Summary:
Complementary preventive therapy for Alzheimer’s disease should include DHA for its biochemical implications, especially in apoE4-genotype obese-diabetic patients. DHA mechanisms involve reducing adiposity and secretions, improving insulin sensitivity, guarding against oxidative stress, and guarding against beta-amyloid plaque, neurofibrillary tangles and advanced glycation end-products.
Background: Urgent Call for Alzheimer’s Disease Preventive Therapies
Foresight warns that the present epidemic of obesity and diabetes in the United States of America will lead to future medical epidemics and among them will be Alzheimer’s disease (AD), the most common neurodegenerative disease seen in aging. AD is seriously debilitating and at present time has no cure. Current treatments are limited to cholinesterase inhibitors to improve function of signaling pathways in memory, but are not intended to prevent or slow further brain damage. Preventive strategies are currently being studied to assist in avoiding Alzheimer-type dementia in the population. Obese-diabetic persons are predisposed to AD, particularly if they are of the apoE4 genotype (Luchsinger & Gustafson, 2009). ApoE4-genotype obese-diabetic individuals, at high risk for AD, represent an ideal population for testing AD-prevention therapies. The last decade has witnessed popularity of researching fish-derived omega-3 fatty acids, notably docosahexaenoic acid (DHA), and their relationship with brain health. New research has begun to associate the use of fish oil with less cognitive decline and lowered risk of AD (Martin, 2008). Along with dieting and exercise directed at improving insulin sensitivity, DHA intake in apoE4-genotype obese-diabetic subjects may reduce the progression of AD. The following are four potential mechanisms that could explain how DHA operates: (a) improving insulin sensitivity to reduce continual hyperglycemia, hyperinsulinemia, and hypertension (b) inhibition of beta-amyloid (Abeta) and plaque production, (c) inhibition of hyperphosphorylation of tau protein, which leads to neurofibrillary tangle formation, and (d) reduction of oxidative stress and advanced glycation end-product (AGE) formation and cross-linking. This paper will discuss the literature supporting this hypothesis.
Biochemistry of AD
The underlying condition seen with AD is impairment of memory and learning, or dementia. It is primarily caused by Abeta plaques. At the core of the plaques is amyloid protein. Autopsy of AD brains shows that plaques are widely distributed over the cerebral cortex. The Abeta aggregates when under oxidative stress, which worsens the AD (Carr, Goate, Phil, & Morris, 1997). The Abeta protein binds to proteases inhibitors suppressing the normal catabolism of proteases, which allows them to damage neurons and other proteins. Neurofibrillary tangles are a secondary factor induced by Abeta. They become localized mainly in the hippocampus, entorhinal cortex and amygdala. The tangles are made up of the tau protein. Tau protein is one of the microtubule associated proteins used to stabilize microtubules and for providing attachment to other cells. The tangles are produced by abnormal hyperphosphorylation of the tau protein. The protein when hyperphosphorylated, also called “paired helical filaments,” becomes aggregated. Neurons affected by plaques and tangles eventually die (Carr et al., 1997). As described before, the tangled up mess causes considerable interference and attenuates damage in the brain. The tangles are susceptible to glycation. Advanced glycation end-products (AGEs) and cross-linking occur. The AGEs are formed by nonenzymatic Maillard reactions, when glucose molecules open and attach to lysine in proteins producing Schiff bases, which form Amadori products. The Amadori products—as also found in glycated hemoglobin—are more stable, but when attacked by free radicals produce oxoaldehydes, otherwise called AGEs. Glycations alter function of proteins causing their degradation. The Maillard reactions also lead to production of reactive oxygen species, which, in turn, promote more glycation (Kikuchi et al., 2003). Glycation on tau protein enhances formation of tangles and is thought to enhance aggregation of Abeta (Sasaki et al., 1998). The AGEs also activate glia producing inflammation and dysfunction as well as fragmentation into glyoxal and methylglyoxal (Kuhla et al., 2005). Thereby, AGEs are implicated as a cause of inflammation, oxidative stress, neuronal dysfunction (Yan et al., 1995). The Abeta aggregation, tangles and AGE cross-linking are ultimately cause for AD pathogenesis.
ApoE4 Genotype
Apolipoproteins are proteins that form lipoproteins to transport fats in the blood stream. They are produced in the liver and their amount in the bloodstream is reflective of dietary fats. An apolipoprotein involved with chylomicron transport across the blood-brain barrier is apolipoprotein E (apoE). These apoE proteins are also found along with Abeta in plaques and along with tau proteins in neurofibrillary tangles. Genetic variations of ApoE are associated with risk of AD. The allele variation episilon2 (E2) appears to be protective while episilon3 is protective to a lesser extent; however, the variant epsilon4 (E4) allele or two alleles has been found to increase AD risk 2.5-fold and 5.6-fold, respectively (Martins, Oulhaj, de Jager, & Williams, 2005; Scarmeas et al., 2002). The E4 allele is not a cause of AD, but predisposes individuals to risk.ApoE4 genotype individuals have increased susceptibility to developing Abeta plaques and neurofibrillary tangles. The mechanism is thought to be dependent on lipidated apoE4. It binds to a specific receptor, apoER2, in brain cells more easily than the other alleles. The receptor allows endocytosis of apoE4 as well as amyloid precursor protein and beta-secretase. Beta- and gamma-secretases then fragment the proteins (He, Cooley, Chung, Dashti, & Tang, 2007). The amyloid precursor protein is fragmented to Abeta. Presence of ApoE4 is also thought to slow clearance of occurring Abeta in the brain. Lipoprotein receptor-related protein-1 (LRP1) is an Abeta-binding molecule that clears Abeta at the blood-brain barrier. Abeta-apoE2 or Abeta-apoE3 complexes are cleared at a much faster rate than Abeta-apoE4 complexes (Deane et al., 2008). These factors lead to risk of “early onset” AD, which is defined as those with AD before age 65. ApoE4 genotype can lead to development of AD as early as ages 30 and 40, especially if obese and diabetic. The apoE4-genotype obese-diabetic population represent ideal candidates for study of AD preventive strategies.
AD Risk Increased by Adiposity and Hyperinsulinemia
Obesity has been consistently linked to the development of dementia and AD (Salihu, Bonnema, & Alio, 2009; Razay, Vreugdenhil, & Wilcock, 2006). Elevated adiposity promotes insulin resistance, an increase of adipokines (cytokines produced from adipocytes) including resistin and tumor necrosis factor-alpha (TNFα). The insulin resistance exacerbates the process leading to metabolic syndrome and diabetes. When obesity is combined with diabetes, the risk of AD increases more than four-fold (Pasinetti et al., 2007). Diabetes and glucose intolerance occurs once the amount of insulin is not enough to overcome elevated plasma glucose. The pancreas secretes more insulin to abnormally high levels to maintain adequate glucose levels in the blood. Abnormal insulin signaling in the brain leads to prolonged elevated insulin levels. Normally insulin would bind to insulin receptors. Under conditions of AD, however, neurons have few insulin receptors and are resistant to insulin. Elevated insulin in the brain that is unable to bind to neurons accumulates in the serum. Hyperinsulinemia stimulation of inflammation is thought to induce formation of Abeta plaques. The loss of appropriate insulin signaling alters activity of phosphorylation leading to increased phosphorylation of tau proteins (Schubert et al., 2004). Prolonged levels of elevated insulin was also suggested by at least one study to peripherally stimulate abnormal signal transduction pathways causing hyperphosphorylation of tau proteins (Freude et al., 2005). The hyperphosphorylation and formation of Abeta plaques caused by hyperinsulinemia in the brain are major factors leading to AD.
Elevated insulin interferes with Abeta degradation. Insulin-degrading enzyme (IDE) breaks down both insulin and Abeta. In addition, it breaks down amylin, which is another amyloidogenic peptide. With all three substrates—insulin, Abeta and amylin competing for the same enzyme—less Abeta and amylin is broken down (Qiu & Folstein, 2006). ApoE4 is also thought to possibly downregulate IDE expression in neurons because it binds to its receptor (Du, Chang, Guo, Zhang, & Wang, 2009). A present target for AD preventive therapy may be to help increase effectiveness of IDE with drugs or by preventing hyperinsulinemia.
Clearance of Abeta is also affected by elevated insulin. The abnormal insulin signaling and inappropriate neuron function causes reduced levels of transthyretin. Transthyretin is a protein that normally supports transport of Abeta out of brain. Therefore, Abeta and amylin elevate in the plasma and becomes aggregated in the environment of inflammation forming plaques (Qiu & Folstein, 2006). In one prospective study, hyperinsulinemia was found to double the risk of AD in subjects ages 65 and older in Manhattan (Luchsinger, Tang, Shea, & Mayeux, 2004). Therefore, the indirect effects of elevated insulin on the brain is one more reason to closely monitor plasma glucose in both diabetics and metabolic syndrome.
Hyperinsulinemia also increases the risk of hypertension. Insulin stimulates sodium reabsorption in the kidneys and causes vasoconstriction that can lead to elevated blood pressure (Ritz, 2008). A seven-year longitudinal study found diabetics patients who had hypertension have a six-fold increased risk of AD (Posner et al., 2002). Hypertension may be involved mainly in progression of AD by producing dysfunction in the blood-brain barrier as well as increasing oxidative stress (Skoog, 1997). Increased permeability in the blood-brain barrier is thought to create greater transport of Abeta across the barrier and less to leave the brain. The oxidative stress presents additional effects by promoting glycation.
Hyperglycemia naturally increases glycation in the brain. Combined with oxidative stress, the excess glucose lead to rapid progression of AGEs (Sato et al., 2006), which can be attenuated by AGEs found in the diet (Gil & Bengmark, 2007). Increased glyoxal levels, resulting from fragments of amadori products, also inactivates enzymes such as superoxide dismutase, needed for neutralizing free radicals, promoting more aggregation, more glycation and more damage to cells (Jabeen, Saleemuddin, Petersen, & Mohammad, 2007). Formation of AGEs and occurrence of AGEs cross-linking neurofibrillary tangles and Abeta aggregates limits neuronal function, produces oxidative stress, increases susceptibility to oxidative stress, and leads to neuronal apoptosis.
Mechanisms of DHA Against AD
The human brain is made up of approximately 60 percent fatty acids. PUFAs make up a major portion of which DHA is in greatest amount followed by EPA. The greatest concentration of DHA in the nervous system is in the membrane phospholipids. Functionally, DHA is heavily involved in retinal and brain processes. Lack of DHA predisposes for neuron dysfunction and stress in various ways, of which some is discussed here, and not of which are all understood. Because DHA and EPA are omega-3 fatty acids, their occurrence in the body relies on dietary intake from fish, crustaceans or other animals, or, to a poorer extent, synthesis from dietary alpha-linolenic acid from plants. DHA is found in greatest amounts in cold-water fatty fish.
The last decade of research has revealed a strong association between DHA and AD. For example, one of the first studies to suggest a role of fish oil and cognitive decline was an observational, prospective study at Rush’s Institute for Healthy Aging. They found elderly subjects who ate fish at least once a week had 60 percent less risk of AD (Morris et al., 2003). Observational and clinical trials on DHA have yet to show benefit in reducing existing AD. According to a systemic review of 11 observational studies and four small clinical trials—of which most only used cognitive decline as an outcome—did not find convincing evidence for prevention or treatment of AD, only that fish-derived omega-3 fatty acids slowed cognitive decline in those without dementia (Fotuhi, Mohassel, & Yaffe, 2009). As a complementary therapy, however, omega-3 fatty acid biochemical nature (especially DHA) should not go ignored. In one large cohort in France involving three cities in 1999-2000, for example, it was found that omega-6 fatty acid intake that was not also met with omega-3 fatty acid intake increased risk of dementia and AD while a diet rich in omega-3 fatty acids from fish, and fruits and vegetables reduced risk of AD, particularly in ApoE4-genotype subjects (Barberger-Gateau et al., 2007). While dieting and exercise may still play the majority role in prevention, DHA’s biochemical implications suggest that there should be continued search for the right dosages of DHA for complementary AD preventive therapy.
DHA and Insulin Sensitivity
DHA as a polyunsaturated fat (PUFA) does not adversely affect insulin sensitivity. Unlike saturated and trans fats, PUFAs are not associated with insulin resistance. Research relating to PUFAs led to a commentary in J Am Diet Assoc recommending displacement of saturated fats with PUFAS, specifically 1 to 2 g of fish-derived omega-3-PUFAs, because of reports of lower glucose intolerance along with lower blood pressure, reduced triglyceride levels, and improved endothelial function (Nettleton & Katz, 2005). The mechanisms are various. PUFAs, particularly DHA and EPA, are thought to improve insulin sensitivity by more than one pathway. The mechanisms are beyond glycemic control (Kuda et al., 2009). In adipose tissue and the liver, PUFAs influence gene transcription to increase amount of proliferator-activated receptors, sterol regulatory element-binding proteins and liver X receptors (Al-Hasani & Joost, 2005). The greater presence of these proteins and receptors result in more sensitivity to various nutrients and insulin. PUFAs also improve lipid metabolism improving prevention of obesity an diabetes. Adipose tissue secretion of adipokines decreases improve insulin sensitivity. PUFAs stimulate mitochondrial beta-oxidation, thereby promoting reduced adiposity (Flachs, Rossmeisl, Bryhn, & Kopecky, 2009). The effects are independent of PUFAs role in eicosanoid synthesis. DHA, in particular, induces lipolysis while reducing lipogenesis in what appear to be various biochemical pathways in the liver and adipocytes. PUFAs regulate gene transcription of lipogenic enzymes—such as glucose-6 phosphate dehydrogenase and fatty acid synthase—and desaturatases—such as stearoyl-C desaturase (Riserus, 2008). DHA is thought to increase lipolytic gene expression and suppressing lipogenic gene expression (Wang et al., 2009). DHA enhances expression of serum amyloid A protein, involved in lipid metabolism, and increases lipases (Wang et al., 2009). All of these are biochemical changes effective for reducing adiposity, subsequent secretions, and the factors leading to insulin resistance.
DHA also improves insulin sensitivity through docosanoid pathways. DHA and EPA immunomodulatory effects are well-known because they inhibit pro-inflammatory cytokine production (Sijben & Calder, 2007). Apart from this role, they increase formation of EPA-derived eicosanoids and DHA-derived docosanoids, resolvins and protectins (Gonzalez-Periz et al., 2009; Pauwels, Volterrani, Mariani, & Kairemo, 2009). The resolvins and protectins then help guard against inflammation as well as insulin resistance. These effects all naturally lead to decreased hyperglycemia, hyperinsulinemia and resulting hypertension.
DHA Lowers Risk of Hypertension
Blood pressure levels are lowered by DHA in various ways. Reduced insulin reduces salt reabsorption in the kidney stemming hypertension. PUFAs such as DHA guard against hypertriacylglycerolemia associated with hypertension (Viljoen & Wierzbicki, 2009). DHA also may help to regulate aldosterone and corticosterone levels associated with hypertension (Engler et al., 1999). A dose of 5 g found to lower blood pressure (Dusing, 1989). In higher amounts (50g), fish oil quite effectively reduces diastolic blood pressure, lowers triglycerides and increases bleeding time, as shown in a six-week randomized, double-blind, parallel-group study on patients with mild hypertension (Levinson, Iosiphidis, Saritelli, Herbert, & Steiner, 1990). Without hypertension to attenuate oxidative stress in the brain, damage in AD may be reduced, but studies are unclear if omega-3 fatty acids would compensate for hyperinsulinemia-induced hypertension.
DHA can also protection against cardiogenic dementia, which can affect AD. Metabolic syndrome factors leading to atherosclerosis and possible thrombosis can result in major cardiac events. DHA improvement of endothelial function, its anti-inflammatory effects from adipokine andiponectin, its inhibition of tumor necrosis factor-alpha protect against factors, and blood platelet effects help protect against heart failure and myocardial infarction (Duda et al., 2009). Heart failure and myocardial infarction can cause cardiogenic dementia, which is a heavy burden on AD patients.
DHA Guards Against Inflammation and Oxidative Stress in the Brain
Depletion of DHA in older adults leads to greater oxidative stress in the brain. Older adults who have not consistently had DHA dietary intake slowly progress to DHA depletion. The depletion leaves membrane phospholipids at greatest risk for oxidative stress insults (Lukiw & Bazan, 2006). DHA-derived neuroprotectins have direct effects on oxidative stress. Because DHA is also involved directly in neuron-to-neuron signaling and in synaptic terminals, depletion and oxidative stress directly affects learning and memory (Lukiw & Bazan, 2006). Its involvement in brain and retinal function is combined with anti-inflammatory effects reducing oxidative damage to brain and retinal cells; thus, DHA may prevent brain damage through antioxidant properties (Farooqui, Horrocks, & Farooqui, 2007). Inhibition of inflammation and oxidative stress as well as antioxidant effects suggest a dual role of DHA protection. DHA antiflammatory properties act via anti-apoptotic and neurotrophic pathways (Orr & Bazinet, 2008).
The omega-3 fatty acid mechanisms are through DHA-derived resolvins, protectins, and neuroprotectins. Each act against the three greatest brain insults occurring in AD: neuroinflammation, oxidative stress and neuron apoptic death (Farooqui, Ong, Horrocks, Chen, & Farooqui, 2007; Farooqui et al., 2007). The effects of DHA depletion is highlighted in animals, which leads to learning and memory deficits with noticeable damage to neurons and synaptic defts; levels of cognitive function are somewhat corrected after DHA supplementation (Farooqui, Horrocks, & Farooqui, 2007). As noted earlier, humans must include DHA in the diet to effectively guard against depletion. DHA-derived neuroprotectin D1 (NPD1) offers main protection against oxidative stress. Along with sphingosine 1-phosphate, DHA inhibits cytokine-mediated cyclooxygenase-2 expression (Farooqui et al., 2007). Cyclooxygenase-2 is an enzyme that produces eicosanoids in the brain. NDP1 also triggers further neuroprotectins and gene-encoding for anti-apoptic proteins (Lukiw & Bazan, 2006). These new findings all point to preservation of DHA amounts during aging.
DHA Guards Against Abeta
DHA-derived protectins protect against Abeta formation and neurotoxicity. NDP1 protects against both. NDP1 synthesis is enhanced by Abeta occurrence. The production of NDP1 is stimulated through activation of growth factors and neurotrophins in the brain, a process that is affected directly by DHA deficits (Lukiw & Bazan, 2008). NDP1 is enhanced especially at times of oxidative stress and the lower the DHA levels, the lower the levels of NDP1 production (Lukiw & Bazan, 2008). NDP1’s effects on Abeta include regulatory interaction with gene-encoding for beta-amyloid precursor protein and Abeta formation. The reduced production of Abeta delays
AD progression by allowing more Abeta to be cleared.
NDP1 inhibits formation of Abeta, thereby against aggregation. NDP1 also displays anti-amyloidogenic effects and suppression of Abeta aggregation significantly in Abeta-infused AD-model rats (Hashimoto et al., 2008). In this way, NDP1 protects against against neurotoxicity and, in the retina, against retinal damage from aggregation and glycation from diabetes (Bazan, 2009). Protection of Abeta would be secondary benefits after DHA’s support for improving insulin sensitivity.
DHA Reduces Tangles and AGEs
DHA inhibits formation of neurofibrillary tangles. Two mechanisms are involved apart from improving helping to reduce risk of elevated insulin. Indirectly, DHA inhibition of Abeta formation reduces hyperphosphorylation. Abeta induces hyperphosphorylation by kinases, which lead to the production of the paired helical filaments that end up in tangles (Cole, Ma, & Frautschy, 2009). The second mechanism is by inhibiting hyperphosphorylation directly. DHA inhibits the enzyme c-Jun N-terminal kinase that leads to tau hyperphosphorylation (Ma et al., 2009). The inhibition of the kinases help keep in check hyperphosphorylation and help correct abnormal insulin signaling. In prolonged hyperinsulinemia, this may offer important protection to brain cells.
DHA antioxidant properties make an impact in suppressing AGE and cross-linking formation. Just as other antioxidants, DHA reduces susceptibility to free radicals. The reduced susceptibility to formation of AGEs while in presence of diabetes and hyperglycemia has been demonstrated in rats (El-seweidy, El-Swefy, Ameen, & Hashem, 2002). According to studies, the suppression of neurofibrillary tangles and AGEs cross-linking by DHA may be even more effective when used with other antioxidants from fruits and vegetables (Cole et al., 2009; Ono & Yamada, 2006). By reducing glycation, DHA suppresses AGEs cross-linking of neurofibrillary tangles and Abeta aggregation as well as inhibition of enzyme pathways. The stemming of Maillard reactions and production of free radicals contributes to less oxidative stress. Reduced glyoxal levels inhibit binding to superoxide dismutase, thereby increasing antioxidant protection. The cascade of benefits suggest DHA intake and suppression of AGEs may improve of protecting neurons from progression to dysfunction and death in AD. DHA Should Be Used
Complementary Therapy in AD
DHA has various biochemical implications that all assist in guarding against factors that lead to risk of AD. Its mechanisms involve docosanoid pathways and genetic expression that lead to reducing adiposity and secretions and improvement of insulin sensitivity. Increased insulin sensitivity helps to guard against hyperinsulinemia, hyperglycemia and hypertension, which lead to abnormal insulin signaling, glycation and oxidative stress, respectively. DHA also directly guards against AD progression through inhibition of formation of Abeta. Reduced Abeta combined with improved insulin sensitivity can lead to greater Abeta degradation from IDE and greater Abeta clearance from the brain across the blood-brain barrier. DHA also inhibits neurofibrillary tangles through suppression of Abeta formation and by modulation of tau phosphorylation. Lastly, DHA antiflammatory and antioxidant effects in the brain reduce glycation, inhibit oxidative stress from glycation and reduce advanced glycation end-product cross-linking. All of these effects support DHA’s role in assisting prevention of AD.In light of epidemiological studies and clinical trials, dieting and exercise combined with DHA should be used in the therapy of obese-diabetes patients, especially those of apoE4-genotype. The most recent of reports suggest patients adhere to a Mediterranean diet (with fish at least once a week) along with daily exercise such as walking (Scarmeas et al., 2009; Scarmeas, Luchsinger, Mayeux, & Stern, 2007). A symposium in 2008 announced the first-ever preventive trial using multi-domain interventions of which results will be available in 2013. The Multidomain Alzheimer Preventive Trial (MAPT) will examine effects of fish-derived omega-3 fatty acids in AD in a three-year, randomized, controlled study conducted in hospitals of four French cities (Gillette-Guyonnet et al., 2009). Four groups of 300 elderly subjects with specific criteria of memory complaints, slow walking speed and one instrumental activity of daily living, will be given either omega-3 fatty acid supplementation alone, multidomain intervention alone, omega-3 plus multidomain intervention, or a placebo (Gillette-Guyonnet et al., 2009). The trial will enlighten omega-3 fatty acid research further. However, more clinical studies are needed to determine effects of omega-3 fatty acids, specifically DHA, on apoE4-genotype obese-diabetic patients who are at highest risk of developing AD. DHA’s biochemical nature presents strong evidence that it will affect the elderly subjects and apoE4-genotype obese-diabetic patients positively.
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Posner, H. B., Tang, M. X., Luchsinger, J., Lantigua, R., Stern, Y., & Mayeux, R. (2002). The relationship of hypertension in the elderly to AD, vascular dementia, and cognitive function. Neurology, 58, 1175-1181.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Qiu, W. Q. & Folstein, M. F. (2006). Insulin, insulin-degrading enzyme and amyloid-beta peptide in Alzheimer's disease: review and hypothesis. Neurobiol.Aging, 27, 190-198.
Razay, G., Vreugdenhil, A., & Wilcock, G. (2006). Obesity, abdominal obesity and Alzheimer disease. Dement.Geriatr.Cogn Disord., 22, 173-176.
Riserus, U. (2008). Fatty acids and insulin sensitivity. Curr.Opin.Clin Nutr Metab Care, 11, 100-105.
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Salihu, H. M., Bonnema, S. M., & Alio, A. P. (2009). Obesity: What is an elderly population growing into? Maturitas, 63, 7-12.
Sasaki, N., Fukatsu, R., Tsuzuki, K., Hayashi, Y., Yoshida, T., Fujii, N. et al. (1998). Advanced glycation end products in Alzheimer's disease and other neurodegenerative diseases. Am J Pathol., 153, 1149-1155.
Sato, T., Shimogaito, N., Wu, X., Kikuchi, S., Yamagishi, S., & Takeuchi, M. (2006). Toxic advanced glycation end products (TAGE) theory in Alzheimer's disease. Am J Alzheimers.Dis.Other Demen., 21, 197-208.
Scarmeas, N., Brandt, J., Albert, M., Devanand, D. P., Marder, K., Bell, K. et al. (2002). Association between the APOE genotype and psychopathologic symptoms in Alzheimer's disease. Neurology, 58, 1182-1188.
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02 September 2009
29 August 2009
Iron in Summary
Humans contain about 2-4g iron of which most is in hemoglobin and to a lesser extent myoglobin. Iron from diet is found in heme (animal foods) and nonheme (plant foods) forms. The heme iron needs to be hydrolyzed where as the nonheme is enzymatically freed.
Heme iron is absorbed intact accross the brushborder of the enterocyte whereas nonheme iron is released as ferric in the stomach, which may be reduced to ferrous. The ferric is absorbed across brush border by binding to transporters and the ferrous facilitated by chelators and membrane proteins.Chelators inhibit or enhance absorption of iron. Absorption is also regulated by hepcidin and ferroportin. Other iron-absorption enhancers are sugars, acids, animal meat, and mucin. Other inhibitors are polyphenols, oxalates, phytates, phosvitin and some minerals.Iron is stored in the liver, bone marrow and spleen. Uptake into tissues depends on transferrin.
Iron needs depend on its loss such as through menstrual losses and dietary intake. Deficiency mainly can affect infants and children, teenagers, menstruating females and pregnant women (whose iron needs expand due to increased blood volume). Iron deficiency can develop gradually into anemia. Toxicity may occur due to taking too much iron in supplements or if one has a genetic disorder called hemochromatosis. In the case of hemochromatosis, which is most prevalent among caucasian males, a diet with limited meat intake may be necessary.
Heme iron is absorbed intact accross the brushborder of the enterocyte whereas nonheme iron is released as ferric in the stomach, which may be reduced to ferrous. The ferric is absorbed across brush border by binding to transporters and the ferrous facilitated by chelators and membrane proteins.Chelators inhibit or enhance absorption of iron. Absorption is also regulated by hepcidin and ferroportin. Other iron-absorption enhancers are sugars, acids, animal meat, and mucin. Other inhibitors are polyphenols, oxalates, phytates, phosvitin and some minerals.Iron is stored in the liver, bone marrow and spleen. Uptake into tissues depends on transferrin.
Iron needs depend on its loss such as through menstrual losses and dietary intake. Deficiency mainly can affect infants and children, teenagers, menstruating females and pregnant women (whose iron needs expand due to increased blood volume). Iron deficiency can develop gradually into anemia. Toxicity may occur due to taking too much iron in supplements or if one has a genetic disorder called hemochromatosis. In the case of hemochromatosis, which is most prevalent among caucasian males, a diet with limited meat intake may be necessary.
28 August 2009
Copper-zinc
A mineral supplement I've taken in the past includes 10mg zinc and 1mg of copper. Thus, the amount of zinc is not at the "higher than 50mg" level that can cause a copper deficiency because of interference with bioavailability (1). This is exactly the 10:1 ratio as suggested to avoid any copper deficiency (2). Someone did his/her homework.
1. http://lpi.oregonstate.edu/infocenter/minerals/zinc/
2. http://www.pccnaturalmarkets.com/health/2934002/
1. http://lpi.oregonstate.edu/infocenter/minerals/zinc/
2. http://www.pccnaturalmarkets.com/health/2934002/
Top zinc-rich foods I eat frequently
1 chicken drumstick, broilers or fryers, meat and skin, cooked, roasted = 2.98mg
3 Eggs, whole, cooked, scrambled = 1.83mg
1 burrito, bean and cheese, microwaved = 1.33mg
1 cup milk, whole, 3.25% milkfat = .98mg
1 fish fillet, trout, rainbow, farmed = .32mg
Data found at: http://www.nal.usda.gov/fnic/foodcomp/
Zinc and copper not effective for acute diarrhea
Purpose of study: Zinc and copper are lost in significant amounts in acute diarrhea and zinc has been suggested as a therapy for its possible facilitation of water and electrolyte transport across intestinal mucosa to prevent villous atrophy and modulate immune response. This study evaluated whether or not zinc and copper supplementation had any beneficial effect on acute watery or bloody diarrhea when given with standard treatment.
Type of study: Randomized, double-blinded placebo-controlled trial
Method used to conduct study: Children ages 6-59 months with acute diarrhea were given standard treatment and randomized to placebo, zinc only (Zn 20mg/5ml elemental zinc), or zinc and copper (2mg/5ml of elemental copper) together via syrup. There were 808 children chosen for the study out of 1,200 screened over the period of Aug 2003 and Oct 2006. Each provided more than three stool samples in prior 24 hours, who had duration of diarrhea for up to 72 hours and who were able to orally accept fluid or food. Exclusions were those with positive HIV, kwashiorkor or participating in another study.
Summary: There was no observed impact on duration or total stool output in acute diarrhea found between the groups supplemented with zinc only, zinc and copper, or placebo. No serious adverse events were associated with the three syrups. Critique: Measures were taken in this study to ensure quality control and appropriate data analysis and interpretation. The quality of the study make its results valid given the amount of subjects and assessment of the data.
Nutritional implications and implications of future study: The researchers offered that the lack of effect would not have been due to low dose, poor adherence to treatment or failure to replenish zinc loss. They did offer that extent of zinc deficiency in study populations could be why other studies showed therapeutic benefits from zinc, but that not all therapeutic studies reported benefits of zinc in children with deficiency. Therapeutic supplementation with zinc may, in fact, depend on diarrhea etiology at different ages in populations. There may also have been interaction with zinc and the standard treatment, which included a multivitamin with vitamin A and B vitamins. Future study may need to evaluate zinc supplementation with different etiologies for diarrhea and separately with regards to multivitamin interaction.
Reference: Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Med 2009;7:22. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19416499
Type of study: Randomized, double-blinded placebo-controlled trial
Method used to conduct study: Children ages 6-59 months with acute diarrhea were given standard treatment and randomized to placebo, zinc only (Zn 20mg/5ml elemental zinc), or zinc and copper (2mg/5ml of elemental copper) together via syrup. There were 808 children chosen for the study out of 1,200 screened over the period of Aug 2003 and Oct 2006. Each provided more than three stool samples in prior 24 hours, who had duration of diarrhea for up to 72 hours and who were able to orally accept fluid or food. Exclusions were those with positive HIV, kwashiorkor or participating in another study.
Summary: There was no observed impact on duration or total stool output in acute diarrhea found between the groups supplemented with zinc only, zinc and copper, or placebo. No serious adverse events were associated with the three syrups. Critique: Measures were taken in this study to ensure quality control and appropriate data analysis and interpretation. The quality of the study make its results valid given the amount of subjects and assessment of the data.
Nutritional implications and implications of future study: The researchers offered that the lack of effect would not have been due to low dose, poor adherence to treatment or failure to replenish zinc loss. They did offer that extent of zinc deficiency in study populations could be why other studies showed therapeutic benefits from zinc, but that not all therapeutic studies reported benefits of zinc in children with deficiency. Therapeutic supplementation with zinc may, in fact, depend on diarrhea etiology at different ages in populations. There may also have been interaction with zinc and the standard treatment, which included a multivitamin with vitamin A and B vitamins. Future study may need to evaluate zinc supplementation with different etiologies for diarrhea and separately with regards to multivitamin interaction.
Reference: Patel A, Dibley MJ, Mamtani M, Badhoniya N, Kulkarni H. Zinc and copper supplementation in acute diarrhea in children: a double-blind randomized controlled trial. BMC Med 2009;7:22. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19416499
23 August 2009
Armour Thyroid vs Synthroid
Armour thyroid is the "natural" therapy from dessicated porcine thyroid gland while Synthroid is produced synthetically as levothyroxine. Armour thyroid contains both T3 and T4 while Synthroid only contains T4. There is debate on whether or not use of both or one is better. Synthroid came into use because it was standardized unlike the natural kind, which varied a lot from batch to batch. But it turns out that patients often don't like T4 alone as much as the natural T3/T4. A new synthetic T3/T4 is now on the market as Liotrix, but is expensive.
Reference
http://www.netwellness.uc.edu/question.cfm/24516.htm
What Controls Basal Metabolic Rate
To regulate basal metabolic rate, the thyroid gland synthesizes hormones thyroxine, or triiodo-L-thyronine (T4), and the more active triiodo-L-tyronine (T3) (1).When secreted into the bloodstream, they associate with transport proteins (thyroxine-binding globulin, albumin, and transthyretin), which circulate the hormones (2). There is nearly 50 times T4 than there is T3, but T3 is more potent. T4 and T3 bind to nuclear receptors that affect gene expression. Increased mRNA and protein synthesis appear to lead to stimulation of oxygen consumption (when awake, at rest or fasting), heat production and also influences enzymes involved in carbohydrate metabolism (3;4).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Pereira BM, Balasubramanian K, Govindarajulu P. Effect of thyroxine treatment on epididymal carbohydrate metabolism in the pubertal rat. Int J Androl 1983;6:283-93.
4. Hashimoto K, Ishida E, Matsumoto S et al. Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 2009;150:3417-24.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Pereira BM, Balasubramanian K, Govindarajulu P. Effect of thyroxine treatment on epididymal carbohydrate metabolism in the pubertal rat. Int J Androl 1983;6:283-93.
4. Hashimoto K, Ishida E, Matsumoto S et al. Carbohydrate response element binding protein gene expression is positively regulated by thyroid hormone. Endocrinology 2009;150:3417-24.
Iron Deficiency Symptoms
As iron deficiency develops gradually without anemia, symptoms can appear that can include pallor and problems of behavior, cognition, learning and attention span. These can particularly manifest themselves in children. Adults may witness problems related to work performance and productivity.
The effects may be related to impairment of the neurotransmitter gamma-aminobutyric acid (GABA) used to inhibit dopamine production in the brain and/or immune system impairment leading to more susceptibility to infection and inability to keep a normal body temperature.
The first stages of iron deficiency result in diminished liver, spleen and bone marrow iron stores and decreased plasma ferritin. Second stages begin when stores are low and iron transport decreases. Transferrin saturation decreases, which increases total iron-binding capacity, and there is limited iron for function in hemoglobin. This leads to a rise in protoporphyrin, the precursor to heme in hemoglobin. Finally, the anemia occurs.
Reference
Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009, pp. 485-87.
The effects may be related to impairment of the neurotransmitter gamma-aminobutyric acid (GABA) used to inhibit dopamine production in the brain and/or immune system impairment leading to more susceptibility to infection and inability to keep a normal body temperature.
The first stages of iron deficiency result in diminished liver, spleen and bone marrow iron stores and decreased plasma ferritin. Second stages begin when stores are low and iron transport decreases. Transferrin saturation decreases, which increases total iron-binding capacity, and there is limited iron for function in hemoglobin. This leads to a rise in protoporphyrin, the precursor to heme in hemoglobin. Finally, the anemia occurs.
Reference
Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009, pp. 485-87.
22 August 2009
Hemochromatosis a Neolithic adaptation?
Hemochromatosis is a genetic disorder caused by one of several mutations related to double-than-normal iron absorption, which increases susceptibility to iron overload (1). Although the disorder affects about one in 200 in the U.S., it’s still largely unrecognized and can lead to deposits in organs—such as the liver—leading to organ damage and failure if not treated early enough (2-4).
Because the disorder is most prevalent in males of Northern European ancestry, particularly Celtic (5), it was hypothesized as recently as 2007 to be a possible Neolithic adaptation (6). The Neolithic period marked an early European dietary transition from high intake of meat to cereal grains (6).
Whether or not this hypothesis is correct, the state of the disorder suggests potential dietary management through eating primarily vegetarian foods such as the one eaten during the time of these early ancestors—cereal grains, little red meat, and limited vitamin C intake. This low-iron diet to prevent to iron overload, according to the Hemochromatosis Management Working Group, can help to “decrease the frequency and severity of iron overload,” thereby preventing many of the detrimental effects of the disorder (4).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Borgaonkar MR. Hemochromatosis. More common than you think. Can Fam Physician 2003;49:36-43.
3. Dolbey CH. Hemochromatosis: a review. Clin J Oncol Nurs 2001;5:257-60.
4. Barton JC, McDonnell SM, Adams PC et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998;129:932-9.
5. Pozzato G, Zorat F, Nascimben F et al. Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry. Eur J Hum Genet 2001;9:445-51.
6. Naugler C. Hemochromatosis: a Neolithic adaptation to cereal grain diets. Med Hypotheses 2008;70:691-2.
Because the disorder is most prevalent in males of Northern European ancestry, particularly Celtic (5), it was hypothesized as recently as 2007 to be a possible Neolithic adaptation (6). The Neolithic period marked an early European dietary transition from high intake of meat to cereal grains (6).
Whether or not this hypothesis is correct, the state of the disorder suggests potential dietary management through eating primarily vegetarian foods such as the one eaten during the time of these early ancestors—cereal grains, little red meat, and limited vitamin C intake. This low-iron diet to prevent to iron overload, according to the Hemochromatosis Management Working Group, can help to “decrease the frequency and severity of iron overload,” thereby preventing many of the detrimental effects of the disorder (4).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Borgaonkar MR. Hemochromatosis. More common than you think. Can Fam Physician 2003;49:36-43.
3. Dolbey CH. Hemochromatosis: a review. Clin J Oncol Nurs 2001;5:257-60.
4. Barton JC, McDonnell SM, Adams PC et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998;129:932-9.
5. Pozzato G, Zorat F, Nascimben F et al. Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry. Eur J Hum Genet 2001;9:445-51.
6. Naugler C. Hemochromatosis: a Neolithic adaptation to cereal grain diets. Med Hypotheses 2008;70:691-2.
16 August 2009
Korsakoff syndrome
Korsakoff’s syndrome, or Wernicke encephalopathy, is a serious neurological disorder occurring under conditions of thiamine deficiency. It’s usually caused by long-term abuse of alcohol, which breaks down thiamine in the body. It is characterized at autopsy by lesions in the brain stem.
Thiamine is necessary for proper glucose metabolism in the brain (1). As a B vitamin it acts as a cofactor for enzymes in the Krebs cycle including pyruvate dehydrogenase. Brain insults result when metabolism is inhibited, particularly where there is high demand for energy.
A cascade of injury to the brain occurs when neuronal death reduces production of succinate and GABA as well as neuron stimulation. Without functioning pyruvate dehydrogenase, lactic acid production increases. Nucleotide synthesis and NADPH production is reduced, which in turn reduces glutathione in blood cells.
Individuals carrying apolipoprotein E (ApoE) epsilon 4 (E4) allele are at higher risk of Korsakoff’s syndrome (2). Thus, the ApoE4 genotype is associated with higher risk of Alzheimer’s disease may also be at higher risk of “alcoholic dementia”. These apolipoproteins are protein moietys of a lipoprotein, which transport lipids in the blood.
Reference List
1. Salan, PN. Emedicine from WebMD. Wernicke Encephalopathy. 2009. Available at: http://emedicine.medscape.com/article/794583-overview.
2. Muramatsu T, Kato M, Matsui T et al. Apolipoprotein E epsilon 4 allele distribution in Wernicke-Korsakoff syndrome with or without global intellectual deficits. J Neural Transm 1997;104:913-20.3.
Thiamine is necessary for proper glucose metabolism in the brain (1). As a B vitamin it acts as a cofactor for enzymes in the Krebs cycle including pyruvate dehydrogenase. Brain insults result when metabolism is inhibited, particularly where there is high demand for energy.
A cascade of injury to the brain occurs when neuronal death reduces production of succinate and GABA as well as neuron stimulation. Without functioning pyruvate dehydrogenase, lactic acid production increases. Nucleotide synthesis and NADPH production is reduced, which in turn reduces glutathione in blood cells.
Individuals carrying apolipoprotein E (ApoE) epsilon 4 (E4) allele are at higher risk of Korsakoff’s syndrome (2). Thus, the ApoE4 genotype is associated with higher risk of Alzheimer’s disease may also be at higher risk of “alcoholic dementia”. These apolipoproteins are protein moietys of a lipoprotein, which transport lipids in the blood.
Reference List
1. Salan, PN. Emedicine from WebMD. Wernicke Encephalopathy. 2009. Available at: http://emedicine.medscape.com/article/794583-overview.
2. Muramatsu T, Kato M, Matsui T et al. Apolipoprotein E epsilon 4 allele distribution in Wernicke-Korsakoff syndrome with or without global intellectual deficits. J Neural Transm 1997;104:913-20.3.
Diabetes: Women and Men
Type 2 diabetes mellitus is considered a major risk factor in cardiovascular disease (CVD) in both men and women, but CVD pathogenesis biochemistry can differ between the sexes.
Both sexes are affected by insulin resistance, which generally precedes the diabetes, and accompanying metabolic syndrome factors dyslipidemia and hypertension (1). The insulin resistance leads to elevated insulin levels, which stimulates sodium reabsorption. The sodium levels can induce prolonged hypertension. The hypertension leads to hardening of the arteries and eventual atherosclerosis. The chronic hyperglycemia leads to glycation of myocardial proteins and microvascular disease (1;2). Gradual nerve damage from abnormal signaling leads to autonomic neuropathy (2).
Although women have overall lower risk of heart disease than men before age 60 due in part because of estrogen, diabetes abolishes difference in CVD risk. In fact, diabetes in women is reported to increase risk of CVD three- to seven-fold whereas in men it increases risk two- to three-fold (3).
Diabetes is thought to affect women uniquely because of hormonal status. Diabetes appears to cancel benefits of estrogen, which “may be lost or hidden by diabetes” (3). With reduced estrogen, other CVD risk factors come into play in a pre-menopausal women just as it would for post-menopausal women (3).
Reference List
1. Grundy SM. Cardiovascular and metabolic risk factors: how can we improve outcomes in the high-risk patient? Am J Med 2007;120:S3-S8.
2. Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-46.
3. Bolego C, Cignarella A, Zancan V, Pinna C, Zanardo R, Puglisi L. Diabetes abolishes the vascular protective effects of estrogen in female rats. Life Sci 1999;64:741-9.
Post-menopausal estrogen therapy
Menopause is the eventual reduced production of sex hormones in women. Follicular cells in the ovaries appear to become exhausted by continual cycles of ovulation and atresia (1). The ovaries become less responsive to stimulation from gonadotropin—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—causing estrogens and progesterone levels to lower. The ovaries degenerate causing further diminished estrogen production until the hormone is only produced in limited amounts by other tissues (1).
The loss of estrogens production also reduces cardioprotective effects of this particular hormone. Estrogens, estradiol in particular, protects cardiovascular health because of its binding to estrogen receptors (ERs). ERs in absence of estrogen are associated with heat shock protein (HSP); estrogen binding promotes dissociation (2). Estrogen binding also changes gene transcription, altering levels and kinds of cellular proteins (2). The alterations directly affect myocardial, vascular smooth muscle and endothelial cells.
In vascular smooth muscle cells, estradiol has vasodilatory effects and functions in contractibility and growth. Its mechanisms may be related to effects on calcium channel currents, increases of Ca2+ and/or activation of K channels (2). In effect, estradiol leads to increased secretion of NO and cGMP production (2). These are thought to be estradiol’s primary antiatherogenic actions, although other mechanisms may exist such as promotion of endothelial cell regeneration and angiogenesis.
Because estrogen has been found to reduce risk of cardiovascular disease in postmenopausal women, future research on estrogen therapy is merited. Side risks involved, however, may be too serious for estrogen to be prescribed at this time.
Authors who analyzed Women’s Health Initiative (WHI) randomized trials from 1993-2004 on use of conjugated equine estrogens found that death from other hazards such as breast cancer did not favor use of estrogen therapy (3;4). Critics suggest that prescribers of estrogen therapy should have waited WHI results to have avoided cases of breast cancer (3). WHI trials, in fact, also found that hormone therapy, unfortunately, did little to reduce risk of coronary heart disease suggesting that more research is needed (5). The WHI data are related to both pre-menopause and post-menopause therapies with estrogen (4).
Reference List
1. Cohn RM, Roth KS. Biochemistry of Disease: Bridging Basic Science and Clinical Practice. Baltimore: Williams & Wilkins, 1996.
2. Skafar DF, Xu R, Morales J, Ram J, Sowers JR. Clinical review 91: Female sex hormones and cardiovascular disease in women. J Clin Endocrinol Metab 1997;82:3913-8. Available at: http://jcem.endojournals.org/cgi/content/full/82/12/3913
3. Postmenopausal hormone therapy and breast cancer. Prescrire Int 2009;18:66-7.
4. Prentice RL, Manson JE, Langer RD et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23.
5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.
Potassium Guards Against Sodium-induced Bone Loss
Reference: Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab 2002;87:2008-12. Available at: http://jcem.endojournals.org/cgi/content/full/87/5/2008?ijkey=b46c2855f83d19e380eb6674c66c94e884ed56a0
Purpose of study: To study effects of dietary potassium citrate added to diets high in sodium, as commonly found in industrialized nations, in postmenopausal women. Postmenopausal women are at higher risk of osteoporosis, especially if consuming a high-sodium diet.
Type of study: Randomized, double-blinded placebo-controlled trial
Method used to conduct study: After three weeks in which 60 post-menopausal women adhered to a low-salt diet, they were provided sodium chloride pills, salt packets (for sprinking on food) and one cup of bouillon per day. They were randomized and either take potassium citrate (90 mmol/d) or placebo. Twenty-four-hour urine samples were analyzed to determine compliance after 12 days. When compliance was compromised, subjects were contacted to enforce regimen. After four weeks, urine samples and fasting blood samples were collected. Fifty two of the women completed seven-week study of which 26 had taken placebo and 26 potassium citrate. Exclusions at the beginning of the study included women who were less than 2 years past menopause, on bone metabolism medications or who had past history of bone disease.
Summary: Calcium excretion increased by 42+-12 mg/d (33%) from low-salt to high-salt diet in the women on placebo. Calcium excretion decreased by 8+- 14mg (4%) in women on potassium citrate. The results suggest that potassium citrate prevented bone resorption in response to salt increase in the diet.
The method is thought to be the natriuretic and chloruretic effects of potassium alkaline salts. These potentially reduce extracellular volume expansion associated with higher salt intake. The alkaline salts also reduce endogenous acid, increase blood pH and bicarbonate. Calcium excretion in the urine can change depending on acid production.
Critique: Examining effects of potassium through a placebo-controlled trial goes far to point out the intracellular cations biological effects on calcium excretion. The results are significant. The researchers took appropriate measures in assuring that the postmenopausal women were compliant in their diets. A seven-week study, however, may not be long enough to determine whether or not potassium citrate will make a significant difference in reducing risk of bone loss and hip fracture.
Nutritional implications and implications of future study: Post-menopausal women at risk for osteoporosis, especially who eat a high-sodium diet, should consider increases of dietary sources of potassium, which are mainly fruits and vegetables. For the benefit of post-menopausal women who may dislike fruits and vegetables and eat mainly processed foods, it may be wise to add potassium to these processed foods. Similar trials should be conducted to determine effects of potassium-added, high-sodium processed foods.
Purpose of study: To study effects of dietary potassium citrate added to diets high in sodium, as commonly found in industrialized nations, in postmenopausal women. Postmenopausal women are at higher risk of osteoporosis, especially if consuming a high-sodium diet.
Type of study: Randomized, double-blinded placebo-controlled trial
Method used to conduct study: After three weeks in which 60 post-menopausal women adhered to a low-salt diet, they were provided sodium chloride pills, salt packets (for sprinking on food) and one cup of bouillon per day. They were randomized and either take potassium citrate (90 mmol/d) or placebo. Twenty-four-hour urine samples were analyzed to determine compliance after 12 days. When compliance was compromised, subjects were contacted to enforce regimen. After four weeks, urine samples and fasting blood samples were collected. Fifty two of the women completed seven-week study of which 26 had taken placebo and 26 potassium citrate. Exclusions at the beginning of the study included women who were less than 2 years past menopause, on bone metabolism medications or who had past history of bone disease.
Summary: Calcium excretion increased by 42+-12 mg/d (33%) from low-salt to high-salt diet in the women on placebo. Calcium excretion decreased by 8+- 14mg (4%) in women on potassium citrate. The results suggest that potassium citrate prevented bone resorption in response to salt increase in the diet.
The method is thought to be the natriuretic and chloruretic effects of potassium alkaline salts. These potentially reduce extracellular volume expansion associated with higher salt intake. The alkaline salts also reduce endogenous acid, increase blood pH and bicarbonate. Calcium excretion in the urine can change depending on acid production.
Critique: Examining effects of potassium through a placebo-controlled trial goes far to point out the intracellular cations biological effects on calcium excretion. The results are significant. The researchers took appropriate measures in assuring that the postmenopausal women were compliant in their diets. A seven-week study, however, may not be long enough to determine whether or not potassium citrate will make a significant difference in reducing risk of bone loss and hip fracture.
Nutritional implications and implications of future study: Post-menopausal women at risk for osteoporosis, especially who eat a high-sodium diet, should consider increases of dietary sources of potassium, which are mainly fruits and vegetables. For the benefit of post-menopausal women who may dislike fruits and vegetables and eat mainly processed foods, it may be wise to add potassium to these processed foods. Similar trials should be conducted to determine effects of potassium-added, high-sodium processed foods.
15 August 2009
Why Gatorade May Not Rehydrate You Any Faster Than Water
Research Summary Critique
Reference: Jeukendrup AE, Currell K, Clarke J, Cole J, Blannin AK. Effect of beverage glucose and sodium content on fluid delivery. Nutr Metab (Lond) 2009;6:9. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19232115
Purpose of study: The objective of many oral rehydration drinks is rapid fluid delivery to correct fluid balance in sports. This study investigated carbohydrate (CHO) and sodium (Na) effects on fluid delivery with a deuterium oxide (D20) tracer.
Previous research suggests Na concentration may increase delivery, but that CHO content is more important factor.
Type of study: Equivalence trial of eight different solutions.
Method used to conduct study: Two groups of 10 male subjects (ages 20 +- 1 y, weight: 81.2 +-7.5kg) were split into a CHO or NA group. The CHO group ingested four drinks, each with 20 mmol/L sodium, and with a stepped increase of 3% glucose from 0-9%. The Na group ingested four drinks, each with 6% glucose, with a stepped increase of 20 mmol/L from 0 mmol/L to 60 mmol/L. All drinks contained 3g of D20.
Each trial was performed in laboratory after overnight fast (7-9a.m.) and emptying of bladder. After ingesting drink, blood was taken every five minutes in the first hour and every 10 minutes in the second hour. Plasma D20 was analysed using isotope ratio mass spectrometry.
Summary: CHO concentration at 3% increased fluid delivery in comparison to 0%. Concentration above 6% led to fluid delivery that was slower than 0% and 3%. Sodium concentration in any amount did not show any increase in intestinal water absorption.
Critique: The researchers acknowledge that the investigation, which used the “triple lumen technique”, takes into account a section of the small intestine, but not gastric emptying. It may not represent total fluid availability in the body. However, D20 is useful to provide an integrative measure of gastric emptying and intestinal fluid absorption.
Nutritional implications and implications of future study: Because the study’s findings are that added sodium to oral rehydration drinks (sport drinks) has no effect on fluid delivery, it may change the way consumers choose these beverages. Sodium addition may not be preferred or it may still be for other reasons unrelated to fluid delivery such as for possible electrolyte replacement.
10 August 2009
Boost brain health by living like an Indian
Getting plenty of sun and eating curry are integral parts of Indian culture. Now scientists have found that this combination also helps guard against Alzheimer's disease.
The biochemical mechanism by which the combination works is through immune system macrophages (1). Vitamin D was found to stimulate type I and II macrophages to break down and clear beta-amyloid plaques through genomic pathways. Curcuminoids, specifically bisdemethoxycurcumin, assisted with stimulating type 1 macrophages through non-geneomic pathways.
Immune therapies to clear beta-amyloid plaque are a new approach that health scientists hope will assist in prevention and treatment of AD.
Because vitamin D and curcumin work in different ways biochemically, both may be used in therapy for most promising effects.
Apart from hereditary implications, obesity, diabetes and hypertension are all risk factors in AD. Other promising dietary interventions are caloric reduction, antioxidant intake from fruits and vegetables, and increased intake of fish-derived omega-3 fatty acids.
Reference List
1. Masoumi A, Goldenson B, Ghirmai S et al. 1alpha,25-dihydroxyvitamin D_3 Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis 2009.
See Nutraingredients release.
The biochemical mechanism by which the combination works is through immune system macrophages (1). Vitamin D was found to stimulate type I and II macrophages to break down and clear beta-amyloid plaques through genomic pathways. Curcuminoids, specifically bisdemethoxycurcumin, assisted with stimulating type 1 macrophages through non-geneomic pathways.
Immune therapies to clear beta-amyloid plaque are a new approach that health scientists hope will assist in prevention and treatment of AD.
Because vitamin D and curcumin work in different ways biochemically, both may be used in therapy for most promising effects.
Apart from hereditary implications, obesity, diabetes and hypertension are all risk factors in AD. Other promising dietary interventions are caloric reduction, antioxidant intake from fruits and vegetables, and increased intake of fish-derived omega-3 fatty acids.
Reference List
1. Masoumi A, Goldenson B, Ghirmai S et al. 1alpha,25-dihydroxyvitamin D_3 Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis 2009.
See Nutraingredients release.
08 August 2009
Biochemistry of Metabolic Syndrome
Connecting the biochemical dots that lead to atherosclerosis is what is best attempted by the term metabolic syndrome (MS) (1). The term, of which is still under controversy, is used as a predictor of cardiovascular disease and type 2 diabetes mellitus (2-4).
MS can begin with abdominal obesity (MS dot 1), a consequence of overeating and a sedentary lifestyle (1;5). The additional adipose tissue can then reduce affinity of insulin receptors and/or create abnormal post-receptor responses resulting in insulin resistance (MS dot 2) (1).
Once insulin resistance overwhelms capacity to produce insulin to overcome it, then type 2 diabetes mellitus (T2DM) ensues (1). T2DM is accompanied by hyperglycemia and often by hyperlipidemia (MS dot 3) (1). The hyperlipidemia results because VLDL and chylomicrons are not cleared by the enzyme lipoprotein lipase of which is dependent on insulin (1). The high levels of free fatty acids then impair insulin action further (1). Plus, new research suggests that reduced secreition of adiponectin along with tumor necrosis factor alpha (TNFa) and a protein called resistin act to impair insulin receptor function (1). Poorly controlled glucose levels is then found along with hyperinsulinemia in cases (1).
Finally, the insulin resistance and hyperinsulinemia can stimulate salt reabsorption in the kidneys causing hypertension (MS dot 4) (5). Hypertension, or elevated blood pressure, and its force on artery walls makes them vulnerable to plaque build-up and narrowing that can ultimately lead to hardening of the arteries or atherosclerosis (6).
Clinically, the knowledge of progressing events in MS is what allows it to serve a valid purpose with patients (5;7). A doctor or nutritionist, for example, can use MS awareness to predict future risk factors and assist in treating obese patients with lower-calorie diet and other methods.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Lau DC. Metabolic syndrome: perception or reality? Curr Atheroscler Rep 2009;11:264-71.
3. Lien LF, Guyton JR. Metabolic syndrome. Dermatol Ther 2008;21:362-75.
4. Gallagher EJ, LeRoith D, Karnieli E. The metabolic syndrome--from insulin resistance to obesity and diabetes. Endocrinol Metab Clin North Am 2008;37:559-79, vii.
5. Ren J, Kelley RO. Cardiac health in women with metabolic syndrome: clinical aspects and pathophysiology. Obesity (Silver Spring) 2009;17:1114-23.
6. Takeuchi K. [Hypertension and metabolic syndrome/lifestyle diseases]. Rinsho Byori 2007;55:452-6.
7. de ZD, Bakker SJ. Does the metabolic syndrome add to the diagnosis and treatment of cardiovascular disease? Nat Clin Pract Cardiovasc Med 2008;5 Suppl 1:S10-S14.
MS can begin with abdominal obesity (MS dot 1), a consequence of overeating and a sedentary lifestyle (1;5). The additional adipose tissue can then reduce affinity of insulin receptors and/or create abnormal post-receptor responses resulting in insulin resistance (MS dot 2) (1).
Once insulin resistance overwhelms capacity to produce insulin to overcome it, then type 2 diabetes mellitus (T2DM) ensues (1). T2DM is accompanied by hyperglycemia and often by hyperlipidemia (MS dot 3) (1). The hyperlipidemia results because VLDL and chylomicrons are not cleared by the enzyme lipoprotein lipase of which is dependent on insulin (1). The high levels of free fatty acids then impair insulin action further (1). Plus, new research suggests that reduced secreition of adiponectin along with tumor necrosis factor alpha (TNFa) and a protein called resistin act to impair insulin receptor function (1). Poorly controlled glucose levels is then found along with hyperinsulinemia in cases (1).
Finally, the insulin resistance and hyperinsulinemia can stimulate salt reabsorption in the kidneys causing hypertension (MS dot 4) (5). Hypertension, or elevated blood pressure, and its force on artery walls makes them vulnerable to plaque build-up and narrowing that can ultimately lead to hardening of the arteries or atherosclerosis (6).
Clinically, the knowledge of progressing events in MS is what allows it to serve a valid purpose with patients (5;7). A doctor or nutritionist, for example, can use MS awareness to predict future risk factors and assist in treating obese patients with lower-calorie diet and other methods.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Lau DC. Metabolic syndrome: perception or reality? Curr Atheroscler Rep 2009;11:264-71.
3. Lien LF, Guyton JR. Metabolic syndrome. Dermatol Ther 2008;21:362-75.
4. Gallagher EJ, LeRoith D, Karnieli E. The metabolic syndrome--from insulin resistance to obesity and diabetes. Endocrinol Metab Clin North Am 2008;37:559-79, vii.
5. Ren J, Kelley RO. Cardiac health in women with metabolic syndrome: clinical aspects and pathophysiology. Obesity (Silver Spring) 2009;17:1114-23.
6. Takeuchi K. [Hypertension and metabolic syndrome/lifestyle diseases]. Rinsho Byori 2007;55:452-6.
7. de ZD, Bakker SJ. Does the metabolic syndrome add to the diagnosis and treatment of cardiovascular disease? Nat Clin Pract Cardiovasc Med 2008;5 Suppl 1:S10-S14.
Glycosylated Hemoglobin to Detect Diabetes
Glycosylated hemoglobin forms when prolonged hyperglycemia leads to glucose in the blood not used for energy to attach itself to hemoglobin (1;2). The reaction does not require an enzyme, but occurs spontaneously (1).
The concentration of glycosylated hemoglobin determined by an assay can be used to determine the status of a diabetic patient and effectiveness of treatment (1;2). The glycosylated hemoglobin assay has been found to be a more effective tests than others such as the oral glucose tolerance test for the detection of diabetes (3).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4.
2. Diabetes and Hormone Center of the Pacific. Glycosylated hemoglobin testing. Available at: http://www.endocrinologist.com/Hemoglobin.htm
3. Dods RF, Bolmey C. Glycosylated Hemoglobin Assay and Oral Glucose Tolerance Test Compared for Detection of Diabetes Mellitus. Clin Chem 25/5, 764-768, 1979. Available at: http://www.clinchem.org/cgi/reprint/25/5/764
Metabolic Syndrome and Physicians
Despite controversy over the current definition of "metabolic syndrome", physicians are using it as a useful clinical tool. It can be used to help with counseling patients and to recommend treatments.
Metabolic syndrome is currently defined as a combination of several risk factors that ultimately lead to diabetes and cardiovascular disease. They include obesity, hypercholesterolemia, hyperlipidemia, hypertension, insulin resistance and inflamation (1).
Each of the several risk factors that makes up metabolic syndrome requires varying treatments, so physicians may find that lumping them together is not useful. In fact, controversy exists on if the term "metabolic syndrome" is even defined correctly (1).
But a 2007 Mayo Clinic meta-analysis found that metabolic syndrome is beginning to find development as a useful clinical tool (2). The review focused on heart disease factors and found that metabolic syndrome increased risk strongly (2).
Reference List
1. Cheng AY, Leiter LA. Metabolic syndrome under fire: weighing in on the truth. Can J Cardiol 2006;22:379-82.
2. Gami AS, Witt BJ, Howard DE et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403-14.
Metabolic syndrome is currently defined as a combination of several risk factors that ultimately lead to diabetes and cardiovascular disease. They include obesity, hypercholesterolemia, hyperlipidemia, hypertension, insulin resistance and inflamation (1).
Each of the several risk factors that makes up metabolic syndrome requires varying treatments, so physicians may find that lumping them together is not useful. In fact, controversy exists on if the term "metabolic syndrome" is even defined correctly (1).
But a 2007 Mayo Clinic meta-analysis found that metabolic syndrome is beginning to find development as a useful clinical tool (2). The review focused on heart disease factors and found that metabolic syndrome increased risk strongly (2).
Reference List
1. Cheng AY, Leiter LA. Metabolic syndrome under fire: weighing in on the truth. Can J Cardiol 2006;22:379-82.
2. Gami AS, Witt BJ, Howard DE et al. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007;49:403-14.
Personal magnesium intake
These are the foods I eat on a daily basis with highest magnesium intake:
Mixed Nuts - 308 mg per cup
Spinach - 150mg per cup
Yerba Mate - 90mg per cup
Chocolate Soymilk - 39mg per cup
Coffee (espresso) - 96mg per 4 oz
Total magnesium: 683mg
Luckily I'm meeting my recommended intake of 400mg per day.
Check your intake here: http://www.nal.usda.gov/fnic/foodcomp/search/
Is High Phosphorus Intake in the U.S. Diet Hazardous?
Controversy arises as to whether or not a high dietary intake of phosphorus is hazardous to health because in the U.S. the typical diet tends to be high in phosphorus and low in calcium (1). But although the need for increasing calcium for bone health has been clearly established, reducing phosphorus to re-balance the calcium:phosphorus ratio has not been shown to have any additional benefits (1;2).
Serum phosphate levels, for example, when high can reduce vitamin D formation in kidneys reducing serum calcium (2). But high phosphorus also appears to reduce urinary calcium indicating a reversal of the prior detriment (2). In addition, the kidney is effective in maintaining normal phosphorus balance by increasing excretion of phosphorus when necessary (1).
At this time no research including at least one controlled trial has not found any adverse effect from a diet high in phosphorus at levels common in the U.S. (1;2). The exception is in those with impaired excretion such as those with kidney dysfunction (2).
It is worth noting that because calcium interferes with phosphorus absorption, a higher calcium diet would lower phosphorus intake naturally (1). And when intake of phosphorus is in the form of phytate—which is plentiful in grains, legumes and nuts—it just might be detrimental because phytate can interfere with absorption of minerals such as calcium (1).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Linus Pauling Institute. Phosphorus. Micronutrient Information Center. Available at: http://lpi.oregonstate.edu/infocenter/minerals/phosphorus/
Calcium with or without vitamin D
Criteria for recommending calcium to a patient should not go without considering a patient’s vitamin D status. Vitamin D status is critical for improving intestinal absorption, for maintaining calcium homeostasis, for promoting reabsorption of calcium in the kidney and is involved in bone mineralization (1;2).
Calcium supplementation along with vitamin D has been subject of at least two randomized controlled trials in Australia. The first performed on 300 elderly women (77+/- 4.6 years) found no short-term benefit as to improving absorption or promoting bone health (3). But another, longer randomized controlled trial evaluated the effects of calcium with or without vitamin D over five years (4). The researchers studied hip bone mineral density and bone turnover in elderly women (ages 70-80) in a sunny climate (4).
Thus, while short-term benefits weren’t found, long-term benefits were, which where likely produced by reduced bone turnover rate over time (3;4). In response to the studies and other research, the Australian and New Zealand Bone and Mineral Society and Osteporosis Australia issued a joint statement explaining that while calcium intake above previously established recommended levels wasn’t likely to help prevent fractures in elderly men and women, the addition of vitamin D in supplements was supported by the evidence (5).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Cashman KD. Calcium and vitamin D. Novartis Found Symp 2007;282:123-38.
3. Zhu K, Bruce D, Austin N, Devine A, Ebeling PR, Prince RL. Randomized controlled trial of the effects of calcium with or without vitamin D on bone structure and bone-related chemistry in elderly women with vitamin D insufficiency. J Bone Miner Res 2008;23:1343-8.
4. Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab 2008;93:743-9.
5. Sanders KM, Nowson CA, Kotowicz MA, Briffa K, Devine A, Reid IR. Calcium and bone health: position statement for the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia and the Endocrine Society of Australia. Med J Aust 2009;190:316-20.
Calcium supplementation along with vitamin D has been subject of at least two randomized controlled trials in Australia. The first performed on 300 elderly women (77+/- 4.6 years) found no short-term benefit as to improving absorption or promoting bone health (3). But another, longer randomized controlled trial evaluated the effects of calcium with or without vitamin D over five years (4). The researchers studied hip bone mineral density and bone turnover in elderly women (ages 70-80) in a sunny climate (4).
Thus, while short-term benefits weren’t found, long-term benefits were, which where likely produced by reduced bone turnover rate over time (3;4). In response to the studies and other research, the Australian and New Zealand Bone and Mineral Society and Osteporosis Australia issued a joint statement explaining that while calcium intake above previously established recommended levels wasn’t likely to help prevent fractures in elderly men and women, the addition of vitamin D in supplements was supported by the evidence (5).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Cashman KD. Calcium and vitamin D. Novartis Found Symp 2007;282:123-38.
3. Zhu K, Bruce D, Austin N, Devine A, Ebeling PR, Prince RL. Randomized controlled trial of the effects of calcium with or without vitamin D on bone structure and bone-related chemistry in elderly women with vitamin D insufficiency. J Bone Miner Res 2008;23:1343-8.
4. Zhu K, Devine A, Dick IM, Wilson SG, Prince RL. Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial. J Clin Endocrinol Metab 2008;93:743-9.
5. Sanders KM, Nowson CA, Kotowicz MA, Briffa K, Devine A, Reid IR. Calcium and bone health: position statement for the Australian and New Zealand Bone and Mineral Society, Osteoporosis Australia and the Endocrine Society of Australia. Med J Aust 2009;190:316-20.
07 August 2009
High-magnesium diet to beat colorectal cancer
At least three cohort studies have been published relating to the possible role of magnesium in reducing risk of colorectal cancer in women.
The first was prospective study from Sweden and reported in JAMA in which researchers found a reduced occurrence of colorectal cancer in women who had a higher dietary intake of magnesium (1).
Hanging on the coat-tails of the Swedish study, U.S. researchers assessed magnesium status of a cohort in Iowa women and found the similar results of reduced risk (2).
The latest was from the Netherlands, which found a few differences from the first two, indicating that there was no significant trend of lowering risk of colorectal cancer except in populations of overweight subjects (3).
According to the latest study, the method by which magnesium has a protective effect is thought to be through decrease of insulin resistance (3). However, as suggested by the U.S. researchers, more observational studies are necessary and, perhaps, clinical trials to assess whether or not the results can be attributed to magnesium or other factors in relation to a high-magnesium diet (2).
Could fiber in green leafy vegetables be a variable? I imagine so.
Reference List
1. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA 2005;293:86-9.
2. Folsom AR, Hong CP. Magnesium intake and reduced risk of colon cancer in a prospective study of women. Am J Epidemiol 2006;163:232-5.
3. van den Brandt PA, Smits KM, Goldbohm RA, Weijenberg MP. Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study. Br J Cancer 2007;96:510-3.
The first was prospective study from Sweden and reported in JAMA in which researchers found a reduced occurrence of colorectal cancer in women who had a higher dietary intake of magnesium (1).
Hanging on the coat-tails of the Swedish study, U.S. researchers assessed magnesium status of a cohort in Iowa women and found the similar results of reduced risk (2).
The latest was from the Netherlands, which found a few differences from the first two, indicating that there was no significant trend of lowering risk of colorectal cancer except in populations of overweight subjects (3).
According to the latest study, the method by which magnesium has a protective effect is thought to be through decrease of insulin resistance (3). However, as suggested by the U.S. researchers, more observational studies are necessary and, perhaps, clinical trials to assess whether or not the results can be attributed to magnesium or other factors in relation to a high-magnesium diet (2).
Could fiber in green leafy vegetables be a variable? I imagine so.
Reference List
1. Larsson SC, Bergkvist L, Wolk A. Magnesium intake in relation to risk of colorectal cancer in women. JAMA 2005;293:86-9.
2. Folsom AR, Hong CP. Magnesium intake and reduced risk of colon cancer in a prospective study of women. Am J Epidemiol 2006;163:232-5.
3. van den Brandt PA, Smits KM, Goldbohm RA, Weijenberg MP. Magnesium intake and colorectal cancer risk in the Netherlands Cohort Study. Br J Cancer 2007;96:510-3.
06 August 2009
Is spinach a good source of magnesium?
Japanese researchers evaluated spinach’s magnesium bioavailability in rats in a study published in 1995 (1). Their conclusions were that spinach was a "one of the most promising" sources of magnesium and that oxalic acid in spinach after cooking (boil or fried) would not affect magnesium bioavailability.
Looking at their data, though, cooking did affect calcium absorption and, of course, oxalic acid had additional effects.
The researchers had divided rats into six groups, which led to this data:
Looking at their data, though, cooking did affect calcium absorption and, of course, oxalic acid had additional effects.
The researchers had divided rats into six groups, which led to this data:
- Mg-deficient diet
o Serum magnesium decrease
o Ca absorption 87.0%
o Increase of calcium and phosphorus in liver and kidneys
o Especially large calcium accumulation in kidneys - Mg-deficient diet supplemented with raw powdered spinach
o Mg absorption 88.9%
o Ca absorption 84.1%
o Large calcium accumulation in kidneys
o Significantly higher liver and kidney Mg and phosphorus - Mg-deficient diet with boiled powdered spinach
o Mg absorption 88.4%
o Ca absorption 57.3%
o Large calcium accumulation in kidneys
o Significantly higher liver and kidney Mg and phosphorus - Mg-deficient diet with powdered fried spinach
o Mg absorption 90.4%
o Ca absorption 66.2%
o Large calcium accumulation in kidneys
o Significantly higher liver and kidney Mg and phosphorus - Control diet with supplemented oxalic acid
o Mg absorption 88.1%
o Ca absorption 53.3%
o Large calcium accumulation in kidneys
o Significant decrease in weight - Control diet
o Mg absorption 87.7%
o Ca absorption 83.5%o
o Significant increase in weight gain in comparison to other groups
Reference List
1. Kikunaga S, Ishii H, Takahashi M. The bioavailability of magnesium in spinach and the effect of oxalic acid on magnesium utilization examined in diets of magnesium-deficient rats. J Nutr Sci Vitaminol (Tokyo) 1995;41:671-85.
05 August 2009
Which exercise should I do to improve calcium status?
We’ve known for awhile that exercise improves bone health, but unsure what effects it has on calcium absorption and loss. There have been recent studies trying to find out more.
Just last April, researchers from San Diego State published a study in which they had investigated urinary calcium excretion in two groups of men—one sedentary and the other on a “high-impact and resistance-exercise program”—in a randomized crossover study of three weeks (1). The active men were found to have “significantly less” urinary calcium loss in comparison to week of restricted activity (1).
But, we should note, an earlier study in 2007 reported that exercise actually increased calcium losses through sweating (2). Quite different than the other study, this one which was evaluating effects of calcium supplementation, came to the conclusion that supplementation should be used to correct the negative calcium balance from dermal loss from exercise (2).
What’s the deal?
While the 2009 study used exercise that was high in impact and resistance, the type of exercise in the 2007 study was cycling, an aerobic exercise not high in impact or high in resistance. One could infer that the type of exercise could have much to do with the type of results researchers get. Could it also be that resistance training has a role in improving calcium absorption and reducing calcium excretion?
Reference List
1. Nemoseck T, Kern M. The effects of high-impact and resistance exercise on urinary calcium excretion. Int J Sport Nutr Exerc Metab 2009;19:162-71. 2. Martin BR, Davis S, Campbell WW, Weaver CM. Exercise and calcium supplementation: effects on calcium homeostasis in sportswomen. Med Sci Sports Exerc 2007;39:1481-6.
Just last April, researchers from San Diego State published a study in which they had investigated urinary calcium excretion in two groups of men—one sedentary and the other on a “high-impact and resistance-exercise program”—in a randomized crossover study of three weeks (1). The active men were found to have “significantly less” urinary calcium loss in comparison to week of restricted activity (1).
But, we should note, an earlier study in 2007 reported that exercise actually increased calcium losses through sweating (2). Quite different than the other study, this one which was evaluating effects of calcium supplementation, came to the conclusion that supplementation should be used to correct the negative calcium balance from dermal loss from exercise (2).
What’s the deal?
While the 2009 study used exercise that was high in impact and resistance, the type of exercise in the 2007 study was cycling, an aerobic exercise not high in impact or high in resistance. One could infer that the type of exercise could have much to do with the type of results researchers get. Could it also be that resistance training has a role in improving calcium absorption and reducing calcium excretion?
Reference List
1. Nemoseck T, Kern M. The effects of high-impact and resistance exercise on urinary calcium excretion. Int J Sport Nutr Exerc Metab 2009;19:162-71. 2. Martin BR, Davis S, Campbell WW, Weaver CM. Exercise and calcium supplementation: effects on calcium homeostasis in sportswomen. Med Sci Sports Exerc 2007;39:1481-6.
“No Single Universal Calcium Requirement”
In 2000, with a bit of an incendiary tone, professor Christopher Nordin of Australia called for a rational position on calcium requirements based on individual variances and culture. The matter was one of controversy, lacking human studies because of their difficulty, but despite plenty of evidence that low calcium causes osteoporosis in animals.
Modern human studies in which researchers deprive subjects of calcium for long periods would be immoral, Nordin points out, although there have been at least a couple in the past. One in particular was performed 50 years ago on Norwegian prisoners that showed deprivation led to negative calcium balance, which would result in osteoporosis.
We also know that diet higher in animal protein and sodium increase urinary calcium; thus, the implication would be that populations of the developed world would need more calcium intake. And status of vitamin D influences calcium absorption; thus, living at a higher latitude, darker skin color, and less exposure to sunlight should never be ignored.
Of course, periods of hormonal changes deserves special attention. According to Nordin in a 2001 interview, “very little work” had been done to determine calcium requirements in postmenopausal state despite that the lacking estrogen effects on the bone are profound.
Still, nine years later and despite the data, many doctors and nutritionists in the U.S.A. and other countries are recommending calcium in general terms of simply meeting RDA. Or, those who understand that certain individuals need more or less calcium, may not be educating patients on facts relating to animal protein, sodium and vitamin D.
A complete, holistic view of each individual patient is necessary and national guidelines should be more forthright in making this assertion. As Nordin states, there is “no single universal calcium requirement” and we need to make sure that our patients know the facts.
Modern human studies in which researchers deprive subjects of calcium for long periods would be immoral, Nordin points out, although there have been at least a couple in the past. One in particular was performed 50 years ago on Norwegian prisoners that showed deprivation led to negative calcium balance, which would result in osteoporosis.
We also know that diet higher in animal protein and sodium increase urinary calcium; thus, the implication would be that populations of the developed world would need more calcium intake. And status of vitamin D influences calcium absorption; thus, living at a higher latitude, darker skin color, and less exposure to sunlight should never be ignored.
Of course, periods of hormonal changes deserves special attention. According to Nordin in a 2001 interview, “very little work” had been done to determine calcium requirements in postmenopausal state despite that the lacking estrogen effects on the bone are profound.
Still, nine years later and despite the data, many doctors and nutritionists in the U.S.A. and other countries are recommending calcium in general terms of simply meeting RDA. Or, those who understand that certain individuals need more or less calcium, may not be educating patients on facts relating to animal protein, sodium and vitamin D.
A complete, holistic view of each individual patient is necessary and national guidelines should be more forthright in making this assertion. As Nordin states, there is “no single universal calcium requirement” and we need to make sure that our patients know the facts.
02 August 2009
Allosteric enzymes
Allosteric enzymes are those that are controlled by the binding of an allosteric effector. The effector may be positive or negative in activating or inactivating the enzyme, respectively, and creates a conformational change of the enzyme. The product may be the allosteric effector in itself producing feedback or feedforward control.
There are two classes of allosteric enzymes based on the effect of the effector on Km and Vmax. If the effector alters Km it is in K class and if the effector alters Vmax it is in V class. There are also enzymes that have both Km and Vmax affected.
K class allosteric enzymes are affected by negative effector binding because it affects the affinity of the binding site for the substrate. V class allosteric enzymes are affective positively or negatively by effectors that increase or decrease rate of enzyme-substrate complex breakdown to products.
Given the conformational change and resulting activation and inactivation of an enzyme, catalysis of reactions would be unidirectional. Examples are hexokinase (or glucokinase), phosphofructokinase, and pyruvate kinase in the regulation of glycolysis. Glucokinase is activated by fructose-6-phosphate and inhibited by fructose-1-phosphate. Phosphofructokinase is activated by fructose 2,6 biphosphate and inhibited by ATP. Pyruvate kinase is activated by fructose-1-6-biphosphate (feedforward) and inhibited by ATP and alanine.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4. p401-4; 587-89; 863-5
2. Stanford. Regulation of glycolysis. Available at: http://cmgm.stanford.edu/biochem200/regulation/
There are two classes of allosteric enzymes based on the effect of the effector on Km and Vmax. If the effector alters Km it is in K class and if the effector alters Vmax it is in V class. There are also enzymes that have both Km and Vmax affected.
K class allosteric enzymes are affected by negative effector binding because it affects the affinity of the binding site for the substrate. V class allosteric enzymes are affective positively or negatively by effectors that increase or decrease rate of enzyme-substrate complex breakdown to products.
Given the conformational change and resulting activation and inactivation of an enzyme, catalysis of reactions would be unidirectional. Examples are hexokinase (or glucokinase), phosphofructokinase, and pyruvate kinase in the regulation of glycolysis. Glucokinase is activated by fructose-6-phosphate and inhibited by fructose-1-phosphate. Phosphofructokinase is activated by fructose 2,6 biphosphate and inhibited by ATP. Pyruvate kinase is activated by fructose-1-6-biphosphate (feedforward) and inhibited by ATP and alanine.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4. p401-4; 587-89; 863-5
2. Stanford. Regulation of glycolysis. Available at: http://cmgm.stanford.edu/biochem200/regulation/
01 August 2009
Why So Many Hormones?
Hormones are any substance in the body that carries a signal to regulate growth, differentiation and function of a variety of cells. The more signals needed, the more hormones in an organism. The big-brained human body is no different. In higher animals signal pathways of many hormonal systems originate in the brain. Because hormones are so specific in communicating between cells, we can expect yet more discovery of hormones in the future to add to the large number already found.
Their are major categories of hormones: peptide and protein, thyroid, catecholamine and steroid. The hormones are specific in targeting cognate receptors that are expressed for specific hormones (1). For example, catecholamine hormones epinephrine and norepinephrine as well as peptide hormones target specific cell surface receptors while steroid hormones target intracellular receptors.
Endocrine hormones are those synthesized in a gland and travels to reach distant target cells. Paracrine hormones are secreted by a cell and travel a short distance to reach a neighboring cell's receptors. Autocrine hormones are produced in a cell that functions as a target for the paracrine hormones.
Hormonal cascade systems may involve a number of hormones. A system may operate through a releasing hormone, anterioir pituitary tropic (or posteror pituitary) hormones and ultimate hormones (1). The posterior pituitary system branches off the right of the hypothalamus and is the system involving oxytocin and vasopressin.
A signal is generally transmitted first through the central nervous system, then innervate the hypothalamus secreting a releasing hormone and it begins the amplified cascade. Generally there is a feedback loop (ultra-short, short, or long) and a final hormone binds a cognate receptor to stop secretion or synthesis of releasing hormone.
If a hormone is not systemic, acting in an anatomically restricted site, it is said to be a local hormone. A hormone that functions locally as an autocrine and paracrine hormone is the neurotransmitter acetylcholine. Acetylcholine in neuron-neuron interaction acts as an excitatory transmitter. It is released after stimulation of a neuron, travels across the synapse and binds to specific nicotinic-acetylcholine receptor.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4.
Their are major categories of hormones: peptide and protein, thyroid, catecholamine and steroid. The hormones are specific in targeting cognate receptors that are expressed for specific hormones (1). For example, catecholamine hormones epinephrine and norepinephrine as well as peptide hormones target specific cell surface receptors while steroid hormones target intracellular receptors.
Endocrine hormones are those synthesized in a gland and travels to reach distant target cells. Paracrine hormones are secreted by a cell and travel a short distance to reach a neighboring cell's receptors. Autocrine hormones are produced in a cell that functions as a target for the paracrine hormones.
Hormonal cascade systems may involve a number of hormones. A system may operate through a releasing hormone, anterioir pituitary tropic (or posteror pituitary) hormones and ultimate hormones (1). The posterior pituitary system branches off the right of the hypothalamus and is the system involving oxytocin and vasopressin.
A signal is generally transmitted first through the central nervous system, then innervate the hypothalamus secreting a releasing hormone and it begins the amplified cascade. Generally there is a feedback loop (ultra-short, short, or long) and a final hormone binds a cognate receptor to stop secretion or synthesis of releasing hormone.
If a hormone is not systemic, acting in an anatomically restricted site, it is said to be a local hormone. A hormone that functions locally as an autocrine and paracrine hormone is the neurotransmitter acetylcholine. Acetylcholine in neuron-neuron interaction acts as an excitatory transmitter. It is released after stimulation of a neuron, travels across the synapse and binds to specific nicotinic-acetylcholine receptor.
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp893-4.
Can vitamin D prevent autoimmune diseases?
Vitamin D, apart from its role in calcium nutrition, has been recently studied for its surprising immunomodulation effects, which could have far implications (1). Not only does the hormone-like vitamin acts on vitamin D receptors, which are present on immune cells such as dentritic cells, but it has also been discovered that activated dentritic cells appear to produce vitamin D (2;3).
Because autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis have each been linked to low vitamin D status, vitamin D supplementation is thought to have potential use as a treatment (3-5). Its use for HIV infection and cancer are also being studied (6;7).
Prevention of autoimmune diseases are also associated with immunomodulation from vitamin D. A higher levels of vitamin D is associated with lower risk of multiple sclerosis (8) and with lower risk of type 1 diabetes mellitus (9;10). Vitamin D’s action for preventing type 1 diabetes and other autoimmune diseases is thought to be modulation of dentritic action and modifying T-cell differentiation (10).
Animal studies make the research more exciting. In an older study on mice, vitamin D was able to completely prevent the mouse model of multiple sclerosis (11). Others have also suggested use in preventing encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus (12). It should be noted that, in each case, a high-calcium diet was required (12).
Reference List
1. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008;4:80-90.
2. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol 2009;70:345-52.
3. Cutolo M, Otsa K. Review: vitamin D, immunity and lupus. Lupus 2008;17:6-10.
4. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008;47:840-8.
5. Vojinovic S, Vojinovic J, Cosic V, Savic V. [Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis]. Srp Arh Celok Lek 2005;133 Suppl 2:124-8.
6. Adorini L, Daniel KC, Penna G. Vitamin D receptor agonists, cancer and the immune system: an intricate relationship. Curr Top Med Chem 2006;6:1297-301.
7. Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006;64:226-33.
8. Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009;132:1146-60.
9. Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42.
10. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab 2005;16:261-6.
11. Hayes CE, Cantorna MT, Deluca HF. Vitamin D and multiple sclerosis. Proc Soc Exp Biol Med 1997;216:21-7.
12. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85.
Because autoimmune diseases such as systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis have each been linked to low vitamin D status, vitamin D supplementation is thought to have potential use as a treatment (3-5). Its use for HIV infection and cancer are also being studied (6;7).
Prevention of autoimmune diseases are also associated with immunomodulation from vitamin D. A higher levels of vitamin D is associated with lower risk of multiple sclerosis (8) and with lower risk of type 1 diabetes mellitus (9;10). Vitamin D’s action for preventing type 1 diabetes and other autoimmune diseases is thought to be modulation of dentritic action and modifying T-cell differentiation (10).
Animal studies make the research more exciting. In an older study on mice, vitamin D was able to completely prevent the mouse model of multiple sclerosis (11). Others have also suggested use in preventing encephalomyelitis, rheumatoid arthritis, and systemic lupus erythematosus (12). It should be noted that, in each case, a high-calcium diet was required (12).
Reference List
1. Adams JS, Hewison M. Unexpected actions of vitamin D: new perspectives on the regulation of innate and adaptive immunity. Nat Clin Pract Endocrinol Metab 2008;4:80-90.
2. Adorini L, Penna G. Dendritic cell tolerogenicity: a key mechanism in immunomodulation by vitamin D receptor agonists. Hum Immunol 2009;70:345-52.
3. Cutolo M, Otsa K. Review: vitamin D, immunity and lupus. Lupus 2008;17:6-10.
4. Do JE, Kwon SY, Park S, Lee ES. Effects of vitamin D on expression of Toll-like receptors of monocytes from patients with Behcet's disease. Rheumatology (Oxford) 2008;47:840-8.
5. Vojinovic S, Vojinovic J, Cosic V, Savic V. [Effects of alfacalcidol therapy on serum cytokine levels in patients with multiple sclerosis]. Srp Arh Celok Lek 2005;133 Suppl 2:124-8.
6. Adorini L, Daniel KC, Penna G. Vitamin D receptor agonists, cancer and the immune system: an intricate relationship. Curr Top Med Chem 2006;6:1297-301.
7. Villamor E. A potential role for vitamin D on HIV infection? Nutr Rev 2006;64:226-33.
8. Correale J, Ysrraelit MC, Gaitan MI. Immunomodulatory effects of Vitamin D in multiple sclerosis. Brain 2009;132:1146-60.
9. Arnson Y, Amital H, Shoenfeld Y. Vitamin D and autoimmunity: new aetiological and therapeutic considerations. Ann Rheum Dis 2007;66:1137-42.
10. Mathieu C, Badenhoop K. Vitamin D and type 1 diabetes mellitus: state of the art. Trends Endocrinol Metab 2005;16:261-6.
11. Hayes CE, Cantorna MT, Deluca HF. Vitamin D and multiple sclerosis. Proc Soc Exp Biol Med 1997;216:21-7.
12. Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 2001;15:2579-85.
Which Vitamin K for Heart Disease?
The most meaningful (and exciting) new data on vitamin K is on it’s relationship with coronary heart disease (CHD), but it’s a bit confusing.
A cross-sectional study published in Atherosclerosis in 2009 indicated menaquinone reduced coronary calcification, but maybe not phylloquinone (1). This supported a hypothesis made earlier that menaquinone, but not phylloquinone reduced risk of cardiovascular disease (2).
However, an intention-to-treat analysis in Am J Clin Nutr also published this year found phylloquinone supplementation appeared to slow coronary artery calcification (3). This study was performed on older adults with preexisting calcification (3).
One more piece of the puzzle is another not-yet-published September cohort study from Nutr Metab Cardiovasc Dis (4). The study followed 16,057 women ages 49-79 who did not have CHD at baseline (4). Questionnaires were used to determine estimation of vitamin K intake and multivariates were reduced as needed (4). According to its conclusions, menaquinones may have preventative effects against CHD, but not phylloquinone (4).
Eventually more studies will be needed to shed more light on the roles of both phylloquinone and menaquinone and, ultimately, the research will reveal best intake levels for CHD prevention.
Reference List
1. Beulens JW, Bots ML, Atsma F et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009;203:489-93.
2. Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19:39-42.
3. Shea MK, O'Donnell CJ, Hoffmann U et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009;89:1799-807.
4. Gast GC, de Roos NM, Sluijs I et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009;19:504-10.
A cross-sectional study published in Atherosclerosis in 2009 indicated menaquinone reduced coronary calcification, but maybe not phylloquinone (1). This supported a hypothesis made earlier that menaquinone, but not phylloquinone reduced risk of cardiovascular disease (2).
However, an intention-to-treat analysis in Am J Clin Nutr also published this year found phylloquinone supplementation appeared to slow coronary artery calcification (3). This study was performed on older adults with preexisting calcification (3).
One more piece of the puzzle is another not-yet-published September cohort study from Nutr Metab Cardiovasc Dis (4). The study followed 16,057 women ages 49-79 who did not have CHD at baseline (4). Questionnaires were used to determine estimation of vitamin K intake and multivariates were reduced as needed (4). According to its conclusions, menaquinones may have preventative effects against CHD, but not phylloquinone (4).
Eventually more studies will be needed to shed more light on the roles of both phylloquinone and menaquinone and, ultimately, the research will reveal best intake levels for CHD prevention.
Reference List
1. Beulens JW, Bots ML, Atsma F et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 2009;203:489-93.
2. Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol 2008;19:39-42.
3. Shea MK, O'Donnell CJ, Hoffmann U et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr 2009;89:1799-807.
4. Gast GC, de Roos NM, Sluijs I et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis 2009;19:504-10.
25 July 2009
Hypoglycemia in Hereditary Fructose Intolerance
What are the specific reasons for hypoglycemia seen in hereditary fructose intolerance?
Hereditary fructose intolerance (HFI) an autosomal recessive disorder in which there is subnormal activity of the enzyme fructose 1-phosphate aldolase B (1;2). Largely found in the liver, the enzyme is needed for normal fructose metabolism for splitting fructose 1-phosphate to form dihydroacetone and glyceraldehyde (1).
Hypoglycemia after consumption of fructose (also sucrose or sorbitol) results because of the lack of maintenance of proper blood glucose levels by the liver (2). The fructose ingestion and the lack of aldolase B results in the accummulation of fructose 1-phosphate in cells, particularly in the liver (1). The accumulation leads to depletion of Pi, which in turn keeps mitochondria in hepatocytes from producing ATP causing cell damage, and inhibition of glycogenolysis and, thus, guconeogenesis (1;2).
HFI often goes unrecognized and is life-threatening due to hypoglycemia along with possible liver and renal failure (3;4). Many of patients afflicted with the disorder have a noted distaste for sweet foods due to having suffered symptoms early in life such as vomiting and abdominal pain (2-4). The cure for HFI is exclusion of sources of fructose from the diet (1-4).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp 597 & 643.
2. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ. Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins, 2009.
3. Yasawy MI, Folsch UR, Schmidt WE, Schwend M. Adult hereditary fructose intolerance. World J Gastroenterol 2009;15:2412-3.
4. Cox TM. Hereditary fructose intolerance. Baillieres Clin Gastroenterol 1990;4:61-78.
Hereditary fructose intolerance (HFI) an autosomal recessive disorder in which there is subnormal activity of the enzyme fructose 1-phosphate aldolase B (1;2). Largely found in the liver, the enzyme is needed for normal fructose metabolism for splitting fructose 1-phosphate to form dihydroacetone and glyceraldehyde (1).
Hypoglycemia after consumption of fructose (also sucrose or sorbitol) results because of the lack of maintenance of proper blood glucose levels by the liver (2). The fructose ingestion and the lack of aldolase B results in the accummulation of fructose 1-phosphate in cells, particularly in the liver (1). The accumulation leads to depletion of Pi, which in turn keeps mitochondria in hepatocytes from producing ATP causing cell damage, and inhibition of glycogenolysis and, thus, guconeogenesis (1;2).
HFI often goes unrecognized and is life-threatening due to hypoglycemia along with possible liver and renal failure (3;4). Many of patients afflicted with the disorder have a noted distaste for sweet foods due to having suffered symptoms early in life such as vomiting and abdominal pain (2-4). The cure for HFI is exclusion of sources of fructose from the diet (1-4).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp 597 & 643.
2. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ. Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins, 2009.
3. Yasawy MI, Folsch UR, Schmidt WE, Schwend M. Adult hereditary fructose intolerance. World J Gastroenterol 2009;15:2412-3.
4. Cox TM. Hereditary fructose intolerance. Baillieres Clin Gastroenterol 1990;4:61-78.
22 July 2009
Niacin and Hyperlipidemia
NIACIN FOR HIGH CHOLESTEROL
The recommended daily intake for niacin, or vitamin B3, is only 14 mg for women and 16 mg for men with a tolerable upper intake level of 35mg (1). Nutrition professionals should also be aware that niacin, as nicotinic acid (not nicotinamide), has also been used in much larger doses—up to 6 g per day—for decades as a treatment for hyperlipidemia (1). Note that nicotinic acid is available as a dietary supplement.
Use as a Drug
High-dose niacin, in fact, was the first-ever lipid-modifying drug treatment. It helps increase HDL cholesterol while lowering total serum cholesterol, triglycerides and LDL cholesterol (2). After initial discovery in the 1950s and research in the ‘70s, it was found that niacin helped prevent myocardial infarction and reduced risk of death from myocardial infarction when used in doses of 3 g daily (2;3).
The mechanism of high-dose nicotinic acid is broad and unique. It inhibits lipolysis in adipose tissue decreasing free fatty plasma levels within minutes (1;2). Within a few hours it inhibits the liver’s synthesis of triglycerides reducing overall triglycerides in plasma (1;2). And, although it’s unclear just how, after only a few days it lowers LDL and increases HDL cholesterol (1;2).
Unpleasant Side Effects
Although an effective treatment and cost effective, the unpleasant side effects of high-dose niacin have kept many patients from adopting niacin as a regular drug treatment (2). By the 1980s, statins were on the market and greater in popularity (2). Still, niacin continues to present potential.
The main side effect is vasodilation, which includes flushing and redness like a temporary sunburn-like sensation (1;2). This is harmless, but bothersome (2). It is mediated partly by release of histamine; thus, an aspirin or COX inhibitors can reduce the response (1;2).
Precautions
Other side effects can include gastrointestinal problems like heartburn, elevated plasma glucose concentration, and hyperuricemia that can lead to gout since niacin competes with uric acid for excretion (1). Most worrisome is possible hepatotoxicity, which can go as far as obstructing bile flow, hepatitis or liver failure (1).
Newer forms of extended-release niacin, such as Niaspan from Abbot, are reported to have fewer side effects and no hepatotoxicity (2). This is significant for re-establishing niacin as the preferred, cost-effective treatment in comparison to other drugs. Newer studies are now researching niacin’s effectiveness in comparison to or in combination with other lipid- and cholesterol-lowering drugs (3). See "Research Summary and Critique" below.
Niacin is available in immediate-release (IR), sustained-release (SR), and extended-release (ER) (Niaspan) (4). They all differ in effectiveness, side effects and safety. Flushing is seen most with IR, hepatotoxicity is mostly noted with SR (4). The hepatotoxicity has to do with absorption rate (4). ER apparently allows absorption to be "intermediate" in comparison to IR and SR (4). In conclusion, avoid SR niacin!
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. E T Bodor and S Offermanns. Nicotinic acid: an old drug with a promising future. Br J Pharmacol. 2008 March; 153(S1): S68–S75. Published online 2007 November 26. doi: 10.1038/sj.bjp.0707528. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18037924.
3. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3
4. Pieper JA. Understanding niacin formulations. Am J Manag Care 2002;8:S308-S314.
RESEARCH SUMMARY AND CRITIQUE
One randomized, double-blind human clinical study in 2000 made a direct comparison using Niaspan and gemfibrozil.
Full reference: Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3
Purpose of Study: To compare effects of Niaspan with gemfibrozil, a lipid-lowering drug from a class called fibrates. Commercially, gemfibrozil goes by names of Lopid, Jezil and Gen-Fibro.
Type of study: Randomized, double-blind human clinical study.
Methods: Patients exhibiting factors for hypercholesterolemia and atherosclerosis were given Niaspan at doses increased sequentially from 1g to 2 g before bedtime and 80 or gemfibrozil at 600 mg given twice daily. Of 173 patients, 72 of 88 given Niaspan and 68 of 85 given gemfibrozil completed the study.
Percentage change from baseline was provided through analysis of blood samples collected after 12-hour fasts. They provided measurements for total cholesterol, HDL cholesterol, LDL cholesterol, lipoprotein levels, total triglycerides and fibrinogen levels.
Exclusions included most diabetics (not with normal-range fasting glucose), patients on blood thinners, patients with active gout as well as those with other serious illnesses and/or abnormalities.
The patients were men and women between ages 21 and 75 years. All were counseled by a National Cholesterol Education Program.
Results Summary: Niaspan increased HDL cholesterol twice as much as gemfibrozil and had better results in improving LDL cholesterol while lowering levels of fibrinogen (protein involved in clotting). The gemfibrozil had greater effects at lowering triglycerides, but increased LDL cholesterol.
Much more Niaspan flushing responses (78% compared to 10%) were observed in comparison to gemfibrozil; however, dyspepsia was observed more often in patients taking gemfibrozil.
Critique of Research Design: The study was well-designed and included appropriate measurements to determine biological response to treatment. The exclusions were appropriate in nature. The support of a pharmaceutical company for the study hinted at a natural bias that could be noted since there was no discussion given by the authors of this study regarding possible confounding variables. The flushing responses clearly indicate that the patients would have known what they were taking, which may have affected results. Also, dietary factors were not noted in the study. There was conversation seeming out of place about the possible use of both drugs for complementary treatment, which would need further research.
Nutritional Implications and Implications for Future Study: Nutrition professionals should have a thorough understanding of its uses and possible side effects when used as a drug for hypercholesterolemia. Because niacin is a vitamin found in many foods, further research should also review the potential role of diet along with niacin treatment.
The recommended daily intake for niacin, or vitamin B3, is only 14 mg for women and 16 mg for men with a tolerable upper intake level of 35mg (1). Nutrition professionals should also be aware that niacin, as nicotinic acid (not nicotinamide), has also been used in much larger doses—up to 6 g per day—for decades as a treatment for hyperlipidemia (1). Note that nicotinic acid is available as a dietary supplement.
Use as a Drug
High-dose niacin, in fact, was the first-ever lipid-modifying drug treatment. It helps increase HDL cholesterol while lowering total serum cholesterol, triglycerides and LDL cholesterol (2). After initial discovery in the 1950s and research in the ‘70s, it was found that niacin helped prevent myocardial infarction and reduced risk of death from myocardial infarction when used in doses of 3 g daily (2;3).
The mechanism of high-dose nicotinic acid is broad and unique. It inhibits lipolysis in adipose tissue decreasing free fatty plasma levels within minutes (1;2). Within a few hours it inhibits the liver’s synthesis of triglycerides reducing overall triglycerides in plasma (1;2). And, although it’s unclear just how, after only a few days it lowers LDL and increases HDL cholesterol (1;2).
Unpleasant Side Effects
Although an effective treatment and cost effective, the unpleasant side effects of high-dose niacin have kept many patients from adopting niacin as a regular drug treatment (2). By the 1980s, statins were on the market and greater in popularity (2). Still, niacin continues to present potential.
The main side effect is vasodilation, which includes flushing and redness like a temporary sunburn-like sensation (1;2). This is harmless, but bothersome (2). It is mediated partly by release of histamine; thus, an aspirin or COX inhibitors can reduce the response (1;2).
Precautions
Other side effects can include gastrointestinal problems like heartburn, elevated plasma glucose concentration, and hyperuricemia that can lead to gout since niacin competes with uric acid for excretion (1). Most worrisome is possible hepatotoxicity, which can go as far as obstructing bile flow, hepatitis or liver failure (1).
Newer forms of extended-release niacin, such as Niaspan from Abbot, are reported to have fewer side effects and no hepatotoxicity (2). This is significant for re-establishing niacin as the preferred, cost-effective treatment in comparison to other drugs. Newer studies are now researching niacin’s effectiveness in comparison to or in combination with other lipid- and cholesterol-lowering drugs (3). See "Research Summary and Critique" below.
Niacin is available in immediate-release (IR), sustained-release (SR), and extended-release (ER) (Niaspan) (4). They all differ in effectiveness, side effects and safety. Flushing is seen most with IR, hepatotoxicity is mostly noted with SR (4). The hepatotoxicity has to do with absorption rate (4). ER apparently allows absorption to be "intermediate" in comparison to IR and SR (4). In conclusion, avoid SR niacin!
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. E T Bodor and S Offermanns. Nicotinic acid: an old drug with a promising future. Br J Pharmacol. 2008 March; 153(S1): S68–S75. Published online 2007 November 26. doi: 10.1038/sj.bjp.0707528. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18037924.
3. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3
4. Pieper JA. Understanding niacin formulations. Am J Manag Care 2002;8:S308-S314.
RESEARCH SUMMARY AND CRITIQUE
One randomized, double-blind human clinical study in 2000 made a direct comparison using Niaspan and gemfibrozil.
Full reference: Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3
Purpose of Study: To compare effects of Niaspan with gemfibrozil, a lipid-lowering drug from a class called fibrates. Commercially, gemfibrozil goes by names of Lopid, Jezil and Gen-Fibro.
Type of study: Randomized, double-blind human clinical study.
Methods: Patients exhibiting factors for hypercholesterolemia and atherosclerosis were given Niaspan at doses increased sequentially from 1g to 2 g before bedtime and 80 or gemfibrozil at 600 mg given twice daily. Of 173 patients, 72 of 88 given Niaspan and 68 of 85 given gemfibrozil completed the study.
Percentage change from baseline was provided through analysis of blood samples collected after 12-hour fasts. They provided measurements for total cholesterol, HDL cholesterol, LDL cholesterol, lipoprotein levels, total triglycerides and fibrinogen levels.
Exclusions included most diabetics (not with normal-range fasting glucose), patients on blood thinners, patients with active gout as well as those with other serious illnesses and/or abnormalities.
The patients were men and women between ages 21 and 75 years. All were counseled by a National Cholesterol Education Program.
Results Summary: Niaspan increased HDL cholesterol twice as much as gemfibrozil and had better results in improving LDL cholesterol while lowering levels of fibrinogen (protein involved in clotting). The gemfibrozil had greater effects at lowering triglycerides, but increased LDL cholesterol.
Much more Niaspan flushing responses (78% compared to 10%) were observed in comparison to gemfibrozil; however, dyspepsia was observed more often in patients taking gemfibrozil.
Critique of Research Design: The study was well-designed and included appropriate measurements to determine biological response to treatment. The exclusions were appropriate in nature. The support of a pharmaceutical company for the study hinted at a natural bias that could be noted since there was no discussion given by the authors of this study regarding possible confounding variables. The flushing responses clearly indicate that the patients would have known what they were taking, which may have affected results. Also, dietary factors were not noted in the study. There was conversation seeming out of place about the possible use of both drugs for complementary treatment, which would need further research.
Nutritional Implications and Implications for Future Study: Nutrition professionals should have a thorough understanding of its uses and possible side effects when used as a drug for hypercholesterolemia. Because niacin is a vitamin found in many foods, further research should also review the potential role of diet along with niacin treatment.
18 July 2009
Bs for Stress and Energy
B-complex supplement products are popular commodities, often marketed for "stress" or "energy." Is there scientific justification for these claims? Why should anyone choose a B-complex supplement as opposed to either broader multivitamin-mineral supplements or narrower single B-vitamin supplements?
You might remember in the early ‘90s when a neuropathy epidemic broke out in Cuba among unsuspecting tobacco growers. They complained of burning sensations in their feet, pain in their arms and legs, frequent urination, blurred vision, weight loss, sensitivity to sunlight, and, well, lots of stress and fatigue (1). After assessing their diets it was discovered they were deficient in B complex vitamins and the amount of alcohol they drank daily contributed to loss of the little Bs they had (1).
The tobacco growers may have not known that B vitamins play essential roles in the health of their bodies relating to energy metabolism and stress, but let’s be sure we do.
Energy
For generating ATP energy in the body, B vitamins act mainly in synergy. Specifically, the vitamins thiamin, riboflavin, niacin and pantothenic acid are all needed to act as co enzymes in the formation of a multi-enzyme complex known as pyruvate dehydrogenase complex (2). Pyruvate dehydrogenase complex is essential for the oxidative decarboxylation of pyruvate to form acetyl CoA, which feeds into the citric acid cycle (2). Take any of the B vitamins away and cellular respiration is no more.
Further, niacin either as nicotinic acid and nicotinamide is necessary for use in the forms of NAD, nicotinamide adenine dinucleotide, and, with a phosphate at the end, NADP. NAD and NADP act as coenzymes for about 200 enzymes (oxidation-reduction reactions). But a major role of NAD in its reduced form as NADH is to shuttle electrons through the electron transport chain creating ATP energy (2). Apart from joining the other Bs in oxidative decarboxylation of pyruvate, NAD and NADH also act as coenzymes in glycolysis, oxidation of acetyl CoA, beta-oxidation of fatty acids and oxidation of ethanol for energy (2).
Riboflavin is needed for its coenzyme derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Like NAD and NADP, FMN and FAD act as coenzymes in oxidative-reduciton reactions for many reactions (2). Apart from use in pyruvate dehydrogenase complex in which FAD acts as an electron carrier, FAD also is needed for the flavoprotein succinate dehydrogenase to remove electrons from succinate to form fumarate (2). Then electrons are passed into electron transport chain by coenzyme Q (2).
Biotin’s role in energy has to do with its coenzyme role in enzymes. Two regulatory enzymes are dependent on biotin: pyruvate carboxylase, regulator of carboxylation of pyruvate, acetyl CoA carboxylase, regulator of fatty acid synthesis (2). Two enzymes need biotin for catabolism of amino acids need biotin, propionyl CoA carboxylase and beta-methylcrotnonyl CoA carboxylase (2). Lack of biotin will produce lethargy, depression, hallucinations and muscle pain (2).
Cobalamin once converted to adenosylcobalamin can act along with biotin in a energy metabolism in which it acts to help convert methylmalonyl CoA mutase convert L-methylmalonyl CoA to succinyl CoA (2). L-methylmalonyl CoA is produced from D-methylmalonyl CoA, which was produced from propionyl CoA that arose from from oxidation of amino acids and odd-chain fatty acids from the biotin-dependent reaction (2).
Pantothenic acid, aside its role in pyruvate dehydrogenase complex as a component of CoA, also acts as a component of CoA in lipid metabolism such as synthesis of ketone bodies and fatty acids (2). Although deficiency is unlikely—it’s ubiquitous in food—among the symptoms would be fatigue and weakness (2). Its deficiency is characterized by numbness in the toes called “burning feet syndrome” of which was no doubt suffered by the Cuban tobacco farmers who lacked it (1;2).
Stress
Some examples of stress were given above, but stress help from B vitamins is largely the work of thiamin. Thiamin, in this case not as a coenzyme, may activate ion transport in nerve membranes as well as regulating sodium channels and acetylcholine receptors in nerve impulse transmissions (2). A thiamin deficiency produces beriberi (beri meaning “weakness”) and one of its first signs is anorexia and weight loss, then neurological symptoms of confusion and apathy in what can only end up as irritability (2).
Riboflavin has its role in stress too—and I’m using the word “stress” as a very wide-reaching general term. FAD-dependent monomaine oxidase is required by neurotransmitters such as dopamine (2). Regeneration of the antioxidant glutathione—which supports against oxidative stress—is dependent also on FAD-dependent glutathione reductase (2).
Without niacin life could be especially stressful due to pellagra, which comes with its four Ds: dermatitis, dementia, diarrhea and death (2). But the B vitamin’s more direct role is in reducing oxidative stress via regeneration of glutathione, vitamin C and thioredoxin (2).
Finally, the pernicious anemia from a deficiency or poor absorption of cobalamin would lead to neuropathy of which is characterized by demyelination of the nerves—painfully stressful indeed (2).
Supplementation
OK, so we know the roles of B vitamins as related to energy and stress. We definitely need them. The question remains, however, whether or not a normally healthy person should supplement? Plus, will taking more of B-complex act as an ergogenic aid such as for athletes?
The studies aren’t showing much promise. There is indication that exercise causes greater need for B-complex supplements (5). Athletes should continue to take them. But, despite widespread use of B-complex supplements among athletes even in massive doses, they should not be expected to increase actual performance unless a deficiency was in existence beforehand (3;4).
Those of us who aren’t athletes would benefit from B-complex vitamins simply to help us avoid deficiency and because of their lack of toxicity. But don’t expect huge increases in “energy” or reductions of “stress” unless you are deficient. Deficiency can happen if you're malnourished, abuse alcohol, are a strict vegetarian (B12 or riboflavin) or if you have a disorder such as pernicious anemia (B12 deficiency) (2).
Reference List
1. Arnaud J, Fleites-Mestre P, Chassagne M et al. Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Br J Nutr 2001;85:741-8.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Williams MH. Vitamin supplementation and athletic performance. Int J Vitam Nutr Res Suppl 1989;30:163-91.
4. Williams MH. Vitamin and mineral supplements to athletes: do they help? Clin Sports Med 1984;3:623-37.
5. Woolf K, Manore MM. B-vitamins and exercise: does exercise alter requirements? Int J Sport Nutr Exerc Metab 2006;16:453-84.
You might remember in the early ‘90s when a neuropathy epidemic broke out in Cuba among unsuspecting tobacco growers. They complained of burning sensations in their feet, pain in their arms and legs, frequent urination, blurred vision, weight loss, sensitivity to sunlight, and, well, lots of stress and fatigue (1). After assessing their diets it was discovered they were deficient in B complex vitamins and the amount of alcohol they drank daily contributed to loss of the little Bs they had (1).
The tobacco growers may have not known that B vitamins play essential roles in the health of their bodies relating to energy metabolism and stress, but let’s be sure we do.
Energy
For generating ATP energy in the body, B vitamins act mainly in synergy. Specifically, the vitamins thiamin, riboflavin, niacin and pantothenic acid are all needed to act as co enzymes in the formation of a multi-enzyme complex known as pyruvate dehydrogenase complex (2). Pyruvate dehydrogenase complex is essential for the oxidative decarboxylation of pyruvate to form acetyl CoA, which feeds into the citric acid cycle (2). Take any of the B vitamins away and cellular respiration is no more.
Further, niacin either as nicotinic acid and nicotinamide is necessary for use in the forms of NAD, nicotinamide adenine dinucleotide, and, with a phosphate at the end, NADP. NAD and NADP act as coenzymes for about 200 enzymes (oxidation-reduction reactions). But a major role of NAD in its reduced form as NADH is to shuttle electrons through the electron transport chain creating ATP energy (2). Apart from joining the other Bs in oxidative decarboxylation of pyruvate, NAD and NADH also act as coenzymes in glycolysis, oxidation of acetyl CoA, beta-oxidation of fatty acids and oxidation of ethanol for energy (2).
Riboflavin is needed for its coenzyme derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Like NAD and NADP, FMN and FAD act as coenzymes in oxidative-reduciton reactions for many reactions (2). Apart from use in pyruvate dehydrogenase complex in which FAD acts as an electron carrier, FAD also is needed for the flavoprotein succinate dehydrogenase to remove electrons from succinate to form fumarate (2). Then electrons are passed into electron transport chain by coenzyme Q (2).
Biotin’s role in energy has to do with its coenzyme role in enzymes. Two regulatory enzymes are dependent on biotin: pyruvate carboxylase, regulator of carboxylation of pyruvate, acetyl CoA carboxylase, regulator of fatty acid synthesis (2). Two enzymes need biotin for catabolism of amino acids need biotin, propionyl CoA carboxylase and beta-methylcrotnonyl CoA carboxylase (2). Lack of biotin will produce lethargy, depression, hallucinations and muscle pain (2).
Cobalamin once converted to adenosylcobalamin can act along with biotin in a energy metabolism in which it acts to help convert methylmalonyl CoA mutase convert L-methylmalonyl CoA to succinyl CoA (2). L-methylmalonyl CoA is produced from D-methylmalonyl CoA, which was produced from propionyl CoA that arose from from oxidation of amino acids and odd-chain fatty acids from the biotin-dependent reaction (2).
Pantothenic acid, aside its role in pyruvate dehydrogenase complex as a component of CoA, also acts as a component of CoA in lipid metabolism such as synthesis of ketone bodies and fatty acids (2). Although deficiency is unlikely—it’s ubiquitous in food—among the symptoms would be fatigue and weakness (2). Its deficiency is characterized by numbness in the toes called “burning feet syndrome” of which was no doubt suffered by the Cuban tobacco farmers who lacked it (1;2).
Stress
Some examples of stress were given above, but stress help from B vitamins is largely the work of thiamin. Thiamin, in this case not as a coenzyme, may activate ion transport in nerve membranes as well as regulating sodium channels and acetylcholine receptors in nerve impulse transmissions (2). A thiamin deficiency produces beriberi (beri meaning “weakness”) and one of its first signs is anorexia and weight loss, then neurological symptoms of confusion and apathy in what can only end up as irritability (2).
Riboflavin has its role in stress too—and I’m using the word “stress” as a very wide-reaching general term. FAD-dependent monomaine oxidase is required by neurotransmitters such as dopamine (2). Regeneration of the antioxidant glutathione—which supports against oxidative stress—is dependent also on FAD-dependent glutathione reductase (2).
Without niacin life could be especially stressful due to pellagra, which comes with its four Ds: dermatitis, dementia, diarrhea and death (2). But the B vitamin’s more direct role is in reducing oxidative stress via regeneration of glutathione, vitamin C and thioredoxin (2).
Finally, the pernicious anemia from a deficiency or poor absorption of cobalamin would lead to neuropathy of which is characterized by demyelination of the nerves—painfully stressful indeed (2).
Supplementation
OK, so we know the roles of B vitamins as related to energy and stress. We definitely need them. The question remains, however, whether or not a normally healthy person should supplement? Plus, will taking more of B-complex act as an ergogenic aid such as for athletes?
The studies aren’t showing much promise. There is indication that exercise causes greater need for B-complex supplements (5). Athletes should continue to take them. But, despite widespread use of B-complex supplements among athletes even in massive doses, they should not be expected to increase actual performance unless a deficiency was in existence beforehand (3;4).
Those of us who aren’t athletes would benefit from B-complex vitamins simply to help us avoid deficiency and because of their lack of toxicity. But don’t expect huge increases in “energy” or reductions of “stress” unless you are deficient. Deficiency can happen if you're malnourished, abuse alcohol, are a strict vegetarian (B12 or riboflavin) or if you have a disorder such as pernicious anemia (B12 deficiency) (2).
Reference List
1. Arnaud J, Fleites-Mestre P, Chassagne M et al. Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Br J Nutr 2001;85:741-8.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Williams MH. Vitamin supplementation and athletic performance. Int J Vitam Nutr Res Suppl 1989;30:163-91.
4. Williams MH. Vitamin and mineral supplements to athletes: do they help? Clin Sports Med 1984;3:623-37.
5. Woolf K, Manore MM. B-vitamins and exercise: does exercise alter requirements? Int J Sport Nutr Exerc Metab 2006;16:453-84.
12 July 2009
Vitamin E
Vitamin E refers to eight compounds (vitamers: tocopherols and tocotrienols) and is found in both plants and animal foods (1). The most studied natural source of vitamin E is alpha-tocopherol because of its prevention of lipoprotein oxidation and inhibition of platelet aggregation, which suggests prevention of cardiovascular disease (1).
Alpha-tocopherol is the only one with biological activity and offers the most protection against oxidative stress through its oxygen-quenching capacity (2). The natural and most active form is designated by its steroisomer RRR alpha-tocopherol and continues to be found on supplement labels as d-alpha tocopherol (2).
Beta-tocopherol also exhibits oxygen-quenching capacity albeit not as much as alpha-tocopherol and its abilities are followed by gamma- and delta-tocopherol (2). The tocotrienols may not exhibit significant antioxidant role, but have another role in which they reduce plasma cholesterol concentration (2).
A recently discovered natural form of vitamin E is alpha-tocopheryl phosphate found to be ubiquitous in tissues of animals and plants (3). Its role is not yet clear.
Supplementation with vitamin E is widely popular for taking guesswork out of how to get enough of this seemingly non-toxic vitamin for cardiovascular health (1;4). Newer research on vitamin E, however, is showing that it may be possible that people are taking too much (1;5).
Clinical trials on alpha-tocopherol have mostly found negative results including possible increased adverse effects on those with high blood pressure and increased risk of death in those with cardiovascular disease (1).
Until further is known about the most appropriate amount to take for reduced risk of disease, the Recommended Dietary Allowance for vitamin E continues to be 15 mg daily, based on the natural form of alpha-tocopherol, and is still considered one of the least toxic vitamins (2).
Reference List
1. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008;45:417-50.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Gianello R, Libinaki R, Azzi A et al. Alpha-tocopheryl phosphate: a novel, natural form of vitamin E. Free Radic Biol Med 2005;39:970-6.
4. Gutierrez AD, de Serna DG, Robinson I, Schade DS. The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C. Metabolism 2009;58:469-78.
5. Bell SJ, Grochoski GT. How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008;48:760-74.
Alpha-tocopherol is the only one with biological activity and offers the most protection against oxidative stress through its oxygen-quenching capacity (2). The natural and most active form is designated by its steroisomer RRR alpha-tocopherol and continues to be found on supplement labels as d-alpha tocopherol (2).
Beta-tocopherol also exhibits oxygen-quenching capacity albeit not as much as alpha-tocopherol and its abilities are followed by gamma- and delta-tocopherol (2). The tocotrienols may not exhibit significant antioxidant role, but have another role in which they reduce plasma cholesterol concentration (2).
A recently discovered natural form of vitamin E is alpha-tocopheryl phosphate found to be ubiquitous in tissues of animals and plants (3). Its role is not yet clear.
Supplementation with vitamin E is widely popular for taking guesswork out of how to get enough of this seemingly non-toxic vitamin for cardiovascular health (1;4). Newer research on vitamin E, however, is showing that it may be possible that people are taking too much (1;5).
Clinical trials on alpha-tocopherol have mostly found negative results including possible increased adverse effects on those with high blood pressure and increased risk of death in those with cardiovascular disease (1).
Until further is known about the most appropriate amount to take for reduced risk of disease, the Recommended Dietary Allowance for vitamin E continues to be 15 mg daily, based on the natural form of alpha-tocopherol, and is still considered one of the least toxic vitamins (2).
Reference List
1. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008;45:417-50.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Gianello R, Libinaki R, Azzi A et al. Alpha-tocopheryl phosphate: a novel, natural form of vitamin E. Free Radic Biol Med 2005;39:970-6.
4. Gutierrez AD, de Serna DG, Robinson I, Schade DS. The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C. Metabolism 2009;58:469-78.
5. Bell SJ, Grochoski GT. How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008;48:760-74.
Bugs Bunny diet
Could it be that when Bugs Bunny chose his special diet of carrots because he knew that the discovery of vitamin A in 1915 found it was an essential growth factor in animals (1)? Maybe he knew that vitamin A kept his skin healthy under all that fur (1). Or, more likely, that vitamin A kept his eyes healthy for seeing underground (1).
Bugs can also celebrate that his enjoyment of carrots might keep him from later having to say, “What’s up doc?” This is because clinical evidence has led the U.S. Food and Drug Administration to approve a cancer health claim for a low-fat diet rich in fruits and vegetables when it includes vitamin A (1).
Vitamin A’s benefits are all appealing to humans too. But while vitamin A deficiency is not common in developed countries, a few are deficient not being regular eaters of foods high in vitamin A like carrots, sardines or liver (1).
How much should you get? What kind of vitamin A should you be getting? And, how do you know when you should supplement? Clinicians should be familiar with the differences of the various kinds of vitamin A because it would affect recommendations.
Vitamin A references any compound that can produce biological activity of all-trans retinol (1). These include preformed vitamin A retinoids (retinol, retinal, retinoic acid, retinyl esters and others) and provitamin A carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin) (1).
Absorption of vitamin A first requires digestion in which enzymes help free up vitamin A from proteins and fats (1). The vitamin A compounds then become solubilized into bile micelles to be transported and absorbed across the brush border membrane of the duodenum and jejunum (1).
The preformed vitamin A retinoids are absorbed easily (about 70-90 percent) as long as a meal includes sufficient fat (1). Provitamin A carotenoids are less absorbed ranging from less than 5 percent in raw foods and juices and up to 60 percent when cooked or taken purely in oil (1).
Retinoids, being lipid-soluble, are not as stable as carotenoids and can oxidize when exposed to light, oxygen, heat or some metals (2). But, again being lipid soluble, about 70-90 percent of the preformed vitamin A retinoids are absorbed (1).
In developing countries, vitamin A deficiency is not common (1). It generally occurs among children leading to increased mortality and infectious morbidity (1). The symptoms of vitamin A deficiency can include xerophthalmia (night blindness, Bitot’s spots, conjunctival abnormalities, corneal scarring and ulcerations), anorexia, retarded growth, karatinization of mucous cells (1).
The best measure of vitamin A from which to make recommendations is retinol activity equivalents (RAE) (1). For example, retinol 1 mcg is equal to RAE 1 mcg, beta-carotene 12 mcg is equal to RAE 1 mcg, and alpha-carotene or beta-cryptoxanthin 24mcg is equal to RAE 1 mcg (1). The requirements of vitamin A intake published by the Institute of Medicine’s Food and Nutrition Board published in 2001 that adult men should consume 625mcg RAE and women 500mcg RAE (1).The Recommended Dietary Allowance (RDA) is 900 and 700 mcg RAE for men and women (1).
Pregnant women have a higher RDA ranging from 770 and 1,300 mcg RAE (1)Smokers, however, should watch any increase because newer research shows vitamin A may increase risk for lung cancer rather than decrease it (1). The biochemical reasons for increasing lung cancer risk are not clear yet, but may have to do with break down products and mitochondriotoxicity (3).
Because main food labels still list vitamin A in the older International Units (IU), it’s important to point out that 1 IU vitamin A is equal to 0.3 mcg regtinal, 3.6 mcg beta-carotene and 7.2 mcg of alpha-carotene and beta-cryptoxanthin (1).
It is possible to get too much vitamin A. Hypervitaminosis A is a disorder that can lead to nausea, vomiting, double vision, headache, dizziness and skin problems (1).
The tolerable upper intake level for preformed vitamin A in adults is 3,000 mcg (1). Beta-carotene and the other provitamin A carotenoids do not have any known tolerable upper intake level (1). A tolerable upper intake level of beta-carotene levels in smokers has yet to be established (1).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Carlotti ME, Rossatto V, Gallarate M, Trotta M, Debernardi F. Vitamin A palmitate photostability and stability over time. J Cosmet Sci 2004;55:233-52.
3. Siems W, Salerno C, Crifo C, Sommerburg O, Wiswedel I. Beta-carotene degradation products - formation, toxicity and prevention of toxicity. Forum Nutr 2009;61:75-86.
Bugs can also celebrate that his enjoyment of carrots might keep him from later having to say, “What’s up doc?” This is because clinical evidence has led the U.S. Food and Drug Administration to approve a cancer health claim for a low-fat diet rich in fruits and vegetables when it includes vitamin A (1).
Vitamin A’s benefits are all appealing to humans too. But while vitamin A deficiency is not common in developed countries, a few are deficient not being regular eaters of foods high in vitamin A like carrots, sardines or liver (1).
How much should you get? What kind of vitamin A should you be getting? And, how do you know when you should supplement? Clinicians should be familiar with the differences of the various kinds of vitamin A because it would affect recommendations.
Vitamin A references any compound that can produce biological activity of all-trans retinol (1). These include preformed vitamin A retinoids (retinol, retinal, retinoic acid, retinyl esters and others) and provitamin A carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin) (1).
Absorption of vitamin A first requires digestion in which enzymes help free up vitamin A from proteins and fats (1). The vitamin A compounds then become solubilized into bile micelles to be transported and absorbed across the brush border membrane of the duodenum and jejunum (1).
The preformed vitamin A retinoids are absorbed easily (about 70-90 percent) as long as a meal includes sufficient fat (1). Provitamin A carotenoids are less absorbed ranging from less than 5 percent in raw foods and juices and up to 60 percent when cooked or taken purely in oil (1).
Retinoids, being lipid-soluble, are not as stable as carotenoids and can oxidize when exposed to light, oxygen, heat or some metals (2). But, again being lipid soluble, about 70-90 percent of the preformed vitamin A retinoids are absorbed (1).
In developing countries, vitamin A deficiency is not common (1). It generally occurs among children leading to increased mortality and infectious morbidity (1). The symptoms of vitamin A deficiency can include xerophthalmia (night blindness, Bitot’s spots, conjunctival abnormalities, corneal scarring and ulcerations), anorexia, retarded growth, karatinization of mucous cells (1).
The best measure of vitamin A from which to make recommendations is retinol activity equivalents (RAE) (1). For example, retinol 1 mcg is equal to RAE 1 mcg, beta-carotene 12 mcg is equal to RAE 1 mcg, and alpha-carotene or beta-cryptoxanthin 24mcg is equal to RAE 1 mcg (1). The requirements of vitamin A intake published by the Institute of Medicine’s Food and Nutrition Board published in 2001 that adult men should consume 625mcg RAE and women 500mcg RAE (1).The Recommended Dietary Allowance (RDA) is 900 and 700 mcg RAE for men and women (1).
Pregnant women have a higher RDA ranging from 770 and 1,300 mcg RAE (1)Smokers, however, should watch any increase because newer research shows vitamin A may increase risk for lung cancer rather than decrease it (1). The biochemical reasons for increasing lung cancer risk are not clear yet, but may have to do with break down products and mitochondriotoxicity (3).
Because main food labels still list vitamin A in the older International Units (IU), it’s important to point out that 1 IU vitamin A is equal to 0.3 mcg regtinal, 3.6 mcg beta-carotene and 7.2 mcg of alpha-carotene and beta-cryptoxanthin (1).
It is possible to get too much vitamin A. Hypervitaminosis A is a disorder that can lead to nausea, vomiting, double vision, headache, dizziness and skin problems (1).
The tolerable upper intake level for preformed vitamin A in adults is 3,000 mcg (1). Beta-carotene and the other provitamin A carotenoids do not have any known tolerable upper intake level (1). A tolerable upper intake level of beta-carotene levels in smokers has yet to be established (1).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Carlotti ME, Rossatto V, Gallarate M, Trotta M, Debernardi F. Vitamin A palmitate photostability and stability over time. J Cosmet Sci 2004;55:233-52.
3. Siems W, Salerno C, Crifo C, Sommerburg O, Wiswedel I. Beta-carotene degradation products - formation, toxicity and prevention of toxicity. Forum Nutr 2009;61:75-86.
11 July 2009
Antioxidants - Comparing Apples to Oranges
Which will keep the doctor way? The orange contains about 10 times more vitamin C, which is an essential antioxidant for many complex roles in the human body (1). On the other hand, the apple contains quercetin, which has been shown to have a higher antioxidant capacity than vitamin C, thus, potentially offering better protect against free radicals (2;3). Clearly these antioxidants are not equal.
Free radicals are atoms or molecules that have one or more unpaired electrons. These are mainly result of the mitochondria leaking electrons that bind to oxygen; however, there are a variety of other free radicals from exposure to smog, ozone, drugs, and drugs (1).
Because “oxidative stress” is thought to be associated with many diseases including cancer, antioxidant nutrients are frequently evaluated for ability to neutralize free radicals, particularly the oxygen-centered radicals: superoxide, hydroxyl and peroxyl radicals (1).
While antioxidants help decrease neutralize free radicals, they themselves become free radicals although—in some cases such as vitamin E, C, ubiquinol and glutathione—regeneration pathways in the body often help them function over again (1). The regeneration process is key for optimal defense against oxidative stress and so is receiving enough of different kind of antioxidants (1).
As science continues to discover more and more, high-antioxidant foods continue to grown in the marketplace. Walk down the isle of any health food store and you’re sure to spot the latest and greatest—pomegranate, blueberry, acai berry, green tea. What makes one food greater than another?
These compete by antioxidant capacity including measures of oxygen radical absorption Capacity (ORAC) (4;5). Each ORAC unit indicates greater antioxidant protection—the higher the score, the more “super” the food (5). Another test more relevant biologically is cellular antioxidant activity (CAA), performed on cell cultures, which has found quercetin, pomegranate and berries clear favorites for decreasing oxidative stress (6). Antioxidant capacity can also be helpful to determine one fruit with another of the same fruit. For example, organically grown fruit and vegetables often have a higher ORAC score indicating greater content of fruit (7).
Should consumers rely strictly on ORAC or CAA tests for making food choices? The answer is, no. While single antioxidants may have unique functions that may link them to reduced risk of disease, such as vitamin C and heart disease (1), quercetin and liver cancer (8), no single antioxidant or antioxidant complex has appeared yet to decreases oxidative stress enough overall to reduce risk of all diseases (1).
As discussed above, however, antioxidants often work with each other synergistically in the body. Thus, for superior nutrition, adopt the “color code”: five to nine servings daily of fruits and vegetables of different colors provides the reds, red-purples, oranges, yellows, and greens for your body daily and is in line the National Cancer Institute and American Institute (9). Until more is known about antioxidants, the color code offers the the best guideline for health and prevention of disease (1).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Wolfe KL, Liu RH. Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 2007;55:8896-907.
3. Kim DO, Lee KW, Lee HJ, Lee CY. Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. J Agric Food Chem 2002;50:3713-7.
4. Kohri S, Fujii H, Oowada S et al. An oxygen radical absorbance capacity-like assay that directly quantifies the antioxidant's scavenging capacity against AAPH-derived free radicals. Anal Biochem 2009;386:167-71.
5. Cao G, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med 1993;14:303-11.
6. Wolfe KL, Kang X, He X, Dong M, Zhang Q, Liu RH. Cellular antioxidant activity of common fruits. J Agric Food Chem 2008;56:8418-26.
7. Di RL, Di PD, Bigioni M et al. Is antioxidant plasma status in humans a consequence of the antioxidant food content influence? Eur Rev Med Pharmacol Sci 2007;11:185-92.
8. Seufi AM, Ibrahim SS, Elmaghraby TK, Hafez EE. Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 2009;28:80.
9. Heber D, Bowerman S. Applying science to changing dietary patterns. J Nutr 2001;131:3078S-81S.
Free radicals are atoms or molecules that have one or more unpaired electrons. These are mainly result of the mitochondria leaking electrons that bind to oxygen; however, there are a variety of other free radicals from exposure to smog, ozone, drugs, and drugs (1).
Because “oxidative stress” is thought to be associated with many diseases including cancer, antioxidant nutrients are frequently evaluated for ability to neutralize free radicals, particularly the oxygen-centered radicals: superoxide, hydroxyl and peroxyl radicals (1).
While antioxidants help decrease neutralize free radicals, they themselves become free radicals although—in some cases such as vitamin E, C, ubiquinol and glutathione—regeneration pathways in the body often help them function over again (1). The regeneration process is key for optimal defense against oxidative stress and so is receiving enough of different kind of antioxidants (1).
As science continues to discover more and more, high-antioxidant foods continue to grown in the marketplace. Walk down the isle of any health food store and you’re sure to spot the latest and greatest—pomegranate, blueberry, acai berry, green tea. What makes one food greater than another?
These compete by antioxidant capacity including measures of oxygen radical absorption Capacity (ORAC) (4;5). Each ORAC unit indicates greater antioxidant protection—the higher the score, the more “super” the food (5). Another test more relevant biologically is cellular antioxidant activity (CAA), performed on cell cultures, which has found quercetin, pomegranate and berries clear favorites for decreasing oxidative stress (6). Antioxidant capacity can also be helpful to determine one fruit with another of the same fruit. For example, organically grown fruit and vegetables often have a higher ORAC score indicating greater content of fruit (7).
Should consumers rely strictly on ORAC or CAA tests for making food choices? The answer is, no. While single antioxidants may have unique functions that may link them to reduced risk of disease, such as vitamin C and heart disease (1), quercetin and liver cancer (8), no single antioxidant or antioxidant complex has appeared yet to decreases oxidative stress enough overall to reduce risk of all diseases (1).
As discussed above, however, antioxidants often work with each other synergistically in the body. Thus, for superior nutrition, adopt the “color code”: five to nine servings daily of fruits and vegetables of different colors provides the reds, red-purples, oranges, yellows, and greens for your body daily and is in line the National Cancer Institute and American Institute (9). Until more is known about antioxidants, the color code offers the the best guideline for health and prevention of disease (1).
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Wolfe KL, Liu RH. Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 2007;55:8896-907.
3. Kim DO, Lee KW, Lee HJ, Lee CY. Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. J Agric Food Chem 2002;50:3713-7.
4. Kohri S, Fujii H, Oowada S et al. An oxygen radical absorbance capacity-like assay that directly quantifies the antioxidant's scavenging capacity against AAPH-derived free radicals. Anal Biochem 2009;386:167-71.
5. Cao G, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med 1993;14:303-11.
6. Wolfe KL, Kang X, He X, Dong M, Zhang Q, Liu RH. Cellular antioxidant activity of common fruits. J Agric Food Chem 2008;56:8418-26.
7. Di RL, Di PD, Bigioni M et al. Is antioxidant plasma status in humans a consequence of the antioxidant food content influence? Eur Rev Med Pharmacol Sci 2007;11:185-92.
8. Seufi AM, Ibrahim SS, Elmaghraby TK, Hafez EE. Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 2009;28:80.
9. Heber D, Bowerman S. Applying science to changing dietary patterns. J Nutr 2001;131:3078S-81S.
05 July 2009
What is the biochemical reason why bile secretion is important for health?
Micelles are made up of amphipathic compounds such as bile acids, fatty acids and monoacylglycerols that interact leaving a relatively stable hydrophilic surface and hydrophobic interior (1). They form at certain temperature ranges when a mixture of lipids is present in concentrated amounts (1). Fatty acid and phospholipid micelles are spherical, but pure bile acid micelles are sandwich-shaped rectangles (1p1062).
During lipid digestion after hydrolysis of triacylglycerols by lipases, it’s up to the bile acid sandwiches to solubilize the spheres, thereby forming “mixed” micelles that appear not unlike rods (1p1062). These rods become longer as more lipids (including limited cholesterol) are solubilized (1p1062). The bile acid micelles form at concentrations of 2-5 mM and at pH values above pK, meaning in equilibrium with other micelles in solution (1p1061-2).
From the lumen, the micelles then transfer the lipids to the mucosal surface for absorption by diffusion (1p1063). Lipid-soluble vitamins A, D, E, and K are also transported within the micelles (1p1065). The delivery is dependent on bile acid micelles increasing effective concentration to create solute flux across the unstirred fluid layer (1p1063). Without bile acids, the absorption of triacylglycerols and the lipid-soluble vitamins would be reduced drastically (1p1063).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
During lipid digestion after hydrolysis of triacylglycerols by lipases, it’s up to the bile acid sandwiches to solubilize the spheres, thereby forming “mixed” micelles that appear not unlike rods (1p1062). These rods become longer as more lipids (including limited cholesterol) are solubilized (1p1062). The bile acid micelles form at concentrations of 2-5 mM and at pH values above pK, meaning in equilibrium with other micelles in solution (1p1061-2).
From the lumen, the micelles then transfer the lipids to the mucosal surface for absorption by diffusion (1p1063). Lipid-soluble vitamins A, D, E, and K are also transported within the micelles (1p1065). The delivery is dependent on bile acid micelles increasing effective concentration to create solute flux across the unstirred fluid layer (1p1063). Without bile acids, the absorption of triacylglycerols and the lipid-soluble vitamins would be reduced drastically (1p1063).
Reference List
1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
04 July 2009
Why so many proteolytic enzymes?
When studying the evolution timeline that led to modern biochemistry, one can always turn to studying protein architecture. Proteins have been called “molecular fossils” that serve to mark milestones in the “history of life” (1). There is a wide diversity of proteolytic enzymes in humans and the network of enzymes have a grand complexity that calls for investigation of how they were shaped over time (2).
In digestion there is a variety of proteolytic enzymes—pepsins, enteropeptidases, carboxypeptidases, and aminopeptidases (3). Each work to hydrolyse proteins by cleaving off amino acids from differing peptide bonds, in different stages and conditions (gastric, pancreatic and intestinal phases) and at varied pH ranges (3). The system is indeed complex, not exactly perfect (a better system may have used only a one or two enzymes), but it works and that's evolution.
Each highly structured enzyme would have evolved accordingly at some time, and some, which may have had major roles in the past, have only minor ones now. An example of biochemical “fossils” studied currently in Germany are particular aspartic proteases (4). They are structurally similar to other proteases suggesting a common "major role" ancestor", but have evolved now only to act in “chaperone-like” fashion for substrate binding in digestion (4).
More than 2 percent of human genes are proteases or protease inhibitors (5). New genomic data is expected reveal more about how proteases, their substrates, proteolytic complexes, inhibitors, and interactions all co-evolved (5;6). The complete human degradome—set of protease genes—is also being compared with degradomes of other mammals such as chimpanzees and mice and serving to provide further understanding of ancestral relationship of species (5;7).
Reference List
1. Caetano-Anolles G, Wang M, Caetano-Anolles D, Mittenthal JE. The origin, evolution and structure of the protein world. Biochem J 2009;417:621-37.
2. Page MJ, Di CE. Evolution of peptidase diversity. J Biol Chem 2008;283:30010-4.
3. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
4. Hulko M, Lupas AN, Martin J. Inherent chaperone-like activity of aspartic proteases reveals a distant evolutionary relation to double-psi barrel domains of AAA-ATPases. Protein Sci 2007;16:644-53.
5. Puente XS, Sanchez LM, Gutierrez-Fernandez A, Velasco G, Lopez-Otin C. A genomic view of the complexity of mammalian proteolytic systems. Biochem Soc Trans 2005;33:331-4.
6. Southan C. Exploiting new genome data and Internet resources for the phylogenetic analysis of proteases, substrates and inhibitors. Biochem Soc Trans 2007;35:599-603.
7. Ordonez GR, Puente XS, Quesada V, Lopez-Otin C. Proteolytic systems: constructing degradomes. Methods Mol Biol 2009;539:33-47.
In digestion there is a variety of proteolytic enzymes—pepsins, enteropeptidases, carboxypeptidases, and aminopeptidases (3). Each work to hydrolyse proteins by cleaving off amino acids from differing peptide bonds, in different stages and conditions (gastric, pancreatic and intestinal phases) and at varied pH ranges (3). The system is indeed complex, not exactly perfect (a better system may have used only a one or two enzymes), but it works and that's evolution.
Each highly structured enzyme would have evolved accordingly at some time, and some, which may have had major roles in the past, have only minor ones now. An example of biochemical “fossils” studied currently in Germany are particular aspartic proteases (4). They are structurally similar to other proteases suggesting a common "major role" ancestor", but have evolved now only to act in “chaperone-like” fashion for substrate binding in digestion (4).
More than 2 percent of human genes are proteases or protease inhibitors (5). New genomic data is expected reveal more about how proteases, their substrates, proteolytic complexes, inhibitors, and interactions all co-evolved (5;6). The complete human degradome—set of protease genes—is also being compared with degradomes of other mammals such as chimpanzees and mice and serving to provide further understanding of ancestral relationship of species (5;7).
Reference List
1. Caetano-Anolles G, Wang M, Caetano-Anolles D, Mittenthal JE. The origin, evolution and structure of the protein world. Biochem J 2009;417:621-37.
2. Page MJ, Di CE. Evolution of peptidase diversity. J Biol Chem 2008;283:30010-4.
3. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
4. Hulko M, Lupas AN, Martin J. Inherent chaperone-like activity of aspartic proteases reveals a distant evolutionary relation to double-psi barrel domains of AAA-ATPases. Protein Sci 2007;16:644-53.
5. Puente XS, Sanchez LM, Gutierrez-Fernandez A, Velasco G, Lopez-Otin C. A genomic view of the complexity of mammalian proteolytic systems. Biochem Soc Trans 2005;33:331-4.
6. Southan C. Exploiting new genome data and Internet resources for the phylogenetic analysis of proteases, substrates and inhibitors. Biochem Soc Trans 2007;35:599-603.
7. Ordonez GR, Puente XS, Quesada V, Lopez-Otin C. Proteolytic systems: constructing degradomes. Methods Mol Biol 2009;539:33-47.
03 July 2009
Whether or Not to Take Vitamin C
Unlike most other mammals, humans and other primates don't synthesize vitamin C because we lack the enzyme glunolactone oxidase (1). The enzyme was lost long ago without affecting our survival due to frequent intake of high-vitamin C fruits and vegetables.
Thus, we must continue to get vitamin C from our diet by the same manner (fruits or veggies) or otherwise, lest we succumb to scurvy as British sailors did in the early 1800s before they adopted rationing limes on naval vessels (1).
Vitamin C deficiency leading to scurvy is now rare (1) and in the developed world, but studies on North American and European populations have found that many people who do not eat enough fruits and high-vitamin C vegetables continue to have inadequate levels of vitamin C (2;3).
Supplementation or dietary change would serve the majority of these patients because—when taken along with other vitamins—vitamin C may lead to reduced risk of chronic diseases such as cancer, cardiovascular disease and cataracts (1). The antioxidant vitamin is thought to possibly have a role in counteracting and detoxifying carcinogens, preventing myocardial lipid peroxidation and LDL oxidation, and prevent oxidative damage to lens in the eye (1).
Note that the vitamin has not been found to have any effect on reducing risk of colds (1). This is in contrast to what's marketed on many dietary supplements.
Large intakes of vitamin C (above 2g daily) can cause diarrhea (1). The vitamin C competes with uric acid inhibiting renal absorption of uric acid that can lead to increases of uric acid excretion, urine acidification and precipitation of uric acid crystals (1). This may increase risk of urate kidney stones if high doses are taken chronically (1). Chronic high doses may not be appropriate also for those with iron metabolism disorders since vitamin C increases iron absorption (1).
Recommended dietary intake levels are 75mg for women and 90 mg for men (1). If pregnant, elderly, smoking or afflicted with chronic disease, a little more may be needed (4-6). Supplementation with a multivitamin may be sufficient for oxidative stress protection, however, findings on reducing risk of chronic disease are mostly related to antioxidant vitamin intake from fruit and vegetables (6-10).
Based on the above rationale, I would recommend patients first attempt to increase fruit and vegetable consumption to meet desired plasma levels and with optimal synergistic effects of other vitamins. If there’s any doubt of the patient’s ability or motivation to eat fruits and vegetables, then vitamin C in form of a multivitamin would be the next step.
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Hampl JS, Taylor CA, Johnston CS. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am J Public Health 2004;94:870-5.
3. Taylor CA, Hampl JS, Johnston CS. Low intakes of vegetables and fruits, especially citrus fruits, lead to inadequate vitamin C intakes among adults. Eur J Clin Nutr 2000;54:573-8.
4. Valdes F. [Vitamin C]. Actas Dermosifiliogr 2006;97:557-68.
5. Brubacher D, Moser U, Jordan P. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res 2000;70:226-37.
6. Goodwin JS, Brodwick M. Diet, aging, and cancer. Clin Geriatr Med 1995;11:577-89.
7. Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ. Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol 2004;160:1223-33.
8. Nagyova A, Krajcovicova-Kudlackova M, Horska A et al. Lipid peroxidation in men after dietary supplementation with a mixture of antioxidant nutrients. Bratisl Lek Listy 2004;105:277-80.
9. Broekmans WM, Klopping-Ketelaars IA, Schuurman CR et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578-83.
10. Zino S, Skeaff M, Williams S, Mann J. Randomised controlled trial of effect of fruit and vegetable consumption on plasma concentrations of lipids and antioxidants. BMJ 1997;314:1787-91.
Thus, we must continue to get vitamin C from our diet by the same manner (fruits or veggies) or otherwise, lest we succumb to scurvy as British sailors did in the early 1800s before they adopted rationing limes on naval vessels (1).
Vitamin C deficiency leading to scurvy is now rare (1) and in the developed world, but studies on North American and European populations have found that many people who do not eat enough fruits and high-vitamin C vegetables continue to have inadequate levels of vitamin C (2;3).
Supplementation or dietary change would serve the majority of these patients because—when taken along with other vitamins—vitamin C may lead to reduced risk of chronic diseases such as cancer, cardiovascular disease and cataracts (1). The antioxidant vitamin is thought to possibly have a role in counteracting and detoxifying carcinogens, preventing myocardial lipid peroxidation and LDL oxidation, and prevent oxidative damage to lens in the eye (1).
Note that the vitamin has not been found to have any effect on reducing risk of colds (1). This is in contrast to what's marketed on many dietary supplements.
Large intakes of vitamin C (above 2g daily) can cause diarrhea (1). The vitamin C competes with uric acid inhibiting renal absorption of uric acid that can lead to increases of uric acid excretion, urine acidification and precipitation of uric acid crystals (1). This may increase risk of urate kidney stones if high doses are taken chronically (1). Chronic high doses may not be appropriate also for those with iron metabolism disorders since vitamin C increases iron absorption (1).
Recommended dietary intake levels are 75mg for women and 90 mg for men (1). If pregnant, elderly, smoking or afflicted with chronic disease, a little more may be needed (4-6). Supplementation with a multivitamin may be sufficient for oxidative stress protection, however, findings on reducing risk of chronic disease are mostly related to antioxidant vitamin intake from fruit and vegetables (6-10).
Based on the above rationale, I would recommend patients first attempt to increase fruit and vegetable consumption to meet desired plasma levels and with optimal synergistic effects of other vitamins. If there’s any doubt of the patient’s ability or motivation to eat fruits and vegetables, then vitamin C in form of a multivitamin would be the next step.
Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Hampl JS, Taylor CA, Johnston CS. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am J Public Health 2004;94:870-5.
3. Taylor CA, Hampl JS, Johnston CS. Low intakes of vegetables and fruits, especially citrus fruits, lead to inadequate vitamin C intakes among adults. Eur J Clin Nutr 2000;54:573-8.
4. Valdes F. [Vitamin C]. Actas Dermosifiliogr 2006;97:557-68.
5. Brubacher D, Moser U, Jordan P. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res 2000;70:226-37.
6. Goodwin JS, Brodwick M. Diet, aging, and cancer. Clin Geriatr Med 1995;11:577-89.
7. Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ. Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol 2004;160:1223-33.
8. Nagyova A, Krajcovicova-Kudlackova M, Horska A et al. Lipid peroxidation in men after dietary supplementation with a mixture of antioxidant nutrients. Bratisl Lek Listy 2004;105:277-80.
9. Broekmans WM, Klopping-Ketelaars IA, Schuurman CR et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578-83.
10. Zino S, Skeaff M, Williams S, Mann J. Randomised controlled trial of effect of fruit and vegetable consumption on plasma concentrations of lipids and antioxidants. BMJ 1997;314:1787-91.
Carrageenans - Good or Bad for You?
Carrageenans are food additives derived from red seaweed such as Chondrus crispus (Irish moss) and other species and are used as a thickening, stabilizing, and texturizing agents in foods and also for reduced-fat meat products (1;2).
They nicely replace animal-based gelatin found in many foods such as soymilk, chocolate milk, yogurts, beers and wines. Lamda-carrageenan, for example, is used to provide a creamy texture to dairy products.
The polymers are high-molecular-weight polysaccharides made up of repeating disaccharide units have a charged nature and their structure gives them their highly reactive properties (2). Concentration and greater molecular weight increases viscosity further (2).
Safety of use of carrageenans in foods has been a matter of controversy and confusion. Leading manufacturers of carrageenan such as FMC corporation have maintained that the use of carrageenan has a centuries-old history of safety in humans that has been confirmed by studies on animals such as dogs and rodents (3). Food-grade carrageenans are not thought to be degraded or absorbed from the gastrointestinal tract of humans (1).
It is known that, when administered systemically, carrageenans are linked to acute liver toxicity (4), are carcinogenic (5) and affect the immune system (6). Also, a substance formed of degraded carrageenan, now known as poligeenan, has long been banned from use in food because of links to fetal toxicity, birth defects, liver toxicity, ulcerative disease, pulmonary lesions and colon cancer in animals (5).
Toxicity concerns of undegraded carrageenans arose when studies in a few experimental animals found that carrageenans were degraded leading to absorption and toxicity (5;6). Another study on rats found that given small quantities of for 90 days, undegraded carrageenans had “penetrated the intestinal barrier degree” in adult rats (7). Low concentrations were also tested on tissue cultures where it was found that lamda-carrageenans entered cells by what appeared to be endocytosis (8).
Despite these data, however, the World Health Organization Expert committee on Food Additives and Joint Food and Agriculture Organization have kept recommendations of allowable daily intake as “not specified” (6).
The groups cited that there was “no credible evidence” to support that food-grade carrageenans were degraded or absorbed in “rodents, dogs, and non-human primates” or that they presented any toxic or carcinogenic effect in these species or in humans long term (6). High doses of carrageenans had been found to lead to cecal enlargement, but the studied amounts were in excess of which humans would consume normally (6).
Reference List
1. Trius A, Sebranek JG. Carrageenans and their use in meat products. Crit Rev Food Sci Nutr 1996;36:69-85.
2. Food and Agriculture Organization. FAO Corporate Document Repository. Training Manual on Gracilaria Culture and Seaweed Processing in China. Available: http://www.fao.org/docrep/field/003/AB730E/AB730E03.htm.
3. Weiner ML. Toxicological properties of carrageenan. Agents Actions 1991;32:46-51.
4. Abe T, Kawamura H, Kawabe S, Watanabe H, Gejyo F, Abo T. Liver injury due to sequential activation of natural killer cells and natural killer T cells by carrageenan. J Hepatol 2002;36:614-23.
5. Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Cancer Detect Prev 1981;4:129-34.
6. Cohen SM, Ito N. A critical review of the toxicological effects of carrageenan and processed eucheuma seaweed on the gastrointestinal tract. Crit Rev Toxicol 2002;32:413-44.
7. Nicklin S, Miller K. Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat. Food Chem Toxicol 1984;22:615-21.
8. Tobacman JK, Walters KS. Carrageenan-induced inclusions in mammary myoepithelial cells. Cancer Detect Prev 2001;25:520-6.
They nicely replace animal-based gelatin found in many foods such as soymilk, chocolate milk, yogurts, beers and wines. Lamda-carrageenan, for example, is used to provide a creamy texture to dairy products.
The polymers are high-molecular-weight polysaccharides made up of repeating disaccharide units have a charged nature and their structure gives them their highly reactive properties (2). Concentration and greater molecular weight increases viscosity further (2).
Safety of use of carrageenans in foods has been a matter of controversy and confusion. Leading manufacturers of carrageenan such as FMC corporation have maintained that the use of carrageenan has a centuries-old history of safety in humans that has been confirmed by studies on animals such as dogs and rodents (3). Food-grade carrageenans are not thought to be degraded or absorbed from the gastrointestinal tract of humans (1).
It is known that, when administered systemically, carrageenans are linked to acute liver toxicity (4), are carcinogenic (5) and affect the immune system (6). Also, a substance formed of degraded carrageenan, now known as poligeenan, has long been banned from use in food because of links to fetal toxicity, birth defects, liver toxicity, ulcerative disease, pulmonary lesions and colon cancer in animals (5).
Toxicity concerns of undegraded carrageenans arose when studies in a few experimental animals found that carrageenans were degraded leading to absorption and toxicity (5;6). Another study on rats found that given small quantities of for 90 days, undegraded carrageenans had “penetrated the intestinal barrier degree” in adult rats (7). Low concentrations were also tested on tissue cultures where it was found that lamda-carrageenans entered cells by what appeared to be endocytosis (8).
Despite these data, however, the World Health Organization Expert committee on Food Additives and Joint Food and Agriculture Organization have kept recommendations of allowable daily intake as “not specified” (6).
The groups cited that there was “no credible evidence” to support that food-grade carrageenans were degraded or absorbed in “rodents, dogs, and non-human primates” or that they presented any toxic or carcinogenic effect in these species or in humans long term (6). High doses of carrageenans had been found to lead to cecal enlargement, but the studied amounts were in excess of which humans would consume normally (6).
Reference List
1. Trius A, Sebranek JG. Carrageenans and their use in meat products. Crit Rev Food Sci Nutr 1996;36:69-85.
2. Food and Agriculture Organization. FAO Corporate Document Repository. Training Manual on Gracilaria Culture and Seaweed Processing in China. Available: http://www.fao.org/docrep/field/003/AB730E/AB730E03.htm.
3. Weiner ML. Toxicological properties of carrageenan. Agents Actions 1991;32:46-51.
4. Abe T, Kawamura H, Kawabe S, Watanabe H, Gejyo F, Abo T. Liver injury due to sequential activation of natural killer cells and natural killer T cells by carrageenan. J Hepatol 2002;36:614-23.
5. Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Cancer Detect Prev 1981;4:129-34.
6. Cohen SM, Ito N. A critical review of the toxicological effects of carrageenan and processed eucheuma seaweed on the gastrointestinal tract. Crit Rev Toxicol 2002;32:413-44.
7. Nicklin S, Miller K. Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat. Food Chem Toxicol 1984;22:615-21.
8. Tobacman JK, Walters KS. Carrageenan-induced inclusions in mammary myoepithelial cells. Cancer Detect Prev 2001;25:520-6.
Tidbit: GLUT6 - the "pseudogene"
GLUT6 is expressed in various tissues in the body, but doesn't encode any functional glucose transport protein (1). Why does it occur at all? It's thought that GLUT6’s nucleotide sequence may have simply occurred from an insertion of GLUT3 reverse transcribed in a region of an untranslated gene (1).
Reference List
1. Kayano T, Burant CF, Fukumoto H et al. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem 1990;265:13276-82.
Reference List
1. Kayano T, Burant CF, Fukumoto H et al. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem 1990;265:13276-82.
Review of study on using antioxidant response as predictor for radiation pneumonitis
A currently unpredictable outcome of radiotherapy on lung cancer patients is radiation pneumonitis (lung inflammation). This study was the first performed on humans to determine how antioxidant response may be used to predict this “potentially lethal treatment-related complication”. The oxidative stress link had been established through studies on irradiated mice.
Type of study: Observational study on humans; physicians grading for pneumonitis were blinded to antioxidant data
Method used to conduct study: Fifteen total lung cancer patients were found eligible for the study after signing informed consents, having stage III disease, receiving concurrent definitive radiotherapy and paclitaxel-based chemotherapy, and having good performance status. Excluded were patients who had received radiotherapy or chemotherapy previously and those with unfavorable Eastern Cooperative Oncology Group performance status or chronic obstructive pulmonary disease.
Blood samples were collected at baseline and weekly during the 6-week treatment. Radiation pneumonitis was diagnosed three months after the treatment according to different grades ranging from mild, moderate, and severe. Cross-validation was used to analyze test sensitivity to variables. Detection of proteins was performed through gel electrophoresis, secondary antibody and enhanced chemiluminescence in the blot analysis.
Summary: Researchers found that the patients who developed pneumonitis had higher levels of superoxide dismutase (SOD) and lower levels of glutathione peroxidase (GPX) overall. The data suggest that higher SOD activity increased the conversion of superoxide anion to hydrogen peroxide. In conjunction with low GPX, an increase of hydrogen peroxide and hydroxyl radicals would occur creating oxidative stress that would predispose patients to radiation pneumonitis.
Critique of research design quality and relevance: Blinding methods and appropriate exclusions make this a well-designed study with few confounding variables. Although strong data from animals confirm its findings, the study’s great weakness is that of being a small one. Its relevance, however, may be large since using GPX/SOD as predictive markers may save lives in the future.
Nutritional implications and implications of future study: High SOD/low GPX activity may serve as a marker for prediction of radiation pneumonits and that increasing the ratio of GPX/SOD would reduce risk of radiation pneumonitis. Clinical trials on use of antioxidant supplements is warranted; however, the researchers warn, antioxidant therapies must take into account other treatments (e.g. chemotherapy) and how it would affect the patient as "a whole".
Reference
Park EM, Ramnath N, Yang GY et al. High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis. Free Radic Biol Med 2007;42:280-7. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892164
Type of study: Observational study on humans; physicians grading for pneumonitis were blinded to antioxidant data
Method used to conduct study: Fifteen total lung cancer patients were found eligible for the study after signing informed consents, having stage III disease, receiving concurrent definitive radiotherapy and paclitaxel-based chemotherapy, and having good performance status. Excluded were patients who had received radiotherapy or chemotherapy previously and those with unfavorable Eastern Cooperative Oncology Group performance status or chronic obstructive pulmonary disease.
Blood samples were collected at baseline and weekly during the 6-week treatment. Radiation pneumonitis was diagnosed three months after the treatment according to different grades ranging from mild, moderate, and severe. Cross-validation was used to analyze test sensitivity to variables. Detection of proteins was performed through gel electrophoresis, secondary antibody and enhanced chemiluminescence in the blot analysis.
Summary: Researchers found that the patients who developed pneumonitis had higher levels of superoxide dismutase (SOD) and lower levels of glutathione peroxidase (GPX) overall. The data suggest that higher SOD activity increased the conversion of superoxide anion to hydrogen peroxide. In conjunction with low GPX, an increase of hydrogen peroxide and hydroxyl radicals would occur creating oxidative stress that would predispose patients to radiation pneumonitis.
Critique of research design quality and relevance: Blinding methods and appropriate exclusions make this a well-designed study with few confounding variables. Although strong data from animals confirm its findings, the study’s great weakness is that of being a small one. Its relevance, however, may be large since using GPX/SOD as predictive markers may save lives in the future.
Nutritional implications and implications of future study: High SOD/low GPX activity may serve as a marker for prediction of radiation pneumonits and that increasing the ratio of GPX/SOD would reduce risk of radiation pneumonitis. Clinical trials on use of antioxidant supplements is warranted; however, the researchers warn, antioxidant therapies must take into account other treatments (e.g. chemotherapy) and how it would affect the patient as "a whole".
Reference
Park EM, Ramnath N, Yang GY et al. High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis. Free Radic Biol Med 2007;42:280-7. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892164
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