George Ferman Profile picture
Nov 7 14 tweets 12 min read Read on X
Oxidative stress is a very important but far more complicated topic than the average person is made to believe.

Here's what you need to know.
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*Standard disclaimer that this does not constitute medical advice*

Oxidative stress is characterized by the overproduction of reactive oxygen species (ROS), which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2+ homeostasis and mitochondrial defense systems.

Calcium homeostasis refers to the maintenance of a constant concentration of calcium ions in the extracellular fluid.

It includes all of the processes that contribute to maintaining calcium at its “set point.”

Because plasma [Ca2+] rapidly equilibrates with the extracellular fluid, ECF [Ca2+] is kept constant by keeping the plasma [Ca2+] constant.Image
Maintaining a constant plasma [Ca2+] is important for things such as nerve transmission and conduction, cardigan contractility, blood clotting, cell to cell adhesion and of course bone formation.

Now a free radical attack occurs directly at complexes in the mitochondrial respiratory chain.

Mitochondria are normally protected from oxidative damage by a multilayer network of mitochondrial antioxidant systems which consist of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase together with a number of low molecular weight antioxidants such as α-tocopherol and ubiquinol.

These molecules are particularly effective in scavenging lipid peroxyl radicals and preventing free radical chain reactions of lipid peroxidation.

Cumulative oxidative injuries to mitochondria, triggered by endogenous metabolic processes and/or exogenous oxidative influences, cause mitochondria to progressively become less efficient.Image
As mitochondria progressively lose their functional integrity, ever-greater proportions of oxygen molecules reaching them are converted to ROS.

So the numerous and disparate mitochondrial functions include the synthesis of most of the ATP present in the cell, apoptosis, ion homeostasis, cellular stress response, antioxidant control, redox regulation, mitophagy and the involvement in various biosynthetic pathways.

Oxidative stress occurs when there is an imbalance between free radical production and their detoxification.Image
Free radicals are unstable compounds that lead to cell destruction and chronic inflammation.

An atom or group of atoms with an unpaired electron is called a free radical.

A free radical can steal electrons from a stable molecule, creating a new free radical and initiating a chain reaction.

This electron-grabbing is called oxidation and can set up a chain reaction, creating new free radicals and damaging important molecules along the way, similar to how one falling domino can bring down countless more.

Antioxidants are molecules that can donate an electron to stabilize and neutralize free radicals.

An antioxidant can "stop" the free radical chain reaction in its tracks by donating an electron and then the antioxidant itself becomes a free radical.

But antioxidants are not very reactive themselves and have processes for quick stabilization.Image
Free radicals are a natural byproduct of metabolic reactions and of exercise, and it’s normal to have low levels of free radicals in the body.

With enough antioxidants present, free radicals can be kept in check so that they aren’t dangerous.

However, too many free radicals and not enough protection from antioxidants creates a situation called oxidative stress.

Free radical development is unavoidable, but human bodies have adapted by setting up and maintaining defense mechanisms that reduce their impact.

The body’s two major defense systems are free radical detoxifying enzymes and antioxidants.Image
Free radical detoxifying enzyme systems are responsible for protecting the insides of cells from free radical damage.

An antioxidant is any molecule that can block free radicals from stealing electrons. antioxidants act both inside and outside of cells.

The three major enzyme systems and the chemical reactions they catalyze are:

1)Superoxide Dismutases (SOD).
They are essential for free radical detoxification and these enzymes either have manganese, copper or zinc as a cofactor.

2)Catalase.
These enzymes convert hydrogen peroxide to water and oxygen and finish the detoxification process that SOD starts.

3)Glutathione Peroxidases.
These selenium dependent enzymes also convert hydrogen peroxide to water and oxygen.Image
The body can synthesize some antioxidants, but others must be obtained from the diet.

There are two antioxidants that the body synthesize:

1) Glutathione (which contains a sulfur group that can donate an electron to a free radical, thereby stabilizing it).

2) Uric acid.

There are many different antioxidants in food as well.

-Antioxidant vitamins (Vitamin E, Vitamin C) donate their electrons to free radicals to stabilize them.

-Antioxidant phytochemicals (beta-carotene and other carotenoids) may inhibit the oxidation of lipids or donate electrons.

-Antioxidant minerals act as cofactors within complex antioxidant enzyme systems (superoxide dismutases, catalase, glutathione peroxidases described earlier) to convert free radicals to less damaging substances that can be excreted.
1)Vitamin E
Functions: Protects cellular membranes and prevents glutathione depletion.

Because vitamin E is fat-soluble, its antioxidant capacity is especially important to lipids, including those in cell membranes and lipoproteins.

For example, free radicals can oxidize LDL cholesterol (stealing an electron from it), and it is this damaged LDL that lodges in blood vessels and forms the fatty plaques characteristic of atherosclerosis, increasing the risk of heart attack, stroke, and other complications of cardiovascular disease.

After alpha-tocopherol interacts with a free radical it is no longer capable of acting as an antioxidant unless it is enzymatically regenerated.

2)Vitamin C
Functions: Protects DNA, RNA, proteins and lipids and aids in regenerating vitamin E. Vitamin C’s ability to easily donate electrons makes it a highly effective antioxidant.

Since it is water-soluble, it acts both inside and outside cells to protect molecules in aqueous environments.

Vitamin C also plays a vital role in regenerating vitamin E after it has acted as an antioxidant, allowing it to be recycled and used again.

3)Selenium
Functions: Cofactor of free radical detoxifying enzymes, maintains glutathione levels, aids in regeneration of vitamins C and E.

Selenium is an essential trace mineral that is part of the structure of at least 25 proteins in the body with functions in thyroid hormone metabolism, DNA synthesis, reproduction and protecting the immune system.

As part of antioxidant enzymes, selenium helps to regenerate other antioxidants, including vitamin C.

These enzymes also protect lipids from free radicals, and, in doing so, spare vitamin E.

4) Carotenoids from sources such as pumpkin, squash, peaches, apricots which function as free radical scavengers.

5) CO2

C02 besides being a great antioxidant, is very essential for our metabolic health since it stabilizes and even activates mitochondria.

CO2 is a great anti-inflammatory, a great tool for someone to protect himself against ammonia and its byproducts, it can speed up the detoxification of polyunsaturated fatty acids and it’s a great tool to boost your performance (both mental and physical) as well.

How to increase CO2?
Two quick ways are:

1)The Buteyko breathing technique which is great for asthma, will help you with increasing CO2 levels.

2) Thiamine (B1) (especially pre workout)

3) Bag breathingImage
BUT, the most powerful antioxidant is not vitamin C, E or even glutathione.

Even though all of these are extremely important since each one has unique roles within the human body (for example, glutathione is critical for detoxification) the most powerful antioxidant is free and it's called melatonin.

Melatonin, chemically known as N-acetyl-5-methoxytryptamine, is classified as an indoleamine that is derived from the amino acid tryptophan.

It is evolutionarily ancient and present in organisms from bacteria to humans.

Now technically speaking, since it is synthesized in many non-endocrine organs and doesn't target a specific organ it’s not a hormone (melatonin fits this in the pineal context only).

So melatonin also acts as a paracrine and autocrine signaling molecule, influencing cellular processes across multiple tissues without requiring endocrine-specific pathways.

-It inhibits cancer cell proliferation, induces apoptosis, and enhances immune surveillance.

Melatonin is crucial for our immune system, gut health, skin health, brain health and is even linked with erectile dysfunction.

For example:

-Melatonin regulates gut motility, protects the mucosal barrier and modulates the gut microbiota.

-It reduces hypertension, improves endothelial func
But it’s not hard to understand why melatonin has these effects.

For example, melatonin as an amphipathic free radical scavenger (it has hydrophilic and hydrophobic nature and this dual solubility gives it broader reach (it goes through membranes and blood alike for example)), neutralizes free radicals like:

-Hydroxyl radical: A ROS capable of damaging DNA, proteins, and lipids.
Melatonin neutralizes this with a reaction rate constant near the diffusion limit making it one of the most efficient scavengers of this radical.
-Superoxide anion : A precursor to other ROS, produced during ETC leakage.
-Hydrogen peroxide.
-Peroxynitrite.Image
"Is melatonin that effective?"
Yes.

A single melatonin molecule can neutralize up to 10 ROS/RNS through its metabolites compared to classical antioxidants like vitamin C (1:1 scavenging ratio).

Not only that but unlike other antioxidants, melatonin does not exhibit significant pro-oxidant activity.

After donating electrons, its reaction products such as N1-acetyl-N2-formyl-5-methoxykynuramine, or AFMK are either inert or continue to scavenge radicals, creating a “cascade” effect.

It also enhances the body’s endogenous antioxidant defenses by upregulating key enzymes and molecules such as the GSH system (glutathione) where melatonin increases GSH levels and the activity of GSH-related enzymes such as γ-Glutamylcysteine ligase, glutathione peroxidase, glutathione reductase, superoxide dismutase, catalase and heme oxygenase-1.

Melatonin’s hydrophobic properties also make it especially effective at preventing lipid peroxidation (a chain reaction where ROS damage polyunsaturated fatty acids in cell membranes) where melatonin interrupts the propagation phase of lipid peroxidation by neutralizing lipid peroxyl radicals and stabilizing membrane fluidity.

And finally when it comes to libido and reproduction melatonin can modulate gonadotropin-releasing hormone (GnRH) secretion from the hypothalamus for example.

It also reduces amyloid-beta production by inhibiting β-secretase (BACE1) (an enzyme that cleaves amyloid precursor protein (APP) into Aβ) and enhancing Aβ clearance by upregulating enzymes like neprilysin.

Or, when it comes to the immune system it stimulates the production of several types of immune system cells such as natural killer cells and CD4+ cells but also it inhibits Warburg metabolism by keeping pyruvate flowing into the TCA cycle and when the immune response is overactive, melatonin reduces inflammatory mediators and neutrophil infiltration.Image
Wrapping up with diving a bit deeper into redox.

When we have an interaction where an oxidizing substance loses electrons and a reducing substance gains electrons, we have a redox reaction.

An easy-to-understand example of a redox reaction is the rusting of iron (where iron loses electrons and oxygen receives electrons (and thus acts as an oxidizing agent)).

So in a redox reaction -> both reduction and oxidation occur.

Also terms such as oxidation, oxidizing agent, reduction, reducing agent and redox are not that hard to understand.

But this transfer of electrons is not a small thing. It's a fundamental process for life itself and when we interrupt it, problems will inevitably happen.

Even when our bodies break down glucose and fat redox reactions occur.

Now, ROS can in fact cause a lot of trouble but here's the deal, some of the them have beneficial roles and are necessary for processes such as apoptosis to run smoothly.

Otherwise we wouldn't adapt to literally having thousands of them.

Or you can think of it in terms of oxidative stress (something that harms the redox state of a cell) and oxidative eustress.

So when it comes to ROS, it's all about balance/the equilibrium.

In this journey redox cofactors or redox pairs (they participate in the transfer of electrons in a number of redox reactions ) such as:

-NAD and NADH

-NADP and NADPH

-Ubiquinone and ubiquinol

-GSSG and GSH

-FAD+ and FADH2

-FMN and FMN2

will be of vital importance.

Wtf are all these?

An easy place to start is with the following: NADH stands for "nicotinamide adenine dinucleotide plus hydrogen (H)" NADH (and FADH2) are generated for example during glucose metabolism via glycolysis and the tricarboxylic acid cycle or β-oxidation of fatty acids and are oxidized to NAD+ (and FAD) while protons are pumped to the inner mitochondrial membrane through respiratory complexes I, III, and IV (NADH is the product and NAD is the reactant)

NAD+ is synthesized from four precursors: tryptophan, nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (nicotinic acid amide), nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR).

So from the get go, two things you can do in order to support redox is trying to get off statins, not over consuming food and getting enough B vitamins.

Especially B2 since it's also essential to the formation of the coenzymes FMN and FAD and the synthesis of the niacin-containing coenzymes, NAD and NADP, from tryptophan involves the FAD-dependent enzyme, kynurenine 3-monooxygenase so a dietary deficiency of riboflavin can decrease the production of NAD as well.Image
Other things you can do in order to support these include:

-Getting quality sleep in a dark room + all the nutrients that are needed for melatonin such as vitamin D and B vitamins.

You can approach this from multiple angles but we will approach it through OXPHOS since a major function of it is to consume NADH and recycle NAD+.

Guess what increases OXPHOS? Melatonin.

Then supplemental tools regarding the NADH/NAD + ratio in general include:

-Quercetin

-Blackseed oil

-M. Blue

So if you want to add something extra choose the one that's more suitable for you.

Things such as hesperidin and naringenin are also shown to help with it but not a lot and can have a bigger downside in the doses that need to be used compared to these 3.

Now what are potential symptoms of messed up redox?

*First you can test the erythrocyte sedimentation rate if you want.

Then, symptoms include things such as anemia, inability to detox properly that can show in the skin and liver, fatigue, low libido/energy in general, very low LDL, sleep issues, dry skin, high cortisol and getting sick very often are the classic ones.

So what you can do in order to improve your redox potential besides the things already mentioned?

-Get natural sunlight first thing in the morning

-Get enough vitamin K and CoQ10

-Avoid pesticides

-Quality seafood

-Avoid alcohol

-Moderate exercise (just get about and walk every day, lift, run/fight/swim etc 3-4/week)

-Blue light blocking programs/glasses

-Some molybdenum since it also is needed for FAD and FMN

-Remember that zinc and BCAAs are crucial for α-MSH

-Avoid things that have sodium fluoride

-Avoid heavy metals

-Ground

-Get thyroid supportive nutrients such as vitamin D, selenium, zinc, iodine etc since thyroid hormones affect flavokinase activity quite a lot and FAD synthetase a bit.

-Lower stress

-Sweat

-Potassium (very very high redox potential).

-Support acetyl-CoA, GGCX etc with other means could also come into play.

-Magnesium

-Regulate iron properly (besides nutrients such as magnesium, B vitamins, copper, zinc, vitamin D etc you'll have to fix your gut if you've been struggling with anemia for a long time)

-Some cold exposure
I hope that you enjoyed this thread.
If you did, make sure to leave a like/RT.

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More from @Helios_Movement

Nov 1
Most people still don't truly understand the impact of thyroid dysfunction.

The thyroid gland directly communicates with the brain, the pituitary, the parathyroid, the pancreas, the liver, the adrenal glands, the intestinal system and much more.

You already know this to be true if you are suffering from any type of thyroid dysfunction but here's an example i always try to mention.

Let's suppose that you want to lose weight, well in order to put in perspective how much the thyroid gland affects our metabolism, resistance training which is promoted as one of the best tools to increase BMR, can only lead to a 10% increase (which is still great).

Now here's what's fascinating, untreated hypothyroidism can lead to a BMR that's even 40% below normal and an even 50mcg of T3 day can increase BMR by even 30% in some cases.

You can also look into for example how T3 influences the tight junctions, how it upregulates the LDL-receptor, how it helps with the release of bile or even how it facilitates the production of lactase in the intestinal tract so thyroid dysfunction could even make you react badly to dairy.

In some studies, up to 90.5% of depressed people have subnormal T3 levels.

So thyroid dysfunction could lead to things such as:
-A variety of gut issues
-Severe fatigue
-Hair loss
-Depression
-High LDL
-Insulin resistance/metabolic dysfunctions
-Low libido
-Low testosterone
and more.

Here's how you can support its function.
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*Standard disclaimer that nothing in this thread should be used as a substitute for medical advice*

It's George.
Let's start with the basics.

The thyroid gland is a 2-inch-long gland that weighs less than 1 ounce and is located in the front of the neck below the larynx.

It has two lobes, one on each side of the windpipe which leads to its “butterfly” shape.

The thyroid is one of the glands that make up the endocrine system.

The glands of the endocrine system produce and store hormones and release them into the bloodstream.

The hormones then travel through the body and direct the activity of the body’s cells.

The thyroid gland makes two thyroid hormones:

-Triiodothyronine (T3)
and
-Thyroxine (T4)Image
Some of the functions of T3 include increasing the metabolic rate, heart rate and aiding in thermogenesis and some of the functions of T4 include lowering blood calcium by inhibiting osteoclasts and increasing renal calcium excretion.

T3 is made from T4 and is the more active hormone, directly affecting the tissues.

When (inactive) T4 is released into the bloodstream, it goes to the liver and other organs to be converted into (active) T3.

This conversion is known as deiodination of T4 and is a process which happens primarily within the liver and organs such as the kidneys and small intestines.

This is the primary action of the thyroid and the second one is to regulate circulating calcium levels (by using calcitonin which regulates too much calcium) along with the parathyroid and its PTH (parathyroid hormone which regulates too little calcium).

Thyroid hormone production is regulated by thyroid-stimulating hormone (TSH), which is made by the pituitary gland in the brain.

When thyroid hormone levels in the blood are low, the pituitary releases more TSH.

When thyroid hormone levels are high, the pituitary responds by dropping TSH production.Image
Read 22 tweets
Oct 31
Every video and blog post about hair loss says the same things.

So, here's a summary of the MOST effective strategies you can use to manage premature hair loss and gray hair that don't have dangerous side effects.

Master thread🧵

Disclaimer: The sooner you start implementing these once you notice these issues, the better your results will be.Image
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*Standard disclaimer that nothing in this thread should not be used as a substitute for medical advice*

Now let's start by stating the following: there's no "one thing" that causes all types of hair loss all the time.

Sorry.

It's a myth capitalized to sell whatever magic solution is trending at the time.

Hair loss is driven by a complex interplay of genetics, hormones, certain lipid compounds, environmental factors and a few more things that we discuss in this thread.

So let's check them out.Image
Now here's a breakdown of the main types of hair loss.

Number 1: Androgenetic Alopecia (AGA) (also known as male pattern baldness (MPB), female pattern hair loss (FPHL)).

This is the most common form of hair loss, affecting even up to 50% of men by age 50 and up to 30% of women as some studies suggest.

Its prevalence is highest in Caucasians (80% by age 70), lower in East Asians (40%) and Africans (30%).

One hypothesis of why this is the case, is because variants such as rs12203592 in IRF4 are more prevalent in Europeans.

It is characterized by progressive thinning of terminal hairs (thick, pigmented hairs), which are gradually replaced by finer, shorter vellus hairs due to follicular miniaturization.

It typically presents as a receding hairline at the temples and thinning or baldness at the crown, following the Norwood-Hamilton scale (types/stages I–VII).

In women, it manifests as diffuse thinning over the crown with preservation of the frontal hairline, graded by the Ludwig scale (Types I–III, from mild widening of the part to extensive thinning) or the Sinclair scale (for subtler patterns).Image
Read 20 tweets
Oct 30
***Gut health masterclass***
If you are struggling with gut issues such as:
-Bloating
-Constipation
-IBS
-Leaky gut
-SIBO
-SIFO
-Candida

Here's the ultimate plan for improving them and repairing your gut once and for all.

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*Standard disclaimer that nothing in this thread should be used as a substitute for medical advice and that plenty of people will not have to apply all of these in order to experience improvements*

When it comes to our health, everything starts from and depends on the gut.

From low testosterone, histamine intolerance, depression, chronic fatigue, ED and skin problems, all the way to hair loss, optimizing ones gut health is a non-negotiable step in improving any health issue that he might want to.

Our gut is connected to every single one of the organs in the human body, so it's fair to say that everything is affected by a great part from it.

You know this to be true if you've ever struggled with a gut issue but in case you haven't and are skeptical about this claim, you can check out these 3 basic studies (one for the skin, one for the immune system and one for testosterone):

pmc.ncbi.nlm.nih.gov/articles/PMC79…
pmc.ncbi.nlm.nih.gov/articles/PMC49…
pmc.ncbi.nlm.nih.gov/articles/PMC76…Image
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For those interested in a more detailed explanation of how the gut influences the major organs we have (it's a long one so please skip it if it does not interest you):

-Gut-liver axis

This one describes the bidirectional relationship between the gut microbiota and the liver.

It’s primarily mediated through the portal vein which transports gut-derived products directly to the liver (it also receives 70% of its blood supply from the gut through it).

The gut microbiota for example produces short-chain fatty acids (butyrate, acetate, and propionate), bile acids and lipopolysaccharides (LPS).

Now on one hand, SCFAs will support the liver, but on the other, LPS can trigger liver inflammation if gut barrier integrity is compromised, promoting liver fat accumulation and inflammation.

Gut dysbiosis also exacerbates liver damage by increasing ammonia production and systemic inflammation.

Then, primary bile acids are modified by gut bacteria into secondary bile acids that regulate lipid metabolism and inflammation in the liver.

-Gut-brain axis
This one describes the bidirectional communication network between the gut microbiota and the central nervous system.

This is possible through things/mechanisms such as the vagus nerve, microbial metabolites such as SCFAs and neurotransmitters that are produced by gut bacteria, the HPA axis and gut-derived cytokines that can cross the blood-brain barrier (which is why dysbiosis is shown to impair blood-brain barrier integrity and BDNF expression.

Not to even mention the neurotoxic effects of things such as acetaldehyde that are common in dysbiosis).

In order to perhaps understand why our gut health is so important when it comes to brain health, keep in mind that reduced Bifidobacterium and Lactobacillus levels are linked to depression, endotoxin infusions to healthy subjects with no history of depressive disorders triggered cytokine release and the subsequent emergence of classical depressive symptoms and altered microbiota composition is implicated in Alzheimer’s and Parkinson’s diseases.

-Gut-heart axis
This one describes the bidirectional relationship between the gut microbiota and the heart.

This is possible through things/mechanisms such as trimethylamine n-oxide (TMAO) (elevated TMAO levels are associated with atherosclerosis and cardiovascular events) where gut bacteria metabolize dietary choline and carnitine into trimethylamine (TMA), which the liver converts to TMAO (so dysbiosis increases TMAO), SCFAs such as butyrate and propionate that have anti-inflammatory effects and have been shown to improve vascular function, not only that, but SCFAs are also quite important for managing our blood pressure and then of course we know that when LPS enter circulation for example, promote vascular inflammation and of course, SCFAs like propionate are needed for us to manage cholesterol though HMG-CoA reductase.

-Gut-immune axis
This one describes the interaction between the gut microbiota and the immune system.

The gut houses 70–80% of the immune system in GALT.

This is why dysbiosis impairs sIgA production and Treg/Th17 balance and contributes to autoimmune diseases, allergies, and chronic infections.

Gut bacteria for example, show to immune cells such as T-regulatory cells and Th17 cells how to distinguish between pathogens and commensals, while SCFAs also influence T-regulatory cell function.
This is why some times the gut-lung axis is not mentioned since the gut modulates lung immunity primarily through GALT.

-This is why dysbiosis exacerbates asthma or COPD so much (it increases Th2/Th17 responses but also SCFAs like butyrate reduce airway inflammation by enhancing Treg cells).

-Gut-kidney axis
This one describes the interaction between the gut microbiota and the kidneys.

This is possible since gut bacteria produce things like p-cresyl sulfate and indoxyl sulfate from dietary amino acids and when these accumulate due to dysbiosis for example, the lead to renal damage.

And on the other hand, a healthy gut supports the kidneys through SCFAs for example that are shown to reduce renal inflammation by increasing renal blood flow and reducing oxidative stress for example.Image
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Read 26 tweets
Oct 30
Melatonin is what expensive anti-ageing supplements want (and pretend) to be.

This 3.5 billion-year-old molecule is the ultimate insurance policy of the human body.

It:
-Prevents and helps treat hair loss.
-Controls mitochondrial oxidative stress (broad-spectrum antioxidant that's 10 times stronger than vitamin C).
-Prevents migraines and protects the brain.
-Has anti-cancer properties via Warburg reversal.
-Regulates gut motility, protects the mucosal barrier and modulates the gut microbiota.
-Inhibiting pro-inflammatory cytokines like TNF-a and interleukins.
-Protects the immune system and enhances immune surveillance (it even prevents thymic atrophy).
-Regulates key inflammatory signaling pathways.
-Controls CRs.
-Reduces hypertension and improves endothelial function.
and does so much more.

Here's what you need to know.
Thread🧵Image
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*Standard disclaimer that nothing in this thread should be used as a substitute for medical advice*

It's George.

Melatonin, chemically known as N-acetyl-5-methoxytryptamine, is classified as an indoleamine that is derived from the amino acid tryptophan.

It is evolutionarily ancient and present in organisms from bacteria to humans.

Now technically speaking, since it is synthesized in many non-endocrine organs and doesn't target a specific organ it’s not a hormone (melatonin fits this in the pineal context only).

So melatonin also acts as a paracrine and autocrine signaling molecule, influencing cellular processes across multiple tissues without requiring endocrine-specific pathways.Image
Image
The most powerful antioxidant is not vitamin C, E or even glutathione. Even though all of these are extremely important since each one has unique roles within the human body (for example, glutathione is critical for detoxification) the most powerful antioxidant is free and it's called melatonin.

A single melatonin molecule can scavenge up to 10 reactive oxygen and nitrogen species (ROS and RNS), more than many classic antioxidants like vitamin C and E.

When a melatonin molecule neutralizes a free radical, it becomes a new, less-reactive intermediate molecule.

These intermediate metabolites, such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N-acetyl-5-methoxykynuramine (AMK), are also potent free radical scavengers.

The process can continue with these metabolites neutralizing additional free radicals in a chain reaction.

This cascade helps explain why melatonin is so effective in protecting cells, lipids, proteins, and DNA from oxidative damage throughout the body, as it is both water- and fat-soluble.Image
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Read 19 tweets
Oct 29
Understanding the topic of mitochondria is probably the best thing you can do if you want to improve your health.

After all, mitochondrial dysfunction is implicated in a host of health conditions ranging from chronic fatigue, low testosterone, depression, bipolar disorders, low testosterone and neurodegenerative diseases all the way to cardiovascular issues, diabetes and even sleep apnea.

Now, what are mitochondria?

Mitochondria are subcellular organelles that likely originated from ancient α-proteobacteria engulfed by eukaryotic cells.

These organelles produce the vast majority of cellular energy through adenosine triphosphate (ATP), which is needed to power every cell's biochemical reactions.

They also modulate processes like cell signaling, calcium homeostasis and apoptosis.

So it’s really no wonder that mitochondrial dysfunction is implicated in a host of health conditions.

When it comes to the structure of these double-membrane organelles, it’s a good idea to be aware of the following.

We have the:

-Outer membrane that is highly permeable due to porins such as voltage-dependent anion channels that allow small molecules and ions to pass freely.

-Inner membrane that is less permeable, with selective transporters, that houses the electron transport chain (ETC) and ATP synthase.

-Intermembrane space that is the region between the membranes.

This one is enriched with protons during ATP synthesis, creating a gradient essential for energy production through chemiosmosis.

-Mitochondrial matrix that is the innermost compartment, containing mitochondrial DNA (mtDNA), 70S ribosomes and enzymes for metabolic pathways like the Krebs cycle.Image
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Now let’s dive a bit deeper into their main functions.

Let's start with ATP production.

Our cells require, well, energy in order to run properly.
Mitochondria produce ATP through oxidative phosphorylation in the ETC.

How?

In a nutshell, electrons from NADH (complex I) and FADH₂ (complex II) pass through complexes III and IV, pumping protons into the intermembrane space. The resulting proton gradient drives ATP synthase to convert ADP and inorganic phosphate (Pi) into ATP.

If you have no idea what these are, ATP production happens primarily through three stages:

-Glycolysis (happens in the cytoplasm)
-The citric acid cycle (or the Krebs cycle (happens in the mitochondrial matrix))
-Oxidative phosphorylation (happens across the mitochondrial inner membrane)

Glycolysis is anaerobic (no oxygen needed) and takes one glucose molecule breaks it into two 3-carbon pyruvate molecules through a 10-step enzymatic process (glucose gets two phosphates added whcich uses 2 ATP and gives us fructose-1,6-bisphosphate which splits into dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, then the former also converts to G3P, so we get two G3Ps and each one is then oxidized (loses electrons to NAD⁺ and forms 2 NADH (these basically “carry” energy)).

Finally phosphates are transferred to ADP making 4 ATP total (only 2 were used). After some shuffling, you’re left with 2 pyruvate.

Now, we take these 2 pyruvate molecules and each one is converted to acetyl-CoA by pyruvate dehydrogenase. This process releases CO₂ and generates 2 NADH.

For each acetyl-CoA, the following happens: Acetyl-CoA and oxaloacetate get together to form citrate which reshuffles into isocitrate, then isocitrate loses CO₂ and electrons, forming α-ketoglutarate and 1 NADH.

Now that the first oxidation is done, we move to the second one were α-Ketoglutarate drops another CO₂, yielding succinyl-CoA and 1 NADH. Now in this critical step, succinyl-CoA transfers a phosphate to GDP (making GTP, which converts to 1 ATP).

The oxidations don’t stop here and succinate becomes fumarate (1 FADH₂), then malate, then oxaloacetate (1 NADH), completing the loop.

And we can finally talk about oxidative phosphorylation and its two parts, the electron transport chain (ETC) and chemiosmosis. The first one is a series of protein complexes (I-IV) and carriers (ubiquinone, cytochrome c) embedded in the inner mitochondrial membrane.

NADH is used in Complex I and FADH₂ in Complex II.

Ubiquionone also plays a critical role (Complex I → Ubiquinone (Q) → Complex III → Cytochrome c → Complex IV and at Complex IV, electrons combine with O₂ and H⁺ to form deueterium depleted H₂O (oxygen is the final electron acceptor).

In some texts, you will find that metabolic reactions such as converting pyruvate to acetyl-CoA, the citric acid cycle and pyruvic oxidation are mentioned on top of ATP production so here's some further analysis in these for the ones interested.

Pyruvic acid is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group.

The conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell.

Pyruvic acid can be made from glucose through glycolysis, converted back to carbohydrates (such as glucose) via gluconeogenesis, or to fatty acids through a reaction with acetyl-CoA.

It can also be used to construct the amino acid alanine and can be converted into ethanol or lactic acid via fermentation.

It supplies energy to cells through the citric acid cycle (the Krebs cycle) when oxygen is present (aerobic respiration) and alternatively ferments to produce lactate when oxygen is lacking.

In pyruvic oxidation, we are starting with a molecule of pyruvate which has 3 carbons.

Then, we’ll make a molecule of acetyl by dropping a carbon and the carbon that is lost will be lost as a molecule of CO2.

All of these carbon atoms have high energy electrons in their orbitals.

NAD will take the electron that became available through the above process for us to utilize and since it now has an electron on it, it becomes NADH.

So NADH is the product and NAD the reactant.

Now acetyl’s destination is the mitochondria. In order for this to happen, CoA will bind to acetyl and is going to produce acetyl-CoA which can now be accepted by the membrane of the mitochondria and now we can start the next step which is the citric acid cycle.

So, pyruvic acid supplies energy to cells through the citric acid cycle (Krebs cycle) when oxygen is present (aerobic respiration), and alternatively ferments to produce lactate when oxygen is lacking.

A pyruvate carboxylase deficiency, will cause lactic acid to accumulate in the blood, it can damage the body's organs and particularly the nervous system.

In aerobic conditions, the process converts one molecule of glucose into two molecules of pyruvate (pyruvic acid), generating energy in the form of two net molecules of ATP.

Four molecules of ATP per glucose are actually produced, but two are consumed as part of the preparatory phase.

The initial phosphorylation of glucose is required to increase the reactivity (decrease its stability) in order for the molecule to be cleaved into two pyruvate molecules by the enzyme aldolase.

During the pay-off phase of glycolysis, four phosphate groups are transferred to ADP by substrate-level phosphorylation to make four ATP, and two NADH are produced when the pyruvate is oxidized.

The overall reaction can be expressed this way:
Glucose + 2 NAD+ + 2 Pi + 2 ADP → 2 pyruvate + 2 H+ + 2 NADH + 2 ATP + 2 H+ + 2 H2O + energy

Starting with glucose, 1 ATP is used to donate a phosphate to glucose to produce glucose 6-phosphate.

Glycogen can be converted into glucose 6-phosphate as well with the help of glycogen phosphorylase.

During energy metabolism, glucose 6-phosphate becomes fructose 6-phosphate. An additional ATP is used to phosphorylate fructose 6-phosphate into fructose 1,6-bisphosphate by the help of phosphofructokinase.

Fructose 1,6-bisphosphate then splits into two phosphorylated molecules with three carbon chains which later degrades into pyruvate.Image
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Moving on to the citric acid cycle.

The citric acid cycle (or else known as the tricarboxylic acid cycle or the Krebs’ cycle) is the major energy yielding metabolic pathway in cells, it is an important part of aerobic respiration and takes place in the matrix of the mitochondria (just like the conversion of pyruvate to acetyl CoA).

In order for ATP to be produced through oxidative phosphorylation, electrons are required for ATP to pass down the electron transport chain.

These electrons come from electron carriers such as NADH and FADH, which are produced by the citric acid cycle .

The citric acid cycle harnesses the available chemical energy of acetyl coenzyme A (acetyl CoA) into the reducing power of nicotinamide adenine dinucleotide (NADH).

Here are some of the basic steps of the cycle.

Step 1: The cycle begins with an enzymatic aldol addition reaction of acetyl CoA to oxaloacetate, forming citrate which is isomerized by a dehydration-hydration sequence to yield (2R,3S)-isocitrate.

Step 2: Citrate is converted to isocitrate .

Step 3: Isocitrate is oxidized to alpha-ketoglutarate which results in the release of carbon dioxide. One NADH molecule is then formed.

Step 4: Alpha-ketoglutarate is oxidized to form a 4 carbon molecule in order to bind to coenzyme A, forming succinyl CoA. A second molecule of NADH and CO2 are then being produced.

Step 5: Succinyl CoA is then converted to succinate and one GTP molecule is produced.

Step 6: Succinate is converted into fumarate and a molecule of FADH is produced.

Step 7: Fumarate is converted to malate.

Step 8: Malate is then converted into oxaloacetate.
The third molecule of NADH is also produced.

So, the products of the first turn of the cycle are one ATP, three NADH, one FADH2 and two CO2.

The total number of ATP molecules obtained after complete oxidation of one glucose in glycolysis, citric acid cycle, and oxidative phosphorylation is estimated to be between 30 and 38.

Note: Calcium is also used as a regulator in the citric acid cycle.

Calcium levels in the mitochondrial matrix can reach up to the tens of micromolar levels during cellular activation.Image
Read 16 tweets
Oct 27
Modern life is quietly sabotaging your immune system.

From spike protein pathology, redox collapse and thymic involution that shrink and starve your naive T-cell factory, all the way to heavy metal exposure, nutrient deficiencies, gut dysbiosis and much more, the list of things that harm our immune system is endless.

So here's how you can build a resilient immune system in a toxic world.

Thread🧵Image
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*Standard disclaimer that nothing in this thread should be used as a substitute for medical advice*

It's George.
First and foremost, when we read the words “immune system”, it should be somewhat obvious that we are talking about a network of organs, tissues, special cells and so on that all work together instead of just “one thing”.

The main parts of the immune system are the:
● Bone marrow
● White blood cells
● Thymus
● Antibodies
● Complement system
● Lymphatic system
● Spleen
● SkinImage
Here's a basic breakdown of these.

Your bone marrow produces 500 billion blood cells daily, including red blood cells for oxygen transport, platelets for clotting, and white blood cells for immune defense.

Key players are hematopoietic stem cells (HSCs), cytokines like IL-3 and GM-CSF, and a nutrient-rich microenvironment.

You can support this part with folate which is essential for DNA synthesis and rapid cell division in HSCs plus deficiency causes megaloblastic anemia and halts white blood cell production.

B12 that works with folate in the methionine cycle to prevent hyperhomocysteinemia, which damages HSC niche and triggers apoptosis.

Retinol that maintains the bone marrow stromal cell niche and prevents squamous metaplasia of supportive fibroblasts.

Silica that strengthens the collagen matrix housing marrow, improving HSC anchorage and cytokine signaling.Image
Read 20 tweets

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