. It is well known that IL-6 induces OS, so that a unifying mechanism might be that cytokine-induced OS alters secondarily the expression and activity of deiodinases [115]. The contribution of the reduction in the levels of thiol cofactor of deiodinases, consequent to the increase in intracellular ROS concentrations, has been suggested by other authors [117].

On the basis of the pathophysiological studies available in the literature, we can conclude that the alterations of the pituitary-thyroid axis depend not only on the severity of the disease, but also on the inflammatory response and the patients’ nutritional status. They also indicate that low-T3 is simply not an adaptive mechanism, but it is associated with tissue hypothyroidism and OS.

A special, reevaluated role could be played by selenium. This essential trace element exerts complex effects on the endocrine system, due to its antioxidant capacity; it is a cofactor of GPx and Trx reductase (TrxR), enzymes that protect the cells from the oxidative damage [118]. On the other hand, selenium is involved in the mechanisms of deiodination: a proposed model involves the formation of selenenyl iodide intermediate [119], even though the catalytic mechanisms and the regulation of deiodinases by selenium are not fully understood [120]. Thus, because of its double function, molecules that compete with this element could, in a reciprocal way, connect hypothyroidism due to low-T3 and OS. This hypothesis is supported by the evidence that NAC, an antioxidant that restores intracellular GSH levels, prevents the IL-6-induced effects on the intracellular redox state [121, 122]. In addition, the administration of sodium selenite in cells expressing deiodinases decreases the IL-6-induced ROS production and carbonyl protein content and enhances GPx and TrxR activities [123].

Also deiodinases may be involved in NTIS pathophysiology, with possible tissue specificity [124]. DIO1 is a T3-responsive gene; thus, D1 activity and intracellular T3 concentrations can affect each other in a reciprocal way. D1 activity has been shown to be suppressed in hepatocytes. The activity of D2 has been reported to be reduced [125], unchanged [126], or increased [127] in skeletal muscle. An increase in DIO2 expression in skeletal muscle has been reported in mice during chronic inflammation that has been linked to enhanced CREB signaling [128]. On the contrary, skeletal muscle DIO2 expression was found to be decreased in sepsis and this decrease was related to the reduction in food intake [129]. DIO2 expression increases in lung and in endothelial cells following LPS-induced injury [130] and in hepatic resident macrophages during acute and chronic inflammation [128]. As far as D3 is concerned, a decrease in DIO3 mRNA levels has been reported in liver during inflammation and sepsis [131, 132]. On the contrary, hepatic expression and activity of D3 were found to be increased in rabbits with prolonged critical illness [133]. Similarly, D3 activity was found to be increased in the skeletal muscle of critically ill patients [134] and in patients after myocardial infarction [135, 136].

In summary, even if the picture appears to be quite complex, some of these changes are mediated by inflammatory pathways, such as NF-kB and AP-1, whereas the CREB pathway seems to be predominant in skeletal muscle [124]. On the other hand, overexpression of D2 in tanycytes, that has been observed in rats after LPS infusion [117, 137, 138], could be responsible for central suppression of the hypothalamic-pituitary-thyroid axis, thereby contributing to the complex picture of the regulation of thyroid function in this clinical condition.

Conclusion

In conclusion, OS seems to be an important mechanism underlying the progress of inflammation. A vicious circle creates a link between these two conditions. Thyroid hormones can have a protective role, modulating antioxidant levels; on the other side, a tissue hypothyroidism can worsen OS (Figure 1). An interesting model is represented by NTIS, in which IL production due to inflammation can reduce the expression of deiodinases, inducing low-T3 levels and consequently a condition of tissue hypothyroidism. In turn, this latter could cause further OS (Figure 2).

These pathophysiological observations suggest the possible therapeutic efficacy of antioxidants in the NTIS.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4802023/

Figure 1
Proposed model of the interrelationships between inflammation, oxidative stress, and thyroid derangement. Inflammation, via hormone and cytokine changes, leads to oxidative stress and also affects thyroid function, causing nonthyroidal illness syndrome …

Figure 2
Both hyperthyroidism and hypothyroidism can cause oxidative stress but with different mechanisms. We speculate that nonthyroidal illness syndrome (NTIS) may represent a tissue hypothyroidism condition linked to intracellular and systemic oxidative stress. …