I often recommend quercetin to my clients that I educate on supplements that are beneficial for modulating inflammation. During my research on the benefits of quercetin, I found some interesting literature that seems promising in the therapy of bladder conditions. UTI’s are one of the most common bacterial infections of the bladder and account for almost 95% of all the visits to physicians for UTI’s (Wang et al., 2012). Patients with acute cystitis always have symptoms of dysuria and increased frequency and urgency of urination. As I have already experienced, this can seriously affect a person’s quality of life. The incidence of acute cystitis is high, and the course of acute cystitis is urgent. If acute cystitis cannot be treated promptly, it will be transformed into chronic cystitis. “It can also be transformed into cystitis glandularis, and finally into bladder cancer. It can also induce nephritis. Therefore, timely treatment of acute cystitis is necessary” (Wang et al., 2012).
Currently, acute cystitis is commonly treated by systemic application of antibiotics and anti-inflammation agents. However, only a small amount of systemically administered drugs can reach the bladder. In recent years, the anti-inflammatory effect of querctin (QU) has been well recognized, demonstrating promising clinical application. Recently, it was found that QU can be used to prevent interstitial cystitis (Wang et al., 2012). There are many quercetin containing supplements available in the market, and some of them specifically aimed to treat the bladder. One of them, Cystoprotek, contains QU and rutin with the aims of reducing bladder wall inflammation (Theoharides, Kempuraj, Vakali, & Sant, 2008). Unfortunately it was recently pulled off the market. An older product, Cysta-Q, was shown to provide symptomatic improvements in patients with IC (Katske et al., 2001). Personally, neither of these supplements did anything significant for my IC symptoms at the time I was taking them. This could be due to the inability of the active ingredients to reach the bladder.
Another product that seems promising is Perque Repair Guard. The antioxidant value is of 12 servings of fruits and vegetables. It has 1g of quercetin per tablet. And other healing ingredients such as pomegranate juice powder, OPC, magnesium, chlorophyll, turmeric, and vegetable fiber.
Interestingly, some clinicians are exploring intravesical administration. This means directly instilling the drug solution into the bladder through a urethral catheter, ensuring maximum delivery of active ingredients to the bladder (Wang et al., 2012). According to Wang et. al, the bladder is an idea organ for regional therapy because it urethra provides easy access of the therapeutic agent to the bladder (Wang et al., 2012). In addition, intravesical drug administration has other potential benefits such as avoiding the first-pass metabolism, increasing drug utilization and reducing system toxicity and side effects (Wang et al., 2012). The study conducted by Wang et. al involved encapsulating nanoparticles of water soluble QU into micelles to ensure proper absorption. The results of this study found that intravesical application of the micelles did not induce any toxicity to the bladder. Even better, intravesical administration of QU micelles efficiently reduced the inflammation of the bladder with E. coli-induced acute cystitis. Results indicated that the quercetin micelle treatment can efficiently reduce the edema and inflammatory cell infiltration of the bladder in an E. coli-induced acute cystitis model (Wang et al., 2012). The data from this study proved the hypothesis that QU had potential application in acute cystitis therapy. I am looking forward to seeing future studies in the application, as there are millions of men, women, and even children suffering from this very debilitating condition!
Katske, F., Shoskes, D. A., Sender, M., Poliakin, R., Gagliano, K., & Rajfer, J. (2001). Treatment of interstitial cystitis with a quercetin supplement. Tech Urol, 7(1), 44-46.
Theoharides, T. C., Kempuraj, D., Vakali, S., & Sant, G. R. (2008). Treatment of refractory interstitial cystitis/painful bladder syndrome with CystoProtek–an oral multi-agent natural supplement. Can J Urol, 15(6), 4410-4414.
Wang, B. L., Gao, X., Men, K., Qiu, J., Yang, B., Gou, M. L., . . . Wei, Y. Q. (2012). Treating acute cystitis with biodegradable micelle-encapsulated quercetin. Int J Nanomedicine, 7, 2239-2247. doi:10.2147/ijn.s29416
Water fasting for reversing Interstitial Cystitis (IC) symptoms? Say it isn’t so! As one study suggests: “In rodents, intermittent or periodic fasting protects against diabetes, cancers, heart disease and neurodegeneration, while in humans it helps reduce obesity, hypertension, asthma and rheumatoid arthritis.”
Can it help overcome the pain associated with IC and is it right for you? Fasting seems to be the latest health trend, with intermittent fasting, alternate-day fasting, and water fasts are becoming quickly popular in the wellness arena. Water fasts have been used for centuries and have been done in a number of different ways and for varying lengths of time, usually five to 40 days.
What is a water fast?
In a true water fast, you are limited to drinking only water and no food for the duration of the fast. Interestingly, modern science has found a variety of verifiable positive effects of fasting that has on human health. However, there are some downsides to fasting as well, so it is important to review both the positive and negative to determine if fasting is right for you.
Benefits of Water Fasting for IC
- Autophagy. My number one favorite benefit is the process of autophagy. The term ‘autophagy’, derived from the Greek meaning ‘eating of self’, was first coined by Christian de Duve over 40 years ago (Glick, Barth, & Macleod, 2010). Autophagy is your body’s normal, natural process for recycling unnecessary or dysfunctional components. The body reprograms itself, clearing out old cells or damaged cells and replacing them with new ones (Cheng et al., 2014). This means that fasting can encourage your body’s natural healing mechanisms to actively destroy and recycle damaged tissues, which may have a positive effect on several serious conditions. This can often lead to improved immunity and reduction in autoimmune symptoms. The idea is the body gets rid of damaged autoimmune cells and replaces them with healthy new ones. This could come handy since IC is characterized by recurrent inflammation and destruction of bladder tissue without obvious cause, that some speculate could be a broken immune system response.
- Improved digestive health. Research suggests that fasting can improve digestive health, allowing good bacteria to flourish, resulting in an overall improvement in metabolism, weight, and many other cardiometabolic conditions. Fasting is also a great break for your gut, which is often helpful if you have food intolerances and allergies. The elimination of food antigens can also reduce inflammation that is often associated with chronic pain and immune dysfunction. This is because water fasting can upregulate a T cell response, called T-regulatory cells, that are involved in oral tolerance of food. In fact, eating foods that your body is intolerant to can make your immune system work too hard and make your more susceptible to infections. Therefore, giving your gut a break can actually enhance immunity and reduce inflammation, a crucial symptom of IC. (Make sure you follow up the fast with a healthy diet and probiotics)
- Improved markers of metabolic syndrome. Water fasting can improve aspects of metabolic syndrome: abdominal fat, inflammation and blood pressure are reduced. Insulin sensitivity is increased, and the functional capacities of the nervous, neuromuscular and cardiovascular systems are improved (Longo & Panda, 2016). Fasting results in a lowering of the hormones insulin and leptin levels and an elevation of adiponectin and ghrelin levels. By increasing insulin and leptin sensitivity, you can suppress inflammation and stimulate autophagy. Fasting can reverse all the major abnormalities of metabolic syndrome such as reduced body fat, blood pressure and glucose metabolism (Longo & Mattson, 2014).
- Slowed aging. There are biomarkers that are associated with reduced aging when you water fast. These include changes in the levels of signals in your body, such as IGF-1, IGFBP1, glucose, and insulin. Fasting for 3 or more days causes a 30% or more decrease in circulating insulin and glucose, as well as rapid decline in the levels of insulin-like growth factor 1 (IGF-1), the major growth factor in mammals. Together with insulin, reducing growth factor is associated with decreased aging and cancer (Longo & Mattson, 2014). It could also slow down the aging of your immune system so that you are less susceptible to infections.
- Reduction in oxidative stress. Oxidative stress is a condition where too much oxygen can wreak havoc in your cells. It’s complicated, but the bottom line is that oxidative stress is an indication that you are out of balance on a cellular level. This condition can cause excessive fatigue, brain fog, muscle and joint pain, wrinkles, gray hair, poor eyesight, headaches and sensitivity to noise, and a decreased immune system. And a decreased immune system makes you more at risk of getting even more infections.
Risks of Water Fasting
- Dehydration. Although it sounds strange, a water fast could make you dehydrated. This is because roughly 20 to 30% of your daily water intake comes from the foods you eat. Symptoms of dehydration include dizziness, nausea, headaches, constipation, low blood pressure and low productivity. To avoid dehydration, you will need to drink a lot more water than you are used to drinking.
- Loss of electrolytes. During a water fast, you may lose electrolytes, which are needed for your heart to function. This can lead to abnormal heartbeats and can potentially be dangerous in susceptible individuals. Drink electrolyte water to prevent this from occurring if you decide to water fast.
- Low blood sugar. Some people have reactive hypoglycemia and may find it difficult to fast. This is because they are not efficient at using fat for energy, and may struggle to transition to ketosis. What is ketosis? Ketosis is actually a normal metabolic process in your body that occurs when your body does not have enough glucose (sugar) for energy, so it burns up stored fat for energy instead (McIntosh, 2017). Ketones are produced as a by-product of this process, which can be measured on home test strips or finger prick tests. Once you can achieve ketosis, the fast gets much easier. It is recommended that you initially do a shorter fast, or experiment with a period of intermittent fasting before trying to do a prolonged water only fast.
- Orthstatic hypotension. This occurs when you get dizzy when you stand up suddenly. It is common when water fasting, but it can also be dangerous. The dizziness and risk of fainting could lead to an accident.
- Sudden death. Although it is rare, there is a chance of sudden death during a water fast. Granted these people did have pre-existing heart conditions, but it is still worth mentioning, particularly in the context of a prolonged water fast over 72 hours.
- Extreme hunger. Face it, hunger is uncomfortable. Although most hunger subsides after 3 days, the first few days can be unbearable, especially if you are surrounded by food. It is best to stay away from any sources of temptation during your fast so that makes it less intolerable.
IC & My Fasting Experience
What provoked me to do a water fast? I had persistent symptoms of urinary inflammation and pain, typical IC. Pain during urination, pain during intercourse and overall heightened sensitivity (mostly in my urethra). I also had digestive issues, gas, severe bloating, maldigestion and was prone to frequent UTIs.
I have experimented with both a 4.5 and a 7.5-day water fast. I did two 4.5 day fasts and one 7.5 days fast. Hands down, I will never do a fast longer than 4 days again! The 4 days were the most therapeutic for my body. It reduced my inflammation substantially and got me out of IC pain. It was also relatively easy to return back to eating normal foods again.
The first time I fasted was the hardest transitioning to ketosis (this is when your body switches from burning calories to burning fat cells instead and you do not feel that hungry anymore). It took me 3 days to achieve ketosis and I even passed out on day 3 due to orthstatic hypotension. I was very weak the entire fast and was very glad to break it.
The 7.5 day fast for me was not as eventful. I was better prepared to go into the fast and was able to achieve ketosis much quicker and had fewer problems overall. However, this one stressed my adrenals and my gut and it took me a long time to get it back to normal. I had indigestion for 8 days, diarrhea, knee and joint pain and even got a UTI after the fast! Luckily, I was able to resolve it rather quickly, but it taught me a lesson: prolonged water fasting is not for everyone.
Overall, I think the second fast was harder on my body because I have done several fasts in the past few months prior and it may have been too soon for me. There is a period of refeeding that is very important in the context of fasting, it is very important for stem cell proliferation of the immune cells. Therefore, it is possible I did not give my body enough time to rebuild new cells after the fast, and perhaps my immune system suffered as a result (Longo, 2018)
A word of advice: If you decide to fast, hire a health coach or nutritionist to help prepare you for your fast. You need have been following a comprehensive elimination diet full of good quality foods for a period of time before you fast to mitigate any negative side effects that could occur during or after the fast. You will also want them to run preliminary blood work on you to make sure you are healthy enough to fast. This will also help them guide you as to the duration of a fast that would be suitable for you.
- Cheng, C. W., Adams, G. B., Perin, L., Wei, M., Zhou, X., Lam, B. S., . . . Longo, V. D. (2014). Prolonged fasting reduces IGF-1/PKA to promote hematopoietic-stem-cell-based regeneration and reverse immunosuppression. Cell Stem Cell, 14(6), 810-823. doi:10.1016/j.stem.2014.04.014
- Glick, D., Barth, S., & Macleod, K. F. (2010). Autophagy: cellular and molecular mechanisms. J Pathol, 221(1), 3-12. doi:10.1002/path.2697
- Longo, V. (2018). Dr. Valter Longo on Resetting Autoimmunity and Rejuvinating Systems with Prolonged Fasting and the FMD. Retrieved (2018, July 19) from https://www.youtube.com/watch?v=evGFWRXEzz8&t=3361s
- Longo, V. D., & Mattson, M. P. (2014). Fasting: molecular mechanisms and clinical applications. Cell Metab, 19(2), 181-192. doi:10.1016/j.cmet.2013.12.008
- Longo, V. D., & Panda, S. (2016). Fasting, Circadian Rhythms, and Time-Restricted Feeding in Healthy Lifespan. Cell Metab, 23(6), 1048-1059. doi:10.1016/j.cmet.2016.06.001
- Mandal, A. (n.d.) What is Autophagy? Retrieved (2018, July 5) from https://www.news-medical.net/health/What-is-Autophagy.aspx
Exposure to toxins may have detrimental effects on humans and animals, even at low concentrations. Specific probiotic and bacterial strains may have properties that enable them to bind to toxins we are exposed to in our environment, such as food and water. Different strains vary in their ability to bind and detoxify, often times relying on pH, contact time, and viability on the binding capacities. Below are 3 bacterial strains and a summary of their mechanisms of action on human biochemistry regarding detoxification.
Mycotoxin Degradation – Mycotoxins are secondary metabolites produced by fungi, and are capable of producing disease and death in humans (Chlebicz & Slizewska, 2019). Humans are exposed to mycotoxins while consuming plant foods such as nuts (hazelnut, almonds, pistachios), peanuts, grains and some fruits. They are also exposed to them in the environment such as often reported in mold that is found in homes that have been water damaged. Aflatoxins are secondary metabolites of Aspergillus flavus and Aspergillus parasiticus, and it has been estimated that 4.5 billion of the world’s population is exposed to aflatoxins (Wild & Gong, 2010). The aflatoxins occur mostly in tropical regions with high humidity and temperature. They accumulate post-harvest when food commodities are stored under conditions that promote fungal growth. The naturally occurring aflatoxins are AFB1, AFB2, AFG1 and AFG2, with AFB1 the most abundant, toxic and carcinogenic, and are linked to liver cancer. “However, in agriculture, other adverse effects, including toxicity, growth and immune impairment, have been widely reported and these end points are rightly of increasing focus in studies of exposed people” (Wild & Gong, 2010).
Aflatoxin B1 (AFB1) is considered to possess the highest toxicity among various types of secondary metabolites produced by a larger number of Aspergillus spp., and classified as a Group I carcinogen for humans by the International Agency for Research on Cancer (Chlebicz & Slizewska, 2019). It has been reported that AFB1 could induce growth retardation, liver cancer, and may suppress immunity. Relevant studies indicated that AFB1was mostly metabolized by cytochrome P450 (CYP 450) enzyme systems after being absorbed in the GI tract. “Subsequently, under the action of CYP 450, including CYP1A2 and CYP 3A4, AFB1 was transformed to exo-AFB1-8,9-epoxide (AFBO), which could bind to DNA, proteins, and other critical cellular macromolecules to exert its carcinogenic effect” (Chlebicz & Slizewska, 2019).
Below are two probiotics that show promise in detoxification of mycotoxins:
- Saccharomyces cerevisiae var boulardii- (note the authors indicate that since S. cerevisiae and S. boulardii are closely similar in molecular structure, they should not be viewed as separate species taxonomically, so they have been renamed as saccharomyces cerevisiae van boulardii). Inhibition of mycotoxin absorption in the GI tract is one of the mechanisms of action of this strain. The mechanism of detoxification by yeast is due to the adhesion of mycotoxins to cell-wall components. In addition, this strain can biodegrade mycotoxins (such as AFB1) to prevent adsorption of these components inside the intestines on those who consume the food that is contaminated with the aflatoxin. As a side note, Saccharomyces cerevisiae var boulardii can also degrade phytates that are also found on many of the same foods that mycotoxins are found, and this may improve adsorption of iron, zinc, magnesium and phosphorus binding (Moslehi-Jenabian, Pedersen, & Jespersen, 2010). This could be viewed as a secondary mechanism involved in detoxification.
- L. plantarum—Lactobacillus species are also able to bind mycotoxins. Via hydrophobic interactions, they are able to bind to mostly cell wall peptidoglycans, polysaccharides and teichoic acid (Chlebicz & Slizewska, 2019). L. plantarum has demonstrated to have good AFB1binding ability in vitro. It can also “increase fecal AFB1excretion, reduce lipid peroxidation, and reverse antioxidant defense systems to alleviate AFB1 toxicity” (Chlebicz & Slizewska, 2019). L. plantarum may also play a role in the suppression of CYP1A2 and CYP3A4 expression to enhance glutathione-conjugating activity and promote detoxification (Chlebicz & Slizewska, 2019). It has been reported that some lactic acid bacteria such as L. plantarum can remove AFB1 or have protective effects against AFB1. Some relevant studies demonstrated that lactobacilli could inhibit the production of aflatoxin as well as the growth of Aspergillus spp. (Huang et al., 2017). L. plantarum also demonstrates strong free radical scavenging activities and can improve antioxidant status, protecting against the effects of AFB1. “L. plantarum might also act as a biological barrier in the intestine under normal conditions, thereby reducing the bioavailability of AFB1 ingested orally and hence avoiding its toxic effects” (Chlebicz & Slizewska, 2019). I attached a chart that demonstrates some of the mechanisms of L. plantarum on detoxification of AFB1., which includes increasing AFB1 excretion, decreasing AFB1 epoxidation catalyzed by CYP1A2 and CYP3A4, coupled with enhancing the activities of different antioxidant enzymes and GST detoxification which are connected with the NrF2 signaling pathway (Chlebicz & Slizewska, 2019).
- Bacillus subtilis– This spore forming species of bacteria had some interesting mechanisms in detoxification.
Cypermethrin belongs to a group of synthetic pyrethroid insecticides which widely used in agriculture, forestry, horticulture, public health and households for the protection of textiles and to check pest infestation (Gangola, Sharma, Bhatt, Khati, & Chaudhary, 2018). . Cypermethrin is also constitute common ingredients of household insecticides (Gangola et al., 2018). Cypermethrin is an environment pollutant because of its widespread use and toxicity. Persistence may lead to serious damage to non-target organisms and various ecosystem (Gangola et al., 2018). Metabolism of cypermethrin is important because cypermethrin possess antimicrobial activities hence it prevents the beneficial microflora.
The mechanism of action is the laccase enzyme that can degrade the pesticide. Bacillus subtilis strain demonstrated to completely metabolize cypermethrin in just 15 days under laboratory conditions. The bacterial isolate harbors the metabolic pathway for the detoxification of the cypermethrin. It can also completely degrades cypermethrin without leaving any persistent or toxic metabolite (Gangola et al., 2018).
Heavy metals (Syed & Chinthala, 2015)
It is estimated that over one billion human beings are currently exposed to elevated concentrations of toxic metals and metalloids in the environment. It is also estimated that several million people may be suffering from subclinical metal poisoning. “In addition, adverse effect of heavy metals includes suppression of the immune system and carcinogenicity, neurotoxicity, mainly in children, and inhibition of the activity of some critical enzymes related to synthesis of vital biomolecules along with accumulation in the body of different organisms causing biomagnifications” (Syed & Chinthala, 2015). B. subtilis has greater ability to bind metals than Gram-negative ones due to their different cell wall structures (Cai et al., 2018). Interestingly, bacterial isolates of B. subtilis showed significant biosorption of lead. Heavy metal biosorption is the ability of bacterial cells or components to adsorb, chelate, or precipitate metal ions in the solution into insoluble particles or aggregates which can be removed either by sedimentation or filtration from the solution. Lead biosorption modifies groups like carboxyl, hydroxyl, and amino where other metal ions cannot compete offering it more affinity. The main agents in the uptake of heavy metals by B. subtilis are carboxyl groups, the sources of which are the teichoic acids associated with the peptidoglycan layers of the cell wall (Cai et al., 2018).
Cai, Y., Li, X., Liu, D., Xu, C., Ai, Y., Sun, X., . . . Yu, H. (2018). A Novel Pb-Resistant Bacillus subtilis Bacterium Isolate for Co-Biosorption of Hazardous Sb(III) and Pb(II): Thermodynamics and Application Strategy. Int J Environ Res Public Health, 15(4). doi:10.3390/ijerph15040702
Chlebicz, A., & Slizewska, K. (2019). In Vitro Detoxification of Aflatoxin B1, Deoxynivalenol, Fumonisins, T-2 Toxin and Zearalenone by Probiotic Bacteria from Genus Lactobacillus and Saccharomyces cerevisiae Yeast. Probiotics Antimicrob Proteins. doi:10.1007/s12602-018-9512-x
Gangola, S., Sharma, A., Bhatt, P., Khati, P., & Chaudhary, P. (2018). Presence of esterase and laccase in Bacillus subtilis facilitates biodegradation and detoxification of cypermethrin. Sci Rep, 8(1), 12755. doi:10.1038/s41598-018-31082-5
Huang, L., Duan, C., Zhao, Y., Gao, L., Niu, C., Xu, J., & Li, S. (2017). Reduction of Aflatoxin B1 Toxicity by Lactobacillus plantarum C88: A Potential Probiotic Strain Isolated from Chinese Traditional Fermented Food “Tofu”. PLoS ONE, 12(1), e0170109. doi:10.1371/journal.pone.0170109
Moslehi-Jenabian, S., Pedersen, L. L., & Jespersen, L. (2010). Beneficial effects of probiotic and food borne yeasts on human health. Nutrients, 2(4), 449-473. doi:10.3390/nu2040449
Syed, S., & Chinthala, P. (2015). Heavy Metal Detoxification by Different Bacillus Species Isolated from Solar Salterns. Scientifica (Cairo), 2015, 319760. doi:10.1155/2015/319760
Wild, C. P., & Gong, Y. Y. (2010). Mycotoxins and human disease: a largely ignored global health issue. Carcinogenesis, 31(1), 71-82. doi:10.1093/carcin/bgp264
Acetaminophen (APAP) (brand name Tylenol) is a commonly used xenobiotic over the counter pain medication, as most people falsely assume that it is safe. In fact, I wish I knew this before I was giving Tylenol to my own children for their ear infections and fevers! With the toxic buildup that we encounter, it is no surprise there is a rise with so many chronic health issues such as autoimmune diseases, CV disease, neurological conditions, infertility and many more. I have not yet obtained clarity from research if Tylenol is harmful in smaller doses, since most of the literature indicates that Tylenol is safe in recommended doses (NIH, n.d). Acetaminophen differs from NSAID’s in its mechanism of action. Rather than influencing the COX-1 and COX-2 enzymes, it producing analgesia by increasing pain thresholds through inhibition of the NO pathway that is activated by many pain NT receptors (NIH, n.d.). The recommended oral dose is 660 to 1000 mg every 4 to 6 hours, but should not to exceed 3 grams per day (NIH, n.d). It is also frequently found in many OTC cold medications and antihistamines as well. Common products in the United States include: Tylenol-PM, Nyquil, Darvocet, Vicodin, and many others. Acetaminophen is one of the most commonly used medications in the United States and more than 25 billion doses are sold yearly.
The liver, and to a lesser extent the kidney and intestine are involved in the metabolism of acetaminophen (Mazaleuskaya et al., 2015). “It involves a complex inter-organ transport of metabolites between the liver, kidney and intestine, through bile and the blood stream, to be ultimately be eliminated in the urine” (Mazaleuskaya et al., 2015).
Unfortunately, Tylenol is often associated with hepatotoxicity. Chronic use of this OTC drug in doses of 4 grams per day have been found to lead to transient levels of serum aminotransferase levels, generally starting after 3 to 7 days, with peak values rising 3-fold in 39% of people (NIH, n.d.). Standard use can lead to severe hypersensitivity reactions including Stevens Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which can cause serious liver injury. The best-known form of hepatoxicity is due to overdose, which can result in large elevation of ALT and AST within 48 to 96 hours after ingestion, including jaundice, confusion, liver failure and death.
Xenobiotic metabolism of Acetaminophen
APAP is extensively metabolized by the liver via three main hepatic pathways: glucuronidation, sulfation, and CYP450 2E1 oxidation (Dimitropoulos & Ambizas, 2015). About 90% of APAP is conjugated to sulfation and glucuronidase metabolites. From the liver, most of the glucuronide and sulfate metabolites get transported through the intestines into the blood. The kidney is the main site of the disposition of the APA-sulfate. However, cytochrome P450 (CPY) enzymes are also involved in converting approximately 2% of acetaminophen to a highly reactive metabolite known as N-acetyl-pbenzoquinonimine (NAPQI). NAPQI is highly reactive and is primarily associated with the hepatoxicity of acetaminophen (Mazaleuskaya et al., 2015). Under normal circumstances, this toxic metabolite reacts with sulfhydryl groups in glutathione, converting it to harmless metabolites before being excreted in urine (Dimitropoulos & Ambizas, 2015). Although most of the NAPQI is formed in the liver, the kidney also metabolizes APAP to toxic metabolites and releases cysteine conjugate of APAP into the bile and blood for even more elimination in the urine (Mazaleuskaya et al., 2015). In human liver microsomes, CYP enzymes (CYP2E1 and CYP1A2) were first reported to convert high doses of APAP to NAPQI. Other enzymes are reported to be involved, such as CP2A6, CYP2D6, CPY3A4 although role of the latter enzyme is still up for debate (Mazaleuskaya et al., 2015). At very high doses, the sulfation pathway becomes saturated, glucuronidation and oxidation increase, and higher amounts of the drug get oxidized to the reactive NAPQI. The problem is, excess NAPQI eventually depletes glutathione stores and can target mitochondrial proteins and ion channels leading to loss of ATP production, ion misbalance and cell death (Mazaleuskaya et al., 2015). That is why replacement of glutathione with NAC (precursor to glutathione) is useful for APAP toxicity (Moyer et al., 2011)
Glucuronidation of APAP is catalyzed by the enzyme UDP-glucuronosyl transferases (UGT), which makes APAP molecule water soluble for excretion. Sulfation is carried out by a group of cytosolic enzymes called sulfotransferases (SULT), which makes it more polar and prone to elimination. “Using human platelet homogenates as a model for xenobiotic metabolism in the liver, SULT1A1 and SULT1A3/4 were first shown to catalyze APAP sulfation” (Mazaleuskaya et al., 2015). Genetic variability in SULT and GST genes are not well established, and only a few studies have been conducted in relation to GST polymorphisms and acetaminophen detoxification (Mazaleuskaya et al., 2015). However, studies on polymorphisms in detoxification genes for the enzymes involved in APAP metabolism can be an opportunity for future applications of preventative treatment of APAP toxicity in susceptible individuals.
Enzymatic breakdown of APAP:
General phase I support:
B vitamins (B2, B3, B6, B12), folate, glutathione, Vitamin E, Vitamin C, Zinc, BCAA’s
Antioxidant protection from intermediate metabolites:
Vitamin A, Vitamin C, Vitamin E, Selenium, Zinc, Copper, Manganese, Coq10, Bioflavonoids
General phase II support:
NAC, glycine, taurine, glutamine, cysteine, methionine
Inducers of CYP2E1 enzyme (for low activity) (Hodges & Minich, 2015):
Fish oil, chicory root
Inhibitors of CY2PE1 enzyme (for overactivity) (Hodges & Minich, 2015):
Garlic, watercress, NAC, ellagic acid, green tea, black tea, dandelion, chrysin, MCT’s
Inducers of glucuronidation (for low activity):
Flavonoids- quercetin (Glucuronidation, n.d.)
Inhibitors of glucuronidation (for overactivity):
Probiotics (Glucuronidation, n.d.)
Calcium-D-glucarate Glucuronidation, n.d.)
Inducers of sulfation (Hodges & Minich, 2015):
Coffee, cocoa, black tea, green tea, vitamin A, Liver, fish, eggs, and fruits and vegetables with vitamin A
Dietary sources of sulfur (Hodges & Minich, 2015):
Fish, shellfish, lamb, beef, turkey, eggs, cabbage, broccoli, Brussel sprouts, apricots, peaches, spinach, watercress, horseradish, brazil nuts, almonds, peanuts, walnuts, mustard, ginger
Food contradicted while using APAP:
Alcohol– Ethanol induced oxidative stress is a major mechanism in which ethanol can cause liver injury, particularly via the CYP2E1 enzymatic pathway (Lu & Cederbaum, 2008). Levels of CYP2E1 are elevated under a variety of physiological and pathophysiological conditions, and after acute and chronic alcohol treatment.
High cholesterol fast food-Fast food can mediate CYP2E1 associated liver fibrosis by promoting oxidative stress, inflammation, endotoxemia and insulin resistance (Abdelmegeed et al., 2017)
Abdelmegeed, M. A., Choi, Y., Godlewski, G., Ha, S. K., Banerjee, A., Jang, S., & Song, B. J. (2017). Cytochrome P450-2E1 promotes fast food-mediated hepatic fibrosis. Sci Rep, 7, 39764. doi:10.1038/srep39764
Dimitropoulos, E.; Ambizas, E.; (2015). Acetaminophen Toxicity: What Pharmacists Need to Know. Retrieved (2019, April 30) from https://www.uspharmacist.com/article/acetaminophen-toxicity-what-pharmacists-need-to-know
Glucoronidation. (n.d.) Retrieved http://www.herbaltransitions.com/Glucuronidation.html
Hodges, R. E., & Minich, D. M. (2015). Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab, 2015, 760689. doi:10.1155/2015/760689
Lu, Y., & Cederbaum, A. I. (2008). CYP2E1 and oxidative liver injury by alcohol. Free Radic Biol Med, 44(5), 723-738. doi:10.1016/j.freeradbiomed.2007.11.004
Mazaleuskaya, L. L., Sangkuhl, K., Thorn, C. F., FitzGerald, G. A., Altman, R. B., & Klein, T. E. (2015). PharmGKB summary: pathways of acetaminophen metabolism at the therapeutic versus toxic doses. Pharmacogenet Genomics, 25(8), 416-426. doi:10.1097/fpc.0000000000000150
Moyer, A. M., Fridley, B. L., Jenkins, G. D., Batzler, A. J., Pelleymounter, L. L., Kalari, K. R., . . . Weinshilboum, R. M. (2011). Acetaminophen-NAPQI hepatotoxicity: a cell line model system genome-wide association study. Toxicol Sci, 120(1), 33-41. doi:10.1093/toxsci/kfq375
National Institute of Health (n.d.) Acetaminophen. Retrieved (2019, April 30) from https://livertox.nih.gov/Acetaminophen.htm
For this review, I want to summarize the findings on the dietary carbohydrate to protein ratio and how it may influence body composition and blood lipid profiles in adult women.
There is evidence that older adults experience age-related changes in body composition, such as increase in body fat and decrease in lean body mass (Kim, O’Connor, Sands, Slebodnik, & Campbell, 2016). A moderate energy restricted diet is often an effective way for overweight adults to reduce bodyfat mass, and improve their health profile, but it often comes with the price of a loss of 25% of body mass being lost as lean body mass (Kim et al., 2016). Accumulating data suggests that increased protein content of the diet, in combination with exercise training, can reduce the loss of lean body mass in overweight and obese subjects following a weight loss diet. This preservation of lean body mass has been attributed to the increased level of essential amino acids, especially leucine, provided by the protein (Mettler, Mitchell, & Tipton, 2010).
Current dietary guidelines recommend a daily macro-nutrient intake of 55% carbohydrate, 30% protein and 15% fat (Layman et al., 2003). However, this balance has been challenged by evidence from epidemiological, clinical and experimental studies, reporting that a higher carbohydrate intake can reduce oxidation of body fat and increase blood triglycerides (Layman et al., 2003). In particular, the optimal ratio of carbohydrate to protein has been challenged on the basis of glucose homeostasis in the context of body mass reduction. Under a higher carbohydrate intake, the body has to rely on insulin to metabolize and dispose large quantities of dietary glucose, whereas under lower carbohydrate intakes (<200g per day), the body would rely more on hepatic production to maintain blood glucose via gluconeogenesis or glycogenolysis (Layman et al., 2003).
A study conducted in 2003 by Layman et al (2003), compared the results of a moderate protein and lower carbohydrate intake to a higher carbohydrate with lower protein intake, and the influence on body mass and blood lipids. In this study, the total energy intake, fat and fiber were consistent among the two groups: 1700 kcal/day, total fat intake was 50g/day and total fiber at 20g per day. In the higher protein group (Protein Group) protein intake averaged 125g/day with a carbohydrate intake of 171g/day. The higher carbohydrate group (CHO) consisted of 68g pf protein per day and 239g of carbohydrates. The relative proportions of energy in the Protein Group were 30% protein, 41% carbohydrate and 29% fat with a ratio of carbohydrate to protein (CHO/protein) of 1.4. The proportion in the CHO Group was 16% protein, 58% carbohydrate and 26% fat with a ratio of 3.5 (Layman et al., 2003). Obviously, the cholesterol and saturated fatty acid intake was higher in the Protein group than the CHO group.
The study duration was 10 weeks. The results of the study indicated the following:
- There was not a big change in body weight between the two groups. The Protein Group lost a total weight of 7.53kg and the CHO group lost 6.96kg.
- Changes in body composition indicate the weight loss was mostly bodyfat. The Protein group lost 14.4% of initial body fat, the CHO group lost 12.2% of initial bodyfat. Loss of lean body mass tended to be greater in the CHO Group compared to the Protein Group. When changes in body composition were expressed as a ratio of fat/lean loss, the Protein group achieved a fat/lean loss of 6.36 vs. 3.92 in the CHO group. The higher protein group clearly had a stronger improvement in body composition.
- There were some differences seen in thyroid hormones, blood lipids and fasting and postprandial glucose and insulin levels, but it was not explained in detail as it was not the main objective of this study.
In summary, the results of this study indicate that the positive changes in body composition associated with the higher protein diet may be associated with either targeting of body fat or sparing of muscle protein, or both. For the purposes of improving body composition, a higher protein diet may be effective for adults.
Before I end this summary, I do want to mention I did stumble upon an interesting study in 2016 that indicates that a high protein intake eliminates the weight loss induced improvement of insulin action on postmenopausal women (Smith et al., 2016). This study indicates that a high protein diet can have adverse effects on postprandial insulin sensitivity. According to the authors, “the beneficial effect of 10% weight loss on muscle insulin action (assessed as glucose disposal rate and phosphorylation of AKT in muscle during a HECP) was eliminated by high protein (HP) intake” (Smith et al., 2016). The failure to improve muscle insulin sensitivity in the higher protein group is clinically important, because it reflects a failure to improve a major mechanism involved in the development of T2D. It also indicates more insulin is required in the higher protein group to dispose of a given amount of glucose. This can be due to:
- BCAA’s, particularly leucine, that can impair insulin mediated uptake of glucose through a negative feedback inhibition
- There may be an association of glycine and tryptophan and metabolites of acylcarnitine in the development of insulin resistance, regardless of the amount of circulating amino acid metabolites measured in the serum.
- There may be a metabolic process related to oxidative stress that is expressed in the higher protein group, as evidenced by gene expression of GSTA4 and PRDX3 that are both associated with oxidative stress. These results suggest that the adverse effect of high protein intake on insulin action during weight loss therapy may have been mediated through its effects on oxidative stress because it prevented the WL-induced decrease, and even increased, metabolic pathways involved in oxidative stress response in muscle.
- Both groups had improved liver insulin sensitivity, but the higher protein group experienced a reduction in muscle insulin sensitivity. This is attributed to the fact that protein is a potent insulin secretagogue, which may overcome the adverse effect of protein on insulin sensitivity by increasing the secretion of insulin (Smith et al., 2016).
I must mention however, protein causes greater satiation and has a greater thermogenic effect of feeding than carbohydrate and fat. This alone can lead to greater weight loss with a higher protein than a standard protein diet. “Therefore, the adverse effect of dietary protein on muscle insulin action could be offset by its effect on hepatic insulin sensitivity, insulin secretion and energy balance” (Smith et al., 2016).
In summary, this review demonstrates that the protein content of a weight loss diet can have significant effects on metabolic function and weight loss outcome. I personally believe that diets should be personalized for the individual. A high protein diet is not suitable for everyone. Neither is a high carbohydrate diet. The individual’s needs should be taken into consideration, along with various markers of health that can be measured in a blood chemistry panel, their nutritional needs (such as macronutrient deficiencies) and even nutrigenomics, health predispositions and family history. The one size fits all approach is not appropriate when prescribing nutrition therapy, as the results of these studies also demonstrate.
What do I think? The evidence is good for a higher protein diet, but I wonder if they looked into the glucogenic amino acids and their effect on insulin sensitivity. In my review, I found another journal that indeed indicated that various amino acids can actually decrease insulin sensitivity. Interestingly, it was leucine that was contributing to this change in muscle insulin sensitivity, and that is actually a ketogenic amino acid! If I find the free time at some point, I would love to research the effects of glucogenic and ketogenic amino acids and how they affect insulin sensitivity and type 2 diabetes. I personally have not been a fan of high protein diets. I feel it is too hard on the kidneys, and considering glycine is often a problem with oxalate metabolism, especially in the context B1 deficiency, I feel the risk of kidney stones is too great to recommend high protein across the board (See image). I prefer a more balance approach, with a balance of macronutrients and incorporating intermittent fasting as a way to improve blood lipids and insulin sensitivity.
Kim, J. E., O’Connor, L. E., Sands, L. P., Slebodnik, M. B., & Campbell, W. W. (2016). Effects of dietary protein intake on body composition changes after weight loss in older adults: a systematic review and meta-analysis. Nutr Rev, 74(3), 210-224. doi:10.1093/nutrit/nuv065
Layman, D. K., Boileau, R. A., Erickson, D. J., Painter, J. E., Shiue, H., Sather, C., & Christou, D. D. (2003). A Reduced Ratio of Dietary Carbohydrate to Protein Improves Body Composition and Blood Lipid Profiles during Weight Loss in Adult Women. J Nutr, 133(2), 411-417. doi:10.1093/jn/133.2.411
Mettler, S., Mitchell, N., & Tipton, K. D. (2010). Increased protein intake reduces lean body mass loss during weight loss in athletes. Med Sci Sports Exerc, 42(2), 326-337. doi:10.1249/MSS.0b013e3181b2ef8e
Smith, G. I., Yoshino, J., Kelly, S. C., Reeds, D. N., Okunade, A., Patterson, B. W., . . . Mittendorfer, B. (2016). High-Protein Intake during Weight Loss Therapy Eliminates the Weight-Loss-Induced Improvement in Insulin Action in Obese Postmenopausal Women. Cell Rep, 17(3), 849-861. doi:10.1016/j.celrep.2016.09.047
During the past two decades, there has been a rapid increase in studies that report associations with gene polymorphisms, nutrition and disease risk (Burdge, Hoile, & Lillycrop, 2012). This is a paradigm shift from traditional nutritional recommendations that have been based on age, sex, and pregnancy. The advances in the association with epigenetics and nutritional requirements have been the driver of the advancement in the field of nutrigenomics, which has been wildly exploding.
What is epigenetics? We learned in middle school that our genetic code is the sequence of nucleotides in our DNA, which can certainly influence health status. However, I was amazed when I learned for the first time that there is another set of instructions that affects our gene expression, and this set of instructions can actually influenced by our environment such as our diet! This is referred to as epigenetics. I remember learning in my Biology Masters that Epigenetics meant “above the genome”. Epigenetics is the “study of heritable changes in gene function that occurs independent of a change in DNA sequence” (Kauwell, 2008) which involves a group of modifications that do not alter the actual DNA structure, but rather chromatin structure that can regulate transcription. “The major epigenetic processes are DNA methylation, histone modification, and noncoding RNA’s” (Burdge et al., 2012).
As we learned once in college, through the process of meiosis, there are multiple ways that diversity occurs among our genotypes to ensure no two genotypes are alike (well, except in the case of identical twins). These include crossing over, independent assortment, and random fertilization. This creates genetic uniqueness that is a result of variations in our DNA in which one nucleotide is substituted for another at specific locations on our genome, often called SNP’s (single nucleotide polymorphism) (Kauwell, 2008). We are finding out that SNP’s can alter certain nutrient requirements and metabolism, and although they do not affect regions that code for proteins, they do affect events that occur at the molecular levels such as transcription factor binding to the promoter region of the gene, which can thus alter the expression of that gene. Studies with identical twins have demonstrated some interesting results in the role environment indeed can play a role as seen in insights from identical twins (Learn Genetics, n.d.).
One common nutritionally relevant SNP that is a hot topic in functional medicine occurs on the MTHFR gene which provides instructions for making an enzyme called methylenetetrahydrofolate reductase. This enzyme plays a role in processing amino acids such as homocysteine to methionine (NIH, n.d.). This SNP involves the substitution of cytosine with thymine (C->T) at the base pair 677 of the gene, that results in a coding change where alanine is replaced with valine at position 222 in the gene product (Kauwell, 2008). Inheriting one or two copies of this gene variant can down-regulate the enzyme function, which has some health implications. For example, someone with two copies of the gene (homozygous) may experience elevated plasma homocysteine, especially when paired with low folate status (Kauwell, 2008). This can put the person at risk for coronary artery disease. “Fortunately, reduced MTHFR activity associated 677C->T polymorphism is attenuated when folate status is adequate” (Kauwell, 2008).
What is fascinating about our epigenome is that it provides an extra layer of instructions besides our genetic sequence that codes for proteins synthesized by our bodies. This “extra layer of instructions” can affect whether certain genes are turned on or off, which can thus affect cellular function and metabolism. In fact, the environment has a strong influence on these instructions, such as nutrient status from food and supplements, which can alter the epigenetic state of the genome and subsequent gene expression. What this means is that the same exact DNA sequence for a particular gene may give rise to different outcomes based on things like diet-induced epigenetic modifications that can influence gene silencing and activation.
This is an exciting time for the field of nutrition and nutrigenomics, as we are finding increasing evidence that nutrition throughout the life course can modify the epigenome in such a way that can influence risk of a number of important diseases. “Therefore, if nutritional recommendations are to be targeted at individuals then epigenetic effects must be included in any attempt at personalized nutrition” (Burdge et al., 2012).
Burdge, G. C., Hoile, S. P., & Lillycrop, K. A. (2012). Epigenetics: are there implications for personalised nutrition? Curr Opin Clin Nutr Metab Care, 15(5), 442-447. doi:10.1097/MCO.0b013e3283567dd2
Kauwell, G. P. (2008). Epigenetics: what it is and how it can affect dietetics practice. J Am Diet Assoc, 108(6), 1056-1059. doi:10.1016/j.jada.2008.03.003
Learn Genetics. Insights from Identical Twins. Retrieved (2019, April 25) from https://learn.genetics.utah.edu/content/epigenetics/twins/
NIH (n.d.) MTHFR gene. Retrieved (2019, April 25) from https://ghr.nlm.nih.gov/gene/MTHFR
The rapidly expanding discoveries in the fields of nutrigenomics and nutrigenetics are transforming the field of nutrition and health education. As a health educator, I plan to use this information to empower and enlighten clients to make informed decisions on their lifestyle choices. It also will help me become a proficient “translator” in the language most people are unfamiliar with. Genetics can be confusing and for many people, unknown territory. As a result, I see my role as a “genetics literate” health educator that can regurgitate the complex terminology into something the average person can understand. I believe it is a skill that every clinician should adopt.
What is the impact of genomics on the practice of nutrition?
By using genetics and molecular biology to predict individual risks, based on genotype, nutrigenomics may have the potential to prevent and treat diet-related chronic disease and conditions. The push for personalized nutrition began in 2003 after the Human Genome Project published the first sequence of the human genome, as it began to uncover that the “one-size-fits-all” nutritional strategies are not as effective as we once thought (Dennett, 2017). Since then, gene-diet interactions that affect various metabolic pathways related to disease risk and health are continuously being uncovered, shaping personalized nutrition, which targets dietary recommendations to an individual’s genetic profile (Nielsen & El-Sohemy, 2012). To date, both nutrigenetics (influence of gene variants and the interaction with the environment) and nutrigenomics (the influence of the environment to our gene expression) both have opportunities as well as challenges. A greater understanding on how gene-nutrient interactions influence key metabolic pathways that influence gene expression and changes in the metabolome can aid in treatment and prevention of disease (Kohlmeier et al., 2016). Genetic data can be integrated with phenotypical, social, cultural and personal preferences to provide a more individual nutritional approach (Kohlmeier et al., 2016).
If we have a greater understanding of potential gene-nutrient interactions, then it may be possible to manipulate diet in such a way to minimize the metabolic risk certain diseases, such as obesity(Phillips, 2013). It may be possible to diagnose disease risk early and target interventions such as lifestyle modifications or changes in nutritional behavior or exercise therapy to reduce the risk of disease development (Phillips, 2013). Knowledge gained from current research in the field could lead to the development of personalized nutritional guidelines for individuals and specific subpopulations, (Nielsen & El-Sohemy, 2012), while also providing the ability to categorize individuals into subgroups (Kohlmeier et al., 2016). And finally since nutrients can regulate gene expression patterns, by influencing gene transcription and translation, the information obtained can provide important insights about the influence of specific food components on important biological processes in risk of certain diseases (Fenech et al., 2011).
As promising as this may sound, there are some challenges. Genomics can make it difficult to make simple, general recommendations (Kohlmeier et al., 2016). As a result, as our understand of genomics expands, nutrition therapy may be perceived as more complex, and that could be a deterrent for individuals who want to make simple lifestyle changes. For example, a subset of the participants who had lower educational status and were members of ethnic minority groups reported a more deterministic interpretation of the results and were more confused by the information (Nielsen & El-Sohemy, 2012). Another issue is that the genetic testing industry is largely unregulated and there are some concerns over the consumer’s ability to accurately interpret the meaning of the test results, given that no healthcare professional involvement is required (Nielsen & El-Sohemy, 2012.
Some questions that still are unanswered include (Fenech et al., 2011):
- Will public health really be improved with individualized tailored recommendations?
- How costly will personalized nutrition be? Will this approach only be available for those with money and education?
- Will people be motivated to adhere to a tailored diet?
- How will this affect those who really need a simplistic view on the role of food on our health? Will this new information dilute general healthy eating messages?
And finally, there are also some legal and social issues that need to be addressed (Kohlmeier et al., 2016).
I believe there is still quite some room for growth in the genomics world to address some of the challenges that arise. However, the opportunities are evident and continuously expanding, and only time will tell what the future holds.
Dennett, C. (2017). The Future of Nutrigenomics. Retrieved (2019, May 5) from https://www.todaysdietitian.com/newarchives/1017p30.shtml (Links to an external site.)Links to an external site.
Fenech, M., El-Sohemy, A., Cahill, L., Ferguson, L. R., French, T. A., Tai, E. S., . . . Head, R. (2011). Nutrigenetics and nutrigenomics: viewpoints on the current status and applications in nutrition research and practice. J Nutrigenet Nutrigenomics, 4(2), 69-89. doi:10.1159/000327772
Kohlmeier, M., De Caterina, R., Ferguson, L. R., Gorman, U., Allayee, H., Prasad, C., . . . Martinez, J. A. (2016). Guide and Position of the International Society of Nutrigenetics/Nutrigenomics on Personalized Nutrition: Part 2 – Ethics, Challenges and Endeavors of Precision Nutrition. J Nutrigenet Nutrigenomics, 9(1), 28-46. doi:10.1159/000446347
Nielsen, D. E., & El-Sohemy, A. (2012). Applying genomics to nutrition and lifestyle modification. Per Med, 9(7), 739-749. doi:10.2217/pme.12.79
Phillips, C. M. (2013). Nutrigenetics and metabolic disease: current status and implications for personalised nutrition. Nutrients, 5(1), 32-57. doi:10.3390/nu5010032
I was interested in learning more about vitamin E supplementation to address oxidative stress. Dr. Tan wrote a nice summary of Vitamin E in his book “The Truth about Vitamin E”. Vitamin E is a family of eight separate but related molecules, and that includes four tocopherols (delta, gamma, alpha and beta) and four tocotrienols (also delta, gamma, alpha and beta). For many years, the nutrition world focused on tocopherols because it was discovered first. Only in the last decade did tocotrienols start to shine in its delta and gamma molecules and it was found that combined with a healthy lifestyle, it can lower lipids, reduce inflammation, protect the liver, promote bone health, facilitate in eradicating cancer cells and increase survival in cancer patients. In fact, studies demonstrate that the “wrong” form of vitamin E (tocopherols) can actually hinder the body’s ability to absorb the “right form” (tocotrienols).
A few interesting things about tocotrienols:
- Delta tocotrienol help maintain the membrane integrity of the cell membrane to protect cellular functions. Phospholipids, cholesterol and a small amount of protein make up most of the cell membrane, creating a lipid bilayer which is important for water, oxygen and CO2 to cross the membrane while blocking out other larger potentially harmful substances
- It can protect the cell from free radical damage
- Antioxidants like vitamin E (C, A, and selenium and zinc) can give the free radical its own electron without destabilizing the cell. Others include resveratrol, curcumin, astaxanthin, lutein, Coq10. Tocotrienols are well suited to protect the cell membrane because their perfect fit into the lipid bilayer allows them to better protect the lipids within this bilayer from oxidation.
The delta- and gamma-tocotrienols spread out and attach themselves to a variety of cell membranes throughout your body and then start patrolling for free radicals. As soon as they sense one closing in (meaning the free radical attaches to a fatty acid in the cell wall), the tocotrienol molecule releases an electron which re-attaches to the free radical, making the damaged (oxidized) fatty acid in the cell wall whole again. The free radical is stable again and leaves the cell. Put simply, the tocotrienol removes the dysfunctional oxygen from the fatty acid.
What is the difference between tocotrienols and tocopherols? First, they are 40-60 times more potent.
Here are some key differences:
- Tocotrienols have shorter tails that do not anchor deeply into the cell membrane- which allows them to move around the cell 50x faster to intercept free radicals more easily. In contrasts to tocopherols that have a longer tail, anchor deeply into cell membranes, and move more slowly. Because of this it is thought that tocotrienols are 40-60x better at giving one of their electrons to invading free radicals and repairing damage to lipids on membranes
- Tocotrienols have a smaller head and delta tocotrienols have the smallest- allowing them to squeeze in parts of the cell easier, giving them wider access to membranes and increasing their ability to capture more free radicals
- Tocotrienols have unsaturated tails where tocopherols have saturated tails- making them unique in that they have double bonds in their tails and can provide more lipid oxidation protection because of superior bioavailability to cell membranes.
I also want to point out that tocotrienols are great for reducing chronic inflammation. Studies demonstrate that alpha, gamma and delta tocotrienols strongly inhibit NFkB and TNF-a, along with other pro-inflammatory cytokines. “Among the most notable biomarkers to be affected by a 250 mg tocotrienol daily dosage were C-reactive protein (CRP; a predictor for chronic inflammation), nitric oxide (NO), and malondialdehyde (MDA), with decreases of 40%, 40%, and 34%, respectively” (Barrie, nd).
Tocotrienols can increase total antioxidant status. Total antioxidant status also increased by 22%, suggesting that delta-tocotrienol can potentiate endogenous antioxidants. This is great news for the use of tocotrienols for reduce inflammation associated with high cholesterol, CV disease, metabolic syndrome, nonalcoholic fatty liver disease, diabetes and pre-diabetes. It also can play a role in cancer, bone and brain health.
Tocotrienols area great for eye health. Interestingly, delta-tocotrienols may also delay the beginning of cataracts when applied to the eye due to reduced oxidative stress and nitrosative stress to the lenses which are exposed to environmental oxidants. Tocotrienol had a beneficial effect on lens antioxidant enzymes, including superoxide dismutase and catalase, both of which returned to normal levels with the topical treatment. Furthermore, tocotrienol significantly decreased malondialdehyde, a lipid peroxidation end product found to be high in cataracts, and restored the lens soluble to insoluble protein ratio to normal levels.
And finally, it has positive influence on the immune system. One study showed that annatto tocotrienol combined with antibiotics had the greatest efficacy in decreasing bacteria when compared with tocotrienol or antibiotic treatment alone (Tan, n.d). This may be due to an influence that tocotrienols have on T cells.
Tan, Barrie. The Truth about Vitamin E: The Secret to Thriving with Annatto Tocotrienols . Kindle Edition.
Zinc is a very interesting mineral. It is also one I commonly see low in hair tissue mineral analysis (HTMA).
It plays an important role in facilitating hundreds of biochemical reactions. Due to its role in enzymatic function, it can impact metabolic pathways such as carbohydrate, protein, nucleic acid, and lipid metabolism. It is also a structural component in thousands of transcription factors and can affect gene expression that impacts many physiological processes in the body. “Zinc appears to be part of more enzyme systems than all the rest of the trace minerals combined; over 300 enzymes from every enzyme class (oxidoreductases, hydrolases, lyases, isomerases, transferases, and ligases) require zinc” (Gropper, n.d.). Some of these zinc dependent enzymes include:
- Carbonic anhydrase: acid base balance- found in erythrocytes and renal tubule cells, essential for maintaining acid-base balance/buffering and respiration. The enzyme catalyzes the reaction that allows rapid disposal of carbon dioxide. Activity of this enzyme in red blood cells diminishes with chronic low zinc status in the diet.
- Alkaline phosphatase: Contains four zinc atoms per enzyme molecule, in which two are required for enzyme activity. This enzyme is found in bones and the liver.
- Alcohol dehydrogenase: contains 4 zinc molecules per enzyme molecule, two are required for catalytic activity. This enzyme is important in the NADH-dependent conversion of alcohols to aldehydes. For example, this enzyme converts retinol (form of Vitamin A) to retinal, which is needed for night vision. It also is required for acetyl aldehyde for alcohol metabolism
- Carboxypeptidases A and B and Aminopeptidases- which is involved in protein digestion. These enzymes are secreted by the pancreas into the duodenum. Zinc is bound tightly to carboxypeptidases and is essential for enzymatic activity; in fact, enzyme activity decreases with zinc deficiency (Gropper, n.d.). Aminopeptidases consist of a group of enzymes also involved in protein digestion which contains 1-2 zinc atoms for catalytic activity.
- Delta (Δ)-Aminolevulinic Acid Dehydratase: Heme Synthesis- needed for heme synthesis is zinc dependent. Interestingly, lead when present in the body in high concentrations can replace zinc in the dehydratase and diminishes heme synthesis.
- Superoxide dismutase (SOD1)- an antioxidant found in the cell cytosol requires two atoms of zinc (and two copper) to function. An extracellular form of the enzyme (SOD3) that is also zinc and copper dependent has been characterized and appears to be more sensitive to zinc than is the cytosolic form of the enzyme. Both the cytosolic and extracellular forms of superoxide dismutase serve important antioxidant defense roles in the body by catalyzing the removal of superoxide radicals, O2
- Phospholipase C-this enzyme hydrolyzes the glycerophosphate bond in phospholipids (a structural component of cell membranes!). It requires 3 zinc atoms for catalytic activity.
- Matrix Metalloproteinases-The matrix metalloproteinases are zinc containing endopeptidases (zinc is located in the catalytic site where substrate binds). They generally function in wound healing, degrading components of the extracellular matrix (among other roles) to allow for remodeling of extracellular matrix proteins and tissue repair
- Polymerases, Kinases, Nucleases, Transferases, Phosphorylases, and Transcriptases- Nucleic Acid Synthesis and Cell Replication and Growth Polymerases, kinases, nucleases, transferases, phosphorylases, and transcriptases all require zinc.
- Gene expression- Zinc plays a major structural role in regulating gene transcription by promoting a confirmation change in the shape of the transcription factor protein. You may have heard the term zinc fingers which is often used to indicate the secondary shape (configuration) of the transcription factor proteins when bound to zinc.
In addition to the above roles, zinc helps maintain cell membranes through multiple actions on membrane proteins including direct effects on membrane proteins’ conformation, on protein-to-protein interactions, and on other membrane components
Zinc itself also is believed to stabilize membrane structure by stabilizing phospholipids and thiol (SH) groups in enzymes and membrane proteins that need to be maintained in a reduced state.
Zinc may also stabilize membranes by quenching free radicals as part of metallothionein and by promoting associations between membrane skeletal and cytoskeletal proteins
Additionally, zinc in cells is found bound to tubulin, a protein that makes up the microtubules. Microtubules are thought to act as a framework for structural support of the cell as well as enable movement.
Zinc is also involved with insulin and thus influences carbohydrate metabolism. Zinc is transported into pancreatic b-cells by zinc transporter ZnT8, which also enables uptake into secretory vesicles. Pancreatic b-cells are responsible for insulin production and secretion (Gropper, n.d.).
Zinc can also influence the basal metabolic rate (BMR). A decrease in thyroid hormones and basal metabolic rate has been observed with consumption of a zinc-restricted diet (Gropper, n.d.).
Zinc is also important for taste; it is a component of gustin, a protein involved in taste acuity (Gropper, n.d.).
Cell mediated and humoral immunity are also influenced by zinc. T-cells are critical to immune system function and with zinc deficiency, thymulin activity diminishes and profoundly affects T-cell numbers and functions, and pre-T-cell apoptosis (programmed cell death) (Gropper, n.d.).
Some signs and symptoms of deficiency in adults include anorexia, diarrhea, lethargy, depression, skin rash/ lesions/dermatitis, hypogeusia (blunting of sense of taste), alopecia (some hair loss; remaining hair make take on a reddish hue), vision problems, and impaired immune function, protein synthesis, and wound healing (Gropper, n.d.).
Zinc deficiency can be associated with decreased mobilization of retinol from the liver (even with adequate liver vitamin A stores) as well as decreased plasma retinol-binding protein concentrations (Gropper, n.d.).
An overall deficiency of zinc stores within the body has been implicated in the systemic susceptibility of infection and in the pathogenesis of some cancers (Liu et al., 2011)
Zinc also demonstrates an important role within the lumen of the alimentary canal, as evidenced on the observations that supplementation of oral diets with Zn2+ has beneficial effects on diarrhea and inflammatory conditions of the gastrointestinal tract (Liu et al., 2011). “In gastric mucosa, adequate intracellular stores and luminal content of Zn2+ may regulate integrity of and acid secretion by the gastric glands and enhance protection of the mucosa as a whole against acid-peptic injury (Liu et al., 2011).
Evaluating zinc nutriture is difficult, owing to homeostatic control of body zinc. A variety of indices have been used to assess zinc status, including measurements of zinc in red blood cells, leukocytes, neutrophils, and plasma or serum.
The most common basis for assessment is serum or plasma zinc, with fasting concentrations less than about 70 µg/dL (10 µmol/L) suggesting deficiency. A cutoff of 50 µg/dL, however, may better predict clinical signs of zinc deficiency (Gropper, n.d.). Plasma zinc concentrations range from about 70 to 120 μg/dL (10–18 µmol/L), with plasma containing about 3 mg of zinc. Plasma zinc concentrations decrease after eating, as well as under conditions of infection and trauma
Low fasting plasma zinc concentrations indicate that little zinc is present in the exchangeable zinc pool and may reflect a loss of tissue zinc (especially from the liver). Plasma zinc concentrations, however, must be interpreted with caution because concentrations are influenced by many factors unrelated to zinc depletion, including meals, time of day (diurnal variation), stress, infection, and medications such as steroid therapy. In fact, postprandial (after eating) plasma zinc concentrations have been found to be more sensitive to low dietary zinc intake than fasting plasma zinc concentrations (Gropper, n.d.)..
Metallothionein has also been used to assess zinc status. Concentrations of metallothionein respond to changes in dietary zinc. For example, liver and red blood cell metallothionein concentrations diminish as dietary zinc intake decreases and are thought to reflect zinc status or stores (Gropper, n.d.).
Serum zinc and serum metallothionein concentrations can be used to indicate poor zinc status if both are low. Elevations in serum metallothionein coupled with low serum zinc, however, usually suggest an acute-phase response, and in such conditions these indices are not reliable. Urinary zinc excretion remains fairly constant over a range of intakes and is thought to be a useful marker of status in those with moderate to severe zinc deficiency (Gropper, n.d.)..
Low hair zinc may be associated with chronic intake of dietary zinc in suboptimal amounts; however, the concentration of zinc in hair depends not only on delivery of zinc to the root but also on the rate of hair growth, which is affected by other conditions (including protein status)(Gropper, n.d.).
.Measurement of the activity of zinc-dependent enzymes has also been employed as an index of zinc status. Studies using enzymes as indicators typically have measured carbonic anhydrase or alkaline phosphatase, which “hold” zinc less securely than other zinc metalloenzymes.
Ideally, measurements of activity should be taken before and after zinc supplementation (Gropper, n.d.)..
Supporting deficiency in adults typically requires oral zinc supplementation; doses of 10–20 mg/day are recommended. Although higher doses (often up to 50 mg given two to three times per day) may be prescribed, use of such doses is more likely to impair copper status.
Some population groups—especially older adults, vegetarians, and those with alcoholism and with limited income—have been found to consume less than adequate amounts of zinc.
Alcohol ingestion additionally reduces intestinal zinc absorption and increases urinary zinc excretion.
Additional conditions associated with an increased need for intake include trauma, sickle-cell anemia, and disorders causing malabsorption such as Crohn’s disease, short bowel syndrome, celiac disease, and liver failure, as well as surgical bariatric procedures, especially Roux-en-Y gastric bypass and duodenal switch, used to treat obesity. Diarrhea and intestinal fistulas also substantially increase fecal zinc losses; supplementation with up to 20 mg of zinc/day may be needed under such conditions.
ZINC and COPPER
The detrimental effect of excessive zinc intake on copper absorption is thought to be attributable to zinc’s stimulation of the synthesis of metallothionein, which has a higher affinity for copper than for zinc. With increased intestinal concentrations of metallothionein induced by high zinc levels, ingested copper readily binds to the metallothionein within the enterocyte and becomes “trapped,” preventing its passage into the plasma. The increased risk of copper deficiency precipitated by zinc supplementation led to the Tolerable Upper Intake Level for elemental zinc of 40 mg daily.
Recent reports have begun to explore the mechanisms that regulate cellular homeostasis of Zn2+ in mucosal cells of the gastrointestinal tract (Liu et al., 2011)
There is a relationship to zinc uptake is dependent on intracellular Ca2+ stores.According to Liu et al (2011), baseline conditions, uptake of Zn2+ across the basolateral membrane depends on adequate stores of intracellular calcium ion (Ca2+) . With stimulation by powerful agonists such as forskolin and carbachol, demand for extracellular Zn2+ increases and depends on influx of extracellular Ca2+ .
“In the current set of studies, we find that Ca2+ facilitates optimal uptake of Zn2+ across the cell membrane, implying that it is either a counter-ion in exchange or it is acting as a regulatory second messenger. Membrane proteins that facilitate Zn2+ transport constitute the SLC30A (ZnT) and SLC39A (Zip) gene families” (Liu et al., 2011).
Diminished calcium absorption has been observed with the ingestion of zinc supplements when calcium intake is low (<300 mg/day of calcium). However, calcium absorption appears to be unaffected by zinc when calcium intake is at adequate (recommended) levels.
Cadmium, if present in high concentrations in the body, appears to bind to sites to which zinc would normally bind and thus disrupts normal zinc functions. For example, cadmium can replace zinc in zinc fingers, preventing the fingers from functioning as they would with zinc present.
Zinc is found in foods complexed with nucleic acids and with amino acids that are part of peptides and proteins. The zinc content of foods varies widely.
Very good sources of zinc are red meats (especially organ meats) and seafood (especially oysters and mollusks). Other relatively good animal sources of zinc include poultry, pork, and dairy products. Animal products are thought to provide 40–70% of zinc consumed by most people in the United States.
Whole grains and legumes also provide moderate amounts of zinc.
Cereals, some of which may be fortified, are thought to provide about 30% of the zinc in the U.S. diet. Fruits contain little zinc.
Plant sources, however, not only have lower zinc contents, but zinc from plants is also absorbed to a lesser extent than zinc from animal sources (e.g., meat).
Zinc absorption is enhanced with:
Ligands or chelators including organic acids (like citric acid and picolinic acid) and prostaglandins may bind and promote zinc absorption
Glutathione and products of protein digestion, such as amino acids, serve as ligands (such as sulfur, cysteine, or nitrogen). Interestingly, amino acids serving as ligands help maintain zinc’s solubility in the gastrointestinal tract
Absorption of zinc is also enhanced by an acidic environment. Thus, the use of medication such as antacids, H2 receptor blockers (such as Zantac [ranitidine], Tagamet [cimetidine], or Pepcid [famotidine]), and proton pump blockers (such as Prevacid [lansoprazole] or Prilosec [omeprazole]), which are commonly taken to treat heartburn, gastroesophageal reflux disease, and ulcers, increases gastric and proximal intestinal pH and decreases zinc absorption
Phytic acid found in plant foods, particularly legumes, lentils, nuts, seeds, and whole-grain cereals decrease absorption
Other minerals such as iron and calcium negatively impact absorption
Gropper, Sareen S.; Smith, Jack L.; Carr, Timothy P.. Advanced Nutrition and Human Metabolism (Page 509). Wadsworth Publishing. Kindle Edition.
Liu, J., Kohler, J. E., Blass, A. L., Moncaster, J. A., Mocofanescu, A., Marcus, M. A., . . . Soybel, D. I. (2011). Demand for Zn2+ in acid-secreting gastric mucosa and its requirement for intracellular Ca2+. PLoS ONE, 6(6), e19638. doi:10.1371/journal.pone.0019638
The relationship between thiamine and diabetes mellitus (DM) has been reported in the literature (Luong & Nguyen, 2012). Thiamine acts as a coenzyme for transketolase (Tk) and for the pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase complexes. These enzymes play a fundamental role for intracellular glucose metabolism by increasing Krebs cycle activity (Luong & Nguyen, 2012). Low thiamine has been reported to be decreased by 76% in T1D and 75% in T2D patients, as evidenced by low blood thiamine levels, erythrocyte transketolase activity and high erythrocyte thiamine pyrophosphate (TPP).
Additionally, thiamine transporter protein concentration has been shown to be increased in erythrocyte membranes of T1D and T2D patients. “Therefore, changes in thiamine levels may be masked by an increase in thiamine transporter expression” (Luong & Nguyen, 2012). The low thiamine values in diabetic patients might also be a reduced apo-enzyme level from the disease itself rather than thiamine deficiency (Luong & Nguyen, 2012)
I think it is important to mention, there are four distinct biochemical pathways that have been identified as mechanisms in which intracellular hyperglycemia can promote some of the complications of diabetes (such as vascular damage, renal impairment, neurological damage and endothelial damage in the retina) (Brownlee, 2005). These include: increased flux through the polyol pathway, formation of AGE’s, activation of protein C kinase pathway and increase flux through hexosamine biosynthetic pathway. I will briefly discuss each below (Luong & Nguyen, 2012).
- Polyol pathway- This pathway focuses on the enzyme aldose reductase, which is responsible for reducing toxic aldehydes in the cell to inactive alcohols. But when the glucose concentration is too high in the cell, aldose reductase reduces the glucose to sorbitol. NADPH is used to drive this reaction forward, but it runs the risk of being overconsumed in this process. When there is elevated blood glucose and energy overload in the cell, we start to waste NADPH which is essential for regeneration of GSH. When we are running through this pathway, it can cause a glutathione deficit in the cell, which is why sometimes diabetes is associated with GSH deficiency. By reducing the amount of reduced glutathione, the polyol pathway can increase susceptibility to intracellular oxidative stress (Luong & Nguyen, 2012).
- Intracellular production of AGE precursors. AGE’s are toxic compounds deriving from non-enzymatic glycoxidation reactions of reducing sugars with proteins, which then result as being structurally and functionally compromised. Protein glycation occurs in vivo in physiological conditions as a post-translational modification that takes place slowly and continuously during the life span, driving AGE accumulation in tissues during aging. AGE’s have been associated with age related conditions such as diabetes and insulin resistance. In addition, accumulation of AGE’s is accelerated leading to other conditions (Aragno & Mastrocola, 2017).
- Activation of the protein Kinase C pathway- High levels of fatty acids and hyperglycemia activate DAG, which turns on PKC. This promotes various processes that results in decreased nitric oxide (NO) bioavailability. Reducing NO availability and produces oxidative stress in the nervous and vascular system, and reduce ability to synthesize NO which can increase oxidative stress(neuro and vascular) and reduce the ability to synthesize NO which can increase vasoconstriction, poor blood flow and oxygenation of tissue (Roberts & Porter, 2013).
- Hexosamine pathway– Chronic high blood pressure can upregulate this pathway. Fructose 6-P is transformed to glucosamine 6-P by the enzyme glutamine fructose 6-P amidotransferase (GFAT). Glucosamine then promotes the synthesis of uridine diphosphate-N-acetylhexosamine (UDP-GlcNAc) that then serves as a substrate for N- or O-glycation of numerous proteins (Luo, Wu, Jing, & Yan, 2016). “This posttranslational modification can enhance glucotoxicity by impairing protein function and has been demonstrated to be involved in insulin resistance and pathogenesis of diabetes” (Luo et al., 2016). If transketolase activity is low, it is likely that fructose 6 pathway will go through hexosamine pathway, instead of the pentose phosphate pathway which thiamine is a cofactor.
Diabetics are associated with tissue specific thiamine deficiency. This is often demonstrated by: a marked decrease of plasma thiamine concentration; decreased activity of the thiamine-dependent enzyme of transketolase (TK); decreased levels of TK protein in renal glomeruli linked to a profound increase in renal clearance of thiamine (Thornalley et al., 2007). According to Thornalley et al (2007), diabetics are statically more likely to be more thiamine deficient since they waste it through kidneys making their requirement higher.
Insulin deficiency is also associated with reduced rate of thiamine transport across the intestine. High prevalence of low plasma concentrations is prevalent in patients with T1 and T2 diabetes, associated with thiamine clearance
What all this means?
Transketolase acts as a bridge between PPP and glycolytic pathway requiring B1 as a cofactor. Thiamine deficiency slows down transketolase. With thiamine, the pentose phosphate pathway can take the extra intermediates of the glycolytic pathway until we need to make more energy. When there is thiamine deficiency, we are unable to effectively shunt these intermediates down the pentose phosphate pathway( PPP), we end up with build up of intermediates. When this energetic block occurs, such as in mitochondrial dysfunction, the intermediates are shunted into alternative pathways. These yield inflammatory products, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
In diabetes, there is an overload of energy, which causes reverse the electron flow which can then increase reactive oxygen species. Decreased availability of thiamine in vascular cells in diabetes exacerbates metabolic dysfunction in hyperglycemia (Thornalley et al., 2007). These yield inflammatory products as indicate above, and it is the products of these pathways that are central in the damage caused by diabetes or involved in diabetic complications.
It is thought that thiamine supplementation is helpful in diabetes. Thiamine supplementation can reduce AGE formation, reduce flow through hexosamine and polyol pathway, reduce protein kinase C activity, inhibits NF-KB activation and normalize markers associated with methylglyoxal and glycation.
High dose supplementation as befothiamine and thiamine hydrochloride possess antioxidant properties, reduces lipid peroxidation, reduces oxidative stress associated with diabetes and activates eNOS (EONutrition, 2019). It may also improve endothelial dysfunction in a hyperglycemic state. In addition, it may improve pain associated with diabetic polyneuropathy and reduce urinary albumin excretion, reducing renal AGE’s and oxidative damage (EONutrition, 2019).
Aragno, M., & Mastrocola, R. (2017). Dietary Sugars and Endogenous Formation of Advanced Glycation Endproducts: Emerging Mechanisms of Disease. Nutrients, 9(4). doi:10.3390/nu9040385
Brownlee, M. (2005). The pathobiology of diabetic complications: a unifying mechanism. Diabetes, 54(6), 1615-1625. doi:10.2337/diabetes.54.6.1615
EONutrition (2019). Retrieved (2020, June 22) from https://www.youtube.com/watch?v=m3DopqTz1Q4&t=801s
Luo, X., Wu, J., Jing, S., & Yan, L. J. (2016). Hyperglycemic Stress and Carbon Stress in Diabetic Glucotoxicity. Aging Dis, 7(1), 90-110. doi:10.14336/ad.2015.0702
Luong, K. V., & Nguyen, L. T. (2012). The impact of thiamine treatment in the diabetes mellitus. J Clin Med Res, 4(3), 153-160. doi:10.4021/jocmr890w
Roberts, A. C., & Porter, K. E. (2013). Cellular and molecular mechanisms of endothelial dysfunction in diabetes. Diab Vasc Dis Res, 10(6), 472-482. doi:10.1177/1479164113500680
Thornalley, P. J., Babaei-Jadidi, R., Al Ali, H., Rabbani, N., Antonysunil, A., Larkin, J., . . . Bodmer, C. W. (2007). High prevalence of low plasma thiamine concentration in diabetes linked to a marker of vascular disease. Diabetologia, 50(10), 2164-2170. doi:10.1007/s00125-007-0771-4