Mouth ulcers and Vitamin U

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Picture - https://en.wikipedia.org/wiki/Mouth_ulcer

Summary - Mouth ulcers result from a breach of the mucous layer that protects the lining of the mouth and an underlying inability to repair the mucous layer quickly. Taking Vitamin U in the form of fresh vegetable juice and/or supplements is a great way to naturally heal mouth ulcers. Talk to your doctor or dentist.

Mouth ulcers (aphthous ulcers or stomatitis) are small, painful, circular sores that form in the lining of the mouth. They are very common. Right this minute, 1-2% of people have a mouth ulcer. Over a lifetime, about half of the US population will get at least one if not many. They mainly afflict teenagers. Ulcers normally heal spontaneously in one to two weeks, although they can reoccur many times. Recurrent ulcers indicate an underlying health problem. Sores in the corner of the mouth or outside the mouth are not ulcers and should be treated differently.  

Why do I have a mouth ulcer? 

The lining of your mouth is covered by a thin layer of mucus. The main purposes of this mucus is to protect the lining of the oral cavity from physical and chemical damage, infection, and to help digest food. Mouth ulcers develop when the protective mucus layer is breached and the body shows a delayed repair response with non-specific oral bacteria infecting. The integrity of the mucus layer is a function of constructive vs destructive factors. 

Destructive factors

Biting your mouth while eating or from a nervous habit is probably the most common way ulcers start. Physical or chemical damage from food is another very common cause - 

• Crusty food like bread or toast
• Crispy food like chips
• Salty food like pretzels
• Sweet food like candy
• Sticky food like cookies
• Sour food like vinegar
• Hot food like coffee

Abrasive, salty and hot foods/drinks physically damage the mouth. Sour foods/drinks chemically burn the mouth instantly. Sweet and sticky foods burn slowly by feeding oral bacteria, which metabolize sugars to produce corrosive acids. 

Drugs are another destructive factor. Alcohol is oxidized by oral bacteria to acetaldehyde, which is toxic and a carcinogen (Tagaino et al, 2019). Some acetaldehyde is even produced from sugar by oral bacteria. Acetaldehyde is also found in cigarette smoke (Sprince et al, 1975). As with peptic ulcers, NSAIDs like aspirin inhibit prostaglandin E2 synthesis which reduces mucin secretion. People swishing aspirin in their mouth to quell inflammation are actually slowing down ulcer healing (Slomiany and Slomiany, 2000).

Poor dental hygiene is yet another destructive factor. Harsh brushing makes tiny holes through which corrosive agents can meet the cell surface. Ineffectual or nonexistent brushing leaves food and bacteria in position to generate more organic acids and acetaldehyde.

Constructive factors

The major factor protecting the mouth is mucus. There are five kinds of mucin produced in the mouth - MUC5B and MUC7 being the most important (Frenkel and Ribbeck, 2015). MUC5B is a very long protein rich in serine and threonine amino acids to which glycans attach. These glycans attract water to form a gel and gives your mouth that slippery feeling. The protein overall looks likes a bottle brush with one end attached to the cell. MUC7 is similar, but is unattached and therefore flows freely aiding in formation of the soft bolus from food. MUC5B proteins form polymers via disulfide bonds. Cysteine is unusually common in MUC5B and is essential for disulfide bond formation.

A shortage of many dietary factors have been suggested to cause mouth ulcers. Examples include vitamin B9 (folate), vitamin B12, vitamin C, vitamin E, selenium. All play a role in antioxidation, and it makes sense that these nutrients are low in ulcers as the environment shows signs of oxidative stress (elevated malondialdehyde and depressed glutathione)(Arikan et al, 2009). 

Despite this speculation, however, the evidence has been inconclusive. There are certainly some patients who respond well to supplementation with one or another of these micronutrients. However, many times mouth ulcers occur in people with no apparent deficiency and/or supplementation has no effect. Considering that some of these micronutrients work in some cases, it's possible that they help in an indirect way, or that chronic mouth ulcers are indicative of a systemic redox imbalance. For example, chronic ulcers are more prevalent in those with other problems in their digestive tract (Brailo et al, 2007).

Can Vitamin U help heal and prevent mouth ulcers?

The use of Vitamin U to treat or prevent mouth ulcers has undergone little investigation (Kato and Takayasu, 1961). Vitamin U has been shown to be a useful treatment for gum disease (Sulym, 2016), and sulfur compounds like cysteine are effective in quenching the damaging effects of acetaldehyde in the mouth, particularly when combined with vitamins B1 and C (Sprince et al, 1975; Syrjanen et al, 2016).

The fact that Vitamin U has been shown to heal and prevent peptic ulcers by stimulating the release of mucin suggests that it may also have this function in other parts of the digestive tract which also secrete mucin (Watanabe et al, 2000). One can't help but wonder whether mouth ulcers have a similar etiology to its more dangerous relatives. If this is indeed the case, one may speculate as to whether Vitamin U or a metabolic derivative could have this effect on the release of mucin from not only the mouth or other parts of the alimentary canal, but even other epithelial tissues, including the lungs, trachea, nose and eyes.  

Vitamin U may also support mucosal function in indirect ways. Firstly, Vitamin U yields cysteine, which is the rate-limiting component of glutathione, the master antioxidant that fights oxidative stress. Secondly, the relatively large amount of cysteine required to tether mucin to the epithelial tissue means that extra cysteine in the form of Vitamin U may prove useful. Thirdly, much of the glycans that attach to mucins are themselves sulfated, requiring more sulfur. 

Many people, especially those whose diet is low in the sulfur amino acids methionine and cysteine, have limited antioxidant capacity due to having low levels of glutathione. For those people, alternative sources of sulfur amino acids like Vitamin U are an important alternative source. Drinking freshly-made vegetable juice or taking Vitamin U supplements in combination with the cessation of destructive practices will probably help clear up your current mouth ulcer and help prevent future ulcers.

Take care and good luck,

Sean

Vitamin U complements H2 blockers

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Image - http://www.vivo.colostate.edu/hbooks/pathphys/digestion/stomach/parietal.html

Summary - H2 blockers are drugs used to reduce stomach acid in people who have pain due to stomach ulcers. Vitamin U in the form of fresh vegetable juice or supplements can be used alongside H2 blockers to speed up the restoration of the protective mucous bilayer.

The human stomach is a very acidic environment. The pH of a correctly-functioning stomach is 1.5 - 3. The acidity of gastric juice is due to hydrochloric acid (HCl), which is produced by parietal cells in the upper parts of the stomach (fundus and cardia). Parietal cells produce acid using enzymes called proton pumps (H+/K+ ATPase), which use the energy derived from the hydrolysis of ATP to pump H+ into the stomach. It is the protons (H+) that cause acidity. 

The parietal cells pump acid into the stomach in response to signal molecules binding receptors. There are numerous kinds of receptors that respond to different stimuli, either positively or negatively. The most important for acid production are the H2 histamine receptors. Protein in food is broken down in the stomach by acid and the enzyme pepsin to form peptides. These peptides stimulate the release of the hormone gastrin from G cells in the stomach and duodenum. Gastrin stimulates the release of histamine from ECL cells. Histamine binds receptors in the base of parietal cells where it stimulates the movement of proton pumps to the apical surface, where they pump acid into the stomach cavity (lumen). This acid accelerates this whole cycle, breaking down more proteins in food by hydrolysis as well as activating pepsin.

H2 blockers bind to the H2 receptors, which stops histamine from binding. If histamine can't bind, the levels of acid in the stomach remain fairly low and the corresponding pH relatively high. (H2 blockers are often referred to as H2 antagonists because they block the binding of histamine without itself stimulating the function of the receptor, an important distinction from agonists). 

H2 blockers were invented in the 1960s and have to a large extent been superseded by proton pump inhibitors due to the latter's more potent acid-suppressing abilities. Commonly used H2 blockers include famotidine (Pepcid) and cimetidine (Tagamet). Ranitidine (Zantac) was the most prescribed drug in the US during the 1980s, but the FDA has recently banned its sale due to carcinogenic impurities. 

Stomach ulcers and gastroesophageal reflux (GERD) are conditions characterized by pain caused by stomach acid coming into direct contact with the lining of the stomach and esophagus, respectively. Contrary to popular opinion, these conditions are rarely caused by excessive production of stomach acid. In fact, the acidity in the stomach of those with stomach ulcers is typically low (i.e. relatively high pH). GERD is caused by normal stomach acid coming into contact with the esophagus, an organ that is not designed to withstand such exposure. Unlike the stomach, the esophagus is not coated with a protective alkaline mucous bilayer and is very sensitive to contact from even small amounts of gastric juice.

One unfortunate problem with taking H2 blockers for stomach ulcers is that they reduce the secretion of mucin (Ichikawa et al., Diebel et al). So while they reduce pain by reducing the amount of acid produced, they also increase the risk of pain by weakening the mucous bilayer. 

Vitamin U is a nutrient abundant in vegetables and fruit that stimulates the secretion of mucin in the stomach. As fresh vegetables and fruit have been a major component of our diet for a very long time, it is reasonable to conclude that dietary Vitamin U plays an important role in the maintenance of optimal stomach function. 

Can Vitamin U be combined with H2 blockers? 

Considering Vitamin U stimulates mucin secretion and H2 blocker reduce it, one may wonder whether Vitamin U can be taken with H2 blockers to negate the negative effects. The evidence suggests yes. In 2009, Ichikawa et al. showed that co-administration of Vitamin U with famotidine reversed the mucin-blocking effects of famotidine without affecting the acid-suppression effects. These results suggest that Vitamin U can add another level of protection to the gut in those taking H2 blockers.

Considering these findings, drinking fresh vegetable juice daily or taking Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

Take care and good luck,

Sean

High salt consumption may cause stomach ulcers

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Summary - High salt consumption is a risk factor for the development of gastritis, gastric ulcers and gastric adenocarcinoma. If you have a stomach ulcer and your salt consumption is high, reducing the amount of salt you eat might help heal your ulcer, especially in combination with other treatments like antibiotics and Vitamin U. Talk to you doctor about your options.

(For clarification, "peptic ulcer" usually refers to ulcers in either the stomach or the duodenum. A "gastric ulcer" is another name for a stomach ulcer.)

The two most cited risk factors for the development of stomach ulcers are infection with Helicobacter pylori and taking NSAIDs (Mayo Clinic, 2020a). High dietary salt is another risk factor that is lesser known, though it has long been considered a risk factor in the development of stomach cancer (Mayo Clinic, 2020b; Cromer et al, 1949). Stomach ulcers and stomach cancer are two different conditions, and ulcers do not automatically lead to stomach cancer. However, these two conditions result from a similar set of risk factors, include high salt intake. What determines whether you develops ulcers or cancer may lie in genetics, diet, and to a certain extent, luck.

 

It has been long noted that at times when salt consumption within a population is low, stomach ulcers are rare (Sonnenberg 1986 and references within). For example, prior to the French Revolution, salt was heavily taxed in France as a means of raising crown revenue. Salt consumption was light among the general population. and the incidence of stomach ulcers was low. As salt taxes were repealed, salt consumption especially via its use as a food preservative increased. Salt consumption in the Western world peaked in the early 20th century, declining with the invention of alternative forms of preservation like canning and refrigeration. Throughout this period, mortality due to stomach ulcers rose, peaked, then declined in lockstep with salt use. 

Another way to show a relationship between salt intake and stomach ulcer prevalence is to look at these factors in different countries at a given time. Countries in which salt intake is high (e.g. Japan, Portugal, Spain) tend to have higher mortalities from stomach ulcers than those in which salt intake is low (Sonnenberg 1986). 

Does this mean your stomach ulcer is caused by eating too much salt? On the one hand, your ulcer is caused by something, and if your diet is heavy in salt, it might be a contributing factor. On the other hand, while the evidence is quite suggestive, it's important to take these findings with a grain of salt (so to speak). If you have a stomach ulcer and eat a lot of salt, reducing dietary salt for a couple of weeks and seeing whether the pain goes away might be worth trying. Even better, talk to your doctor as a combination of reduced salt intake and other treatments might be even more effective.

How does a high-salt diet cause stomach ulcers? 

By itself, high salt intake can cause a non-inflammatory atrophic gastritis (Bergin et al, 2003). Concentrated salt strips off the mucous bilayer by inducing edema, increasing the percentage of replicating cells susceptible to mutagenesis, and exposing the underlying epithelial cells to damaging stomach acid (Charnley and Tannenbaum, 1985). The heightened cell turnover especially in combination with mutagens increases the chances of a cancer-causing mutation occurring. Acidic damage reduces production of mucus and acid required for digestion, with chronic damage resulting in low stomach acid (hypochlorhydria) (Cromer et al, 1949) and predisposes to ulcer formation. 

Like salt, H. pylori can induce atrophic gastritis in and of itself, while also inducing an inflammatory response. However, it seems that a combination of H. pylori infection and a high-salt environment leads to a much greater chance of developing stomach ulcers and/or cancer. Damaging the mucous bilayer with salt enables H. pylori to directly contact the epithelial cells. Low stomach acid allows H. pylori to more easily survive in the stomach, especially in parts prone to ulceration/cancer such as the corpus. Inflammation generates reactive oxygen species that damage the DNA of epithelial cells, resulting in immediate reduction in function as well as debilitating mutations. Reactive oxygen species generate mutations in the cells lining the stomach that are then enriched by heightened cell turnover. Most mutations result in reduced cell function, which often shows up as cells that produce less mucus or less gastric acid on a permanent basis. However, some mutations are in genes that when damaged result in the cells reproducing at an inappropriately increased rate, oftentimes producing cancer. 

A high-salt environment also seems to induce physiological changes in H. pylori that enable the bacterium to survive under the unusual conditions. When the salt concentration in the stomach increases above a certain level, H. pylori becomes stressed and its growth slows. It changes its shape from its regular spiral to an elongated filamentous form (Gancz et al, 2008). Virulence factors (e.g. cagA, vacA, adherins) may be induced depending on the strain of H. pylori present, which enable the bacterium to invade the cells lining the stomach (Loh et al, 2007).

What constitutes high salt? Charnley and Tannenbaum (1985) stated that frequent consumption of foods rich in salt such as soy sauce (18%), dried fish (20%), and pickles (13-25%) would probably lead to increased gastric cell proliferation. Chips and pretzels are similarly salt-rich, and in large and regular amounts would be expected to have similar effects on the gastric lining. The best measure of whether you are taking in too much salt is by having your doctor measure your 24 h urinary sodium output (Sonnenberg 1986).

Stomach ulcers result from an imbalance between destructive factors such as high salt intake and H. pylori infection, and constructive factors such as the mucus-stimulating ability of prostaglandin E2 and Vitamin U. Taking Vitamin U in the form of fresh vegetable juice or supplements will to some extent counteract the negative effects resulting from high salt consumption by rebuilding the protective mucous bilayer lining the stomach. Recall the pioneering cabbage juice studies of Cheney from 70 years ago (more). The role of H. pylori infection was unknown at the time, yet cabbage juice in the absence of supporting antibiotics was effective in healing peptic ulcers. 

Whatever means you take to treat your stomach ulcer, it would be wise to reduce exposure to the causative agent(s), whether that be infection with Helicobacter pylori, NSAIDs, a stressful job, the morning donuts, or in this case, a high-salt diet. If you have stomach issues but are not sure what condition you have, visit your doctor for a diagnosis. 

Please don't treat stomach cancer with vegetable juice or Vitamin U supplements. The primary role of nutrients is to promote good health and reduce the risk of developing cancer in the first place. Once a cancer has formed, it should be treated with chemotherapy, radiation and/or surgery. 

Take care and good luck,

Sean

Vitamin U may help combat the ulcergenic effects of NSAIDs

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Summary - Taking NSAIDs increases the risk of you developing stomach ulcers by inhibiting your natural protective system. There are several measures you can take to help get rid of stomach ulcers due to NSAIDs -

    1) reduce the dose

    2) change the NSAID to one less irritating 

    3) counteract with other drugs

    4) switch from NSAIDs to other pain relievers

    4) take Vitamin U

Vitamin U in the form of fresh vegetable juice or supplements can be used in combination with other measures to combat ulcers. However, Vitamin U will not counteract all of these negative effects as NSAIDs are powerful drugs. If you have an ulcer and are taking NSAIDs, talk to your doctor as there may be a solution.

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Stomach ulcers result from an imbalance between protective and destructive factors. There are several destructive factors including infection with Helicobacter pylori, overproduction of stomach acid, overeating salt, alcohol and sugar, and taking NSAIDs. Ulcers often result from a combination of these factors. The focus of this post is the role NSAIDs play in causing your ulcer.

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) are widely used to reduce pain and inflammation. The most commonly taken NSAIDs are aspirin (e.g. Bayer), ibuprofen (e.g. Advil, Motrin), naproxen (e.g. Aleve), mefenamic acid (e.g. Ponstal), diclofenac (e.g. Voltaren), piroxicam (e.g. Feldene). A more complete list is linked here.

NSAIDs reduce inflammation and pain by inhibiting the enzyme COX-2. COX-2 is part of your body's inflammatory response. A certain amount of inflammation is good and necessary for healing. However, too much inflammation causes pain and further damage, which is why we take NSAIDs.

How do NSAIDs cause stomach ulcers? 

In addition to inhibiting COX-2, NSAIDs also inhibit the related enzyme COX-1, albeit to a lesser extent. COX-1 catalyzes the same reaction as COX-2, that being the synthesis of prostaglandins from arachidonic acid. However, COX-1 and COX-2 have different functions due to their different expression patterns. COX-1 is expressed throughout the body continuously, in contrast to COX-2 which is only expressed during inflammation. In the gastrointestinal tract, the continuous production of prostaglandin E2 catalyzed by COX-1 stimulates mucin production. Mucin forms a mucus bilayer in the stomach that protects the lining against corrosive agents such as stomach acid. The inadvertent inhibition of COX-1 by NSAIDs reduces mucin production, leaving the stomach wall vulnerable. To compound the problem, NSAIDs also have a multitude of other negative effects including increasing the production of stomach acid and increasing oxidative stress (Matsui et al, 2011), which for people with an ulcer will cause more discomfort and make the ulcer worse.

Fortunately, not all NSAIDs inhibit COX-1 equally. Some NSAIDs are more ulcergenic than others. For example, some of the early NSAIDs like aspirin are notorious for upsetting the stomach. More recently, scientists have developed NSAIDs that don't inhibit COX-1 as much as their predecessors and while still inhibiting COX-2 strongly, so-called COX-2 inhibitors, e.g. celecoxib (Celebrex). Consequently, these newer NSAIDs may reduce ulcer formation while still providing pain relief elsewhere in your body. If you have an ulcer and are taking NSAIDs, talk to your doctor about alterative NSAIDs. Be warned that these new generation NSAIDs are not without other side effects.

 

Can Vitamin U help?

The short answer is probably. Vitamin U is a naturally-occurring nutrient found in all vegetables, fruit and grains. One of its functions is to stimulate the secretion of mucin onto the walls of the stomach. How it does this is not well understood, but it is doesn't seem to have anything to do with COX-1/2 and prostaglandins. As a result, Vitamin U can be used to counteract the mucus-depleting effects of NSAIDs.

Are there any studies supporting the use of Vitamin U to counteract the ulcergenic effects of  NSAIDs?

Yes. In 1993, Salim reported the findings of a clinical trial in which Vitamin U was found to accelerate healing of patients hospitalized for erosive gastritis (bleeding from the stomach) caused by NSAID intake. Erosive gastritis is a common precursor to stomach ulcers. The majority of the patients had been taking NSAIDs for either osteo- or rheumatoid arthritis for less than 3 months. The NSAIDs used included diclofenac, piroxicam, mefenamic acid, naproxen and ibuprofen. The double-blind study found that the patients who received 4 x 500 mg of Vitamin U (DL-methylmethionine sulfonium chloride) per day had significantly less bleeding than the negative controls. Similarly to Vitamin U, patients given the sulfhydryl amino acid L-cysteine were also found to have significantly reduced bleeding, demonstrating the action of Vitamin U is likely via its conversion to a sulfhydryl. Endoscopies performed two days after treatment revealed significantly greater healing in those who were given either Vitamin U or cysteine. Of the 57 patients who were not treated with either Vitamin U or cysteine, 4 died from their condition. In contrast, there were no fatalities in those who were treated with either of these compounds. 

Currently, it is standard medical practice in cases of erosive gastritis to get the patient to stop taking NSAIDs, or at least take less irritating types, and/or to suppress stomach acid production. For a person who is taking NSAIDs for arthritic pain, reducing the amount of NSAIDs taken is clearly not desirable. Switching to less irritating NSAIDs is an option. Talk to your doctor.

Suppressing acid production will reduce irritation of the stomach, but at what cost? Unless you are producing too much stomach acid (a rare condition), reducing stomach acid will have side effects. The major role of stomach acid is to digest protein in our food. Dietary protein must be unraveled then enzymatically chopped up by pepsin to produce peptides. Without an acidic environment, protein passes through to the duodenum half digested. Enzymes in the duodenum that further digest protein into tiny peptides or amino acids can only do so much, leaving a significant portion of protein to pass into the colon. Consequently, low stomach acid can result in inadequate protein absorption as well as colonic fermentation (smelly gas). Furthermore, long-term suppression of stomach acid production promotes the growth of Helicobacter pylori, a known carcinogen (more).

While the results of this clinical trial are promising, Vitamin U is not infinitely powerful. There is only a certain amount Vitamin U can do to reverse or prevent damaged induced by NSAIDs. Large doses of NSAIDs will probably damage the stomach faster than Vitamin U can reverse this damage. However, these findings suggest that Vitamin U may be of some use in counteracting some of the negative effects caused by NSAIDs. Drinking freshly-made vegetable juice on a daily basis provides Vitamin U as well as other beneficial nutrients such as folate. 

For those who prefer a supplement, one capsule of Bioremediation's Vitamin U supplements contains 500 mg of the same compound used in the abovementioned clinical trial. 

Take care and good luck,

Sean

Vitamin U and acne, dandruff and eczema

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Acne, dandruff and eczema are skin conditions the origins of which are often idiosyncratic and mysterious. However, one characteristic shared by all three conditions is low glutathione levels. Glutathione is by far the most important antioxidant in the human body, yet we absorb little of it from our food- that's why our body makes it. 

There are three main causes of low glutathione - 

1. A medical condition that drains large amounts of glutathione

2. A genetic block that prevents the biosynthesis or regeneration of glutathione

3. Not enough glutathione precursors in our diet

Identifying the root cause of your skin condition is an important first step in the healing process. However, this is easier said than done. Often we just don't know why these conditions happen. Sometimes they can break out suddenly and worsen quickly, particularly under stress. At other times, symptoms can persist chronically for years.

Irrespective of the root cause, restoring your glutathione levels is a vital part of this rebalancing act. Glutathione is a tripeptide comprised of cysteine, glutamate and glycine. Of these amino acids, cysteine is most commonly in short supply. If glutathione levels are low due to dietary factors, it is usually due to a shortage of cysteine. Cysteine is found in protein, especially that derived from animals. Cysteine is also made from methionine, again abundant in animal proteins. These sulfur amino acids are also plentiful in grain proteins. However, some people find that meat/dairy/grain are inflammatory for other reasons like hormones or allergens. 

Vitamin U is S-methylmethionine, a soluble nutrient abundant in vegetables and fruit that is converted into methionine by the enzyme BHMT2. There have not been any direct studies into whether Vitamin U has any effect on these three conditions, whether taken internally in the diet or as a supplement, or when applied topically as an active component of a lotion. However, taking Vitamin U can help restore glutathione levels which are low in the tissues affected by acne, dandruff and eczema, so it is quite likely that increasing your intake of Vitamin U will help with these conditions, especially in combination with the identification and removal of triggers of these conditions in you. 

A glass of freshly-made vegetable juice every day is an excellent way to boost your Vitamin U intake along with a slew of vitamins and minerals essential for good skin health. For those who prefer a supplement, one capsule per day of Bioremediation's Vitamin U may be a useful alternative.

Take care and good luck,

Sean

The methionine cycle and Vitamin U

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Summary - The methionine cycle is a multistep enzymatic process than enables Vitamin U to be used as a source of methyl groups vital for gene regulation and the regeneration of creatine/ATP in muscles, as well as its use as a precursor of glutathione required to fight oxidative stress and inflammation.

This is a simple depiction of the four-step methionine cycle in our body. In the first step, the adenosyl group of ATP is transferred to methionine to form S-adenosylmethionine (SAM), thereby activating the methyl group of methionine. In the second step, SAM donates its methyl group to a range of acceptor molecules (notably DNA, guanidinoacetate, and phosphatidylethanolamines), also yielding S-adenosylhomocysteine (SAH). In the third step, the adenosyl group SAH is removed by hydrolysis leaving homocysteine. In the fourth step, homocysteine is either remethylated using one of three methyl donors to reform methionine (step 4a) or is directed into the transsulfuration pathway to form cystathionine (step 4b).

The methionine cycle has a myriad of functions including -

1. The generation of methylation capacity, 

2. The biosynthesis of cysteine as a component of proteins and glutathione, and as a precursor to taurine and hydrogen sulfide, 

3. The biosynthesis of polyamines from SAM. 

The most important function of the methionine cycle is to generate methylation capacity. A measure of our body's methylation capacity is the SAM:SAH ratio, i.e. the relative amounts of the two intermediates. If this ratio is low (below 4), the first enzyme in transsulfuration (cystathionine beta synthase) will have low activity and homocysteine will be remethylated to reenter the methionine cycle (step 4a). This tendency will continue until the ratio is above 4, at which point the relatively high concentration of SAM activates cystathionine beta synthase (CBS) resulting in excess homocysteine being funneled into the transsulfuration pathway. 

Another important function of the methionine cycle is the biosynthesis of cysteine via transsulfuration. Transsulfuration adds cysteine to that obtained from our diet as a component of protein (~50%). Cysteine is used as a building block in human proteins, is the catalytic center of the master antioxidant glutathione as well as acting as a precursor to molecules such as taurine and hydrogen sulfide. Increased oxidative stress will result in activation of CBS activity via allosteric binding by glutathione and transcriptional upregulation by hydrogen sulfide, nitric oxide and carbon monoxide. However, despite the negative health effects of high homocysteine levels (associated with cardiovascular disease) and low glutathione levels (associated with inflammation), the maintenance of methylation capacity trumps that of the provision of transsulfuration products.

The most common cause of a low SAM:SAH is a shortfall in the supply of dietary methyl donors. Other causes of low flux include shortages in vitamins that help catalyze reactions (e.g, folate, B12, B6), mutations in genes that encode enzymes involved in catalysis (e.g. MTHFR, CBS), and very low calorie diets.

There are several nutrients that can contribute methyl groups to the methionine cycle. Aside from methionine, which enters the methionine cycle directly, the other dietary methyl donors enter the methionine cycle via methylation of homocysteine. There are three enzymes known to catalyze this reaction in humans, with each enzyme acting upon a single methyl donor molecule. Other molecules that can contribute methyl groups must do so indirectly. Consequently, the three classes of dietary methyl donor are characterized by the enzyme that catalyzes the reaction with homocysteine and its substrate -

1. Betaine:homocysteine methyltransferase 1 (BHMT1) and betaine (trimethylglycine or TMG)
2. Methionine synthase (MS) and folate (5'-methyltetrahydrofolate or MTHF)

3. Betaine:homocysteine methyltransferase 2 (BHMT2) and Vitamin U (S-methylmethionine)

Betaine (trimethyl glycine) has three methyl groups, one of which is transferred to homocysteine to form methionine and dimethyl glycine. The other two methyl groups contribute to methylation, though via assimilation through the folate cycle. Dimethyl glycine dehydrogenase catalyzes the transfer of a methyl group from dimethyl glycine to tetrahydrofolate to produce 5, 10-methylenetetrahydrofolate. The other product, methyl glycine (sarcosine) yields the last methyl group to tetrahydrofolate in a similar reaction catalyzed by the homologue sarcosine dehydrogenase.

Betaine is plentiful in whole grains, with the notable exception of rice (betaine is an osmoprotectant in plants and it appears that under the wet conditions in which rice is usually grown betaine formation is suppressed). Betaine is also produced in our body from choline, which is abundant in the fatty component of food as phosphatidylcholine. Consequently, food with more naturally occurring fat such as meat, eggs, dairy and nuts are the richest sources of choline, with produce and grains contributing a lesser amount.

The active form of folate (Vitamin B9) is 5'-methyltetrahydrofolate, which supplies a methyl group to homocysteine to yield methionine and tetrahydrofolate. Once folate has donated its methyl group, it must be remethylated in the folate cycle to be reused. The primary source of these methyl groups is serine. Contrary to popular belief, folate itself is a minor dietary source of methyl groups. Even taking supplements labelled "methyl folate" or "activated folate" or eating green leafy vegetables provides minimal extra methylation substrate. With regards to its role in methylation, folate is better thought of as a carrier molecule analagous to homocysteine rather than as a methyl source.

Most methionine in our diet is found as a component of protein, which requires extensive digestion by a slew of enzymes to release methionine as an amino acid before it can enter the methionine cycle. Vitamin U (S-methylmethionine) is methionine with an extra methyl group, although unlike methionine, Vitamin U is rarely a component of proteins. It supplies a methyl group to homocysteine yielding two molecules of methionine. Vitamin U is abundant in vegetables and fruits, especially cruciferous (e.g. cabbage, kale) and stalky (e.g. celery, asparagus) vegetables.

The degree to which these methyl donors contribute to the methionine cycle is dependent upon our diet. In a diet rich in protein and fats, methionine and choline will be major sources. In a diet in which more calories are gleaned from whole grains, betaine will make a greater contribution. Folate and Vitamin U will make larger contributions in diets rich in fresh produce.

Take care and good luck,

Sean

References

1. Finkelstein (1990) https://pubmed.ncbi.nlm.nih.gov/15539209/
2. Mudd and Poole (1975) https://pubmed.ncbi.nlm.nih.gov/1128236/
3. Benevenga (2007) https://pubmed.ncbi.nlm.nih.gov/17413090/
4. Bertolo and McBrearity (2013) https://pubmed.ncbi.nlm.nih.gov/23196816/
5. Olszewski (1989) https://pubmed.ncbi.nlm.nih.gov/2930611/
6. Reed (2008) https://pubmed.ncbi.nlm.nih.gov/18442411/
   
7. Filipcev (2018) https://pubmed.ncbi.nlm.nih.gov/29596314/
8. Dai (2020) https://pubmed.ncbi.nlm.nih.gov/32503840/

Vitamin U is a mucin secretagogue

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Summary - Vitamin U is a nutrient abundant in vegetables and fruit whose main function is to stimulate the secretion of mucin and enable the formation of the mucous bilayer that protects the stomach from acid and Helicobacter pylori.

In the human body, Vitamin U heals and protects against peptic ulcers. It does so by stimulating the secretion of mucins onto the walls of the digestive tract, acting as a precursor to the biosynthesis of the master antioxidant glutathione, and supplies methyl groups for gene regulation, polyamine biosynthesis and a range of other molecules. Of these three functions, stimulating mucin secretion is the most direct way in which Vitamin U works.

In the stomach, there is an alkaline mucous bilayer gel that protects the stomach from gastric acid, pepsin digestion and bacterial infection. Mucus consists of two layers - a deep gel-like layer attached to cells and a superficial loosely-attached layer on top. The proteins that make up mucus are called mucins (MUC1, MUC5AC, MUC6), which are heavily-glycosylated proteins that attract water, thereby forming a gel. Mucins are made in foveolar cells lining the stomach and are stored in vesicles awaiting summons to the lumen. At the surface, some mucins stay attached to the cells and act as an anchor for the loosely-bound mucins to attach by disulfide bonds. When this mucous bilayer is disrupted, gastric juice can reach the lining of the stomach causing irritation and inflammation. Left long enough, a peptic ulcer may form.

Your body has a number of different ways to stimulate the secretion of mucin. The molecules that trigger secretion are called mucin secretagogues. The prime mucin secretagogue is prostaglandin E2, a hormone-like molecule that has many functions in the human body. It has a protective role in stomach function, suppressing production of gastric acid and pepsin, while at the same time promoting secretion of mucin and the alkaline molecule bicarbonate (Park et al). NSAIDs reduce prostaglandin E2 synthesis by inhibiting COX-1, leading to less mucin, less protection and a greater risk of ulcers.

Vitamin U (S-methylmethionine) is a nutrient found in all vegetables and fruit, and especially members of the cabbage family. Vitamin U protects the digestive tract by stimulating the secretion of mucin from the foveolar cells. In 1996, Watanabe et al. showed that exposing gastric mucous cells to L-cysteine or methylmethionine sulfonium chloride (MMSC or Vitamin U) prevented the formation of stomach ulcers caused by exposure to 50% ethanol. They demonstrated that Vitamin U and cysteine work in a similar manner via a sulfhydryl group. Interestingly, Vitamin U does not have a sulfhydryl group, but rather a sulfonium group. Consequently, Vitamin U is usually described as a latent sulfhydryl. The fact that Vitamin U and L-cysteine activities were inhibited by the pre-administration of the sulfhydryl inhibitor N-ethylmaleimide suggests that Vitamin U is active as a sulfhydryl. Vitamin U is stable at acid pH, so activation probably takes place in foveolar cells. 

In a follow up study, Watanabe et al. (2000) found that Vitamin U and cysteine induced the transport of vesicles containing mucin from deep within the cytosol to the cell surface for release into the stomach lumen, thereby forming a protective barrier. Interestingly, the movement they observed was independent of Ca2+ and cAMP. When signal transduction occurs via an endogenous molecule like prostaglandin-E2, there is a rise in the concentration of cAMP. When the P2 purinic receptor is activated by ATP, there is an accompanying rise in Ca2+. Yet sulfhydryl-instigated movement did not induce a change in Ca2+ or cAMP levels. The authors suggested sulfhydryls promote mucus movement by a non-receptor mediated process.

Irrespective of how Vitamin U works, there's good evidence that drinking fresh vegetable juice or taking Bioremediation's Vitamin U supplements may help restore your mucous bilayer, ease discomfort and heal your ulcers.

Take care and good luck,

Sean

Celery Juice and Vitamin U

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Recently, drinking celery juice has been promoted as a cure for a whole range of ailments. The original promoter Anthony William recommends drinking 16-32 oz of celery juice daily. He stipulates the juice should be fresh, not mixed with other ingredients and that juicing is better than blending. Williams has stated that the science behind the healing powers of celery juice have yet to be discovered. Hollywood types and regular people who get with the program report improved skin quality and gut function among other health improvements, though results are still pending on its effect on most conditions.

Please don't drink celery juice as your sole means of treating cancer.

Nutritionists have responded that while celery juice can be part of a well-rounded diet, it should not be considered the cure-all being touted. Some are concerned by the removal of fiber. Some consider the positive effects result primarily from the water content rather than any nutrient in the juice. Others generally state that celery juice is nothing special and won't cure anything. There are also skeptics who question William's conflation of the scientifically-backed benefits of eating vegetables with the nonscientific rationale for how this improves health.

Drinking celery juice is most likely good for us. From a scientific standpoint, celery juice contains lots of vitamins, minerals and other nutrients that will improve our health if we are not getting enough from our regular diet. Celery juice is also low in calories, unlike most fruit juices. Celery juice might help people psychologically in helping people make healthy lifestyle choices like avoiding bad foods and getting regular exercise.

It is quite likely that some of the health benefits resulting from drinking celery juice daily can be ascribed to boosting one's intake of Vitamin U. For those unfamiliar with Vitamin U (S-methylmethionine), it was discovered as an anti peptic ulcer factor during the 1940s-1950s by Dr Garnett Cheney. Patients with peptic ulcer disease were cured by drinking 1 liter of fresh cabbage juice every day for 7-10 days. Cheney found that other vegetables like celery also worked and increased the palatability of the treatment. Later research found that all vegetables and fruit have Vitamin U, especially in the stalky part. One of its functions in plants is to facilitate the movement of methionine between roots and leaves/fruit. Being mostly stalk, celery makes large amounts of Vitamin U to function. 

Most people have chronically low levels of glutathione, which results in chronically high levels of inflammation. People differ in their susceptibility to inflammation according to their genetic makeup, their diet and lifestyle. Vitamin U in celery juice probably improves the function of every body part by helping to restore glutathione levels, thereby reducing inflammation. 

For more information on Vitamin U, feel free to browse other posts on this blog.

Take care and good luck,

Sean