My husband and I put this in our local papers as a bit of a shit- stir when the NSW Health Dept. enacted the draconian ammendment of the Fluoridation Act, and used the stupidity of local councillors to ride roughshod over residents of the Mid North Coast of NSW Australia. Every major centre had in the recent past voted against Forced mass medication with Sodium Silicio Fluoride/ or Hydrofluorosilicic Acid ( such chemicals are used unrefined and industrial grade straight fromthe heavy industrial complexes of China and other countries.)One local doctor in particular was most miffed , and waddled right up to my husband to give him a right serve at a council meeting. Brave man. My husband has been a Quadriplegic for 23 years and you could knock him over with a feather. But only physically. Mmentally and spiritually he is a giant! Unlike Mr bully Dr. Broom up the bottom... (some people do look like they have a broom stick lodged up you know where, when they walk, and they usually are jumped up self important right little turds).
Re Fluoridation We have had a big con done on us on this . Please in the interests of balance have a look at www.nofluoride.com or www.glenwalker.net or/and http://bruha.com/pfpc/ the last one is "Parents for Children poisened by Fluoridation"
1 comment:
GLYCONUTRITIONAL IMPLICATIONS IN FIBROMYALGIA AND CHRONIC FATIGUE SYNDROMEAuthor(s): Tom Gardiner, Ph.D. PDF of this article
Author biographies
Abstract In order to understand how the biological activities of specific nutritional elements, such as glycoconjugate sugars, relate to fibromyalgia/chronic fatigue syndrome (FM/CFS), this review will first discuss what is known regarding the possible causes and mechanisms of FM and CFS, and then review which of those mechanisms involve glycoconjugate sugars and complex carbohydrates. Although they are considered by some clinicians as separate disorders with overlapping symptoms, FM/CFS will be discussed together, whenever possible, since affected systems are similar. Scientific studies of the effects of specific glyconutritional elements on FM/CFS are reviewed. Conclusions are then summarized regarding nutritional implications in FM/CFS patients. Most of the journal articles referenced in this review were published in the last 3-5 years and represent the most current information available on this topic. Introduction Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are two similar disorders with overlapping symptoms, such as chronic fatigue, sleep disturbances, immune system dysfunction, and psychological depression. FM is further characterized by muscle and fibrous tissue pain, and its prevalence has been estimated at greater than 7% in women aged 60-79 years and 3.4% for women vs. 0.5% for men in the general population.1 Although accurate numbers are not available for the prevalence of CFS, since definitive diagnosis is more difficult, CFS mainly affects middle-aged females, with a peak age of onset of 20-40 years.2 Even though FM/CFS disorders affect several millions of people each year, medical management and treatment consist mainly of education, relief of discomfort, and improvement of quality of sleep, exercise, and emotional balance.3 Since the cause(s) of FM/CFS and mechanism(s) for the disorders are still unclear, it has not been possible for specific drugs to be developed which would target a discreet, causative, malfunction; only symptomatic drug therapy is available. In fact, it appears that there are subpopulations within these disorders that may have more or less involvement of certain biologic systems (eg. immune, nervous, muscular), which further complicates diagnosis and treatment with conventional drugs.4 Some clinicians actually prefer to think of FM/CFS as syndromes rather than discrete diseases.5 With all these complexities, it is understandable that the role of nutrition in FM/CFS has largely been overlooked. However, since we now understand the importance of dietary ingredients, such as the necessary glycoconjugate sugars (mannose, galactose, fucose, glucose, N-acetylgalactosamine, N-acetylglucosamine, sialic acid, xylose) and complex carbohydrates in regulating the immune, nervous, and muscular systems, as well as cell-to-cell communications in general,6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 it is not surprising that the biological activities of such nutritional elements play a significant role in maintaining the health of these systems. More specifically, glycoproteins and glycolipids, containing one or more of eight necessary sugars, function as receptors on the surface of mammalian cells and invading pathogens. These glycoconjugate sugar residues on the surface of one cell bind to glycoconjugate receptors on another cell, which allows the cells to communicate with one another.16 These communications then result in other cellular events, such as secretion of bioactive substances like interferon, interleukin-1 and complement,17 phagocytosis of bacteria and cell debris18 and inhibition of adherence necessary for bacterial infection.19 The principal symptoms of FM/CFS include muscle and joint pain, chronic (> 6 months) fatigability, non-restorative sleep, chronic tension and migraine headaches, and bowel and bladder irritability.20 , 21 , 22 Due to the fatigue and pain associated with movement, muscular systems are also significantly affected in FM/CFS patients. For example, physical and cardiovascular deconditioning is clearly evident in some CFS patients. Findings include smaller left heart ventricles and smaller diameter carotid arteries and changes in serum cholesterol, triglycerides, and thyroid hormone levels, consistent with physical deconditioning.23 Cardiovascular deconditioning also explains changes in the autonomic nervous system control of orthostatic blood pressure in CFS patients.24 Several possible causes of FM/CFS have been proposed. For example, it has been hypothesized that there is a relationship between sleep disturbance and the pathogenesis of FM/CFS, and that correction of the disturbed sleep pattern can effect improvement in symptoms.2 , 3 A strong association with sleep disturbance is suggested by a) increased frequency of non-restorative sleep, b) electroencephalographic evidence of reduced deep non-REM sleep, and c) reproduction of FM symptoms and painfully tender sites in normal subjects by selective deprivation of non-REM sleep.20 It has also been suggested that FM pain might be caused by muscle microtrauma associated with sleep interference, and that lower serum levels of the growth hormone, somatomedin C, seen in FM patients, may affect their ability to heal from the microtrauma.3 Somatomedin C is necessary for proper muscle tissue repair and homeostasis and is produced during non-REM (stage IV) sleep, which is decreased in FM/CFS. Growth hormone response to hypoglycemia was reduced in CFS patients, further suggesting a pathogenic role for the hormone.25 With regard to a role for proper nutrition in this mechanism, the necessary conjugate sugar, mannose, functions to promote wound healing and tissue repair.26 Also, glycoconjugate sugar residues form an essential part of the cellular receptors to which many hormones bind in order to produce their biological effects.17 Another possible cause of FM/CFS is an imbalance of neurotransmitters.27 For example, the amino acid tryptophan is metabolized to serotonin, an important neurotransmitter in sleep and pain nerve pathways. FM/CFS patients have reduced plasma levels of both tryptophan and serotonin and a higher density of serotonin receptors on their circulating blood platelets. These findings, plus lower levels of serotonin-related amino acids and lower cerebrospinal fluid levels of biogenic amines in FM patients, suggest a possible deficit of serotonin metabolism in FM/CFS patients. In fact, when serotonin is depleted, there is a decrease in restorative non-REM sleep and an increase in somatic complaints, depression, and perceived pain.21 , 28 Substance P, another neurotransmitter involved in pain transmission, is believed to be inhibited by endorphins (neuropeptides), which increase with exercise; this would modulate pain and further indicate the importance of balance of neurotransmitters in FM/CFS .21 In this regard, cerebrospinal fluid levels of substance P were found to be threefold higher in blood mononuclear cells of CFS patients,1 and endorphin concentrations were fivefold lower in CFS patients.29 In addition, serotonin is known to influence pain thresholds by interacting with substance P and potentiating the effect of endorphins. It is possible that the tender points in FM patients may be nothing more than normally tender anatomic structures that become more tender when levels of substance P fall.30 Interestingly, CFS is not characterized by tender points, and differs from FM, in that substance P levels are not elevated in cerebrospinal fluid from CFS patients.31 The necessary conjugate sugars appear to be important in modulating the activity of neurotransmitters. For example, neurotransmitter transporters are cell membrane glycoproteins that are responsible for termination of neurotransmission impulses. It has been shown that N-glycosylation (attachment of sugars to the nitrogen atom in the side chain of asparagine) of these transporters is important for the stability of the proteins that transport norepinephrine32 and serotonin33 to appropriate membrane compartments. Removal of essential sugar residues from the dopamine (another neurotransmitter) transporter also results in decreased dopamine uptake.34 Several virus groups, including herpes viruses, retroviruses, and enteroviruses, and other pathogens have been implicated in FM/CFS, because symptoms of these disorders are often found associated with an active virus infection,35 although none is considered a uniquely causative agent of the disorders.35 , 36 , 37 For example, Coxsackie B virus and herpes virus 6 have been identified in CFS patients by antibody or actual virus presence. In fact, it has been postulated that CFS patients may have a genetic predisposition to viral infection.37 Enteroviral infection is a common feature of some groups of CFS patients, and there is evidence for enteroviral persistence in CFS patients.38 Chronic parvovirus B19 infection has been observed in a CFS patient,39 and a cytopathic stealth virus was cultured from the cerebrospinal fluid of another CFS patient.40 CFS patients have also had antibody titers to Epstein-Barr virus, cytomegalovirus, herpes simplex virus, and measles virus.35 Evidence of lentivirus infection was also seen in CFS patients but not in controls.41 Other non-viral pathogens, such as Mycoplasma, have been found with some frequency in CFS patients.42 The frequency of Mycoplasma infection was found to be 52% in CFS patients and only 15% in healthy individuals. Although Yersinia enterocolitica is unlikely to cause CFS, it can persist in gut-associated lymphatic tissue and cause a variety of CFS symptoms. Glycoconjugate sugars have biological activities that can prevent viral or bacterial infection in mammalian hosts. For example, bacteria have sugar binding proteins (lectins) on their surface, which bind glycoconjugate receptors on the surface of mammalian host cells, resulting in attachment and infection. Dietary galactose and glucose are also important in maintaining normal colonic bacteria.43 In animals, mannose blocks Salmonella typhimurium adherence to chicken intestine in vitro44 and markedly reduces (50-100%) the incidence of Salmonella infection in vivo when given to chickens in their drinking water.45 Mannose reduces Escherichia coli infection in newborn mice (from 77% normally to 25% post-treatment) when a solution is applied topically to maternal vaginas prior to delivery.46 Sialic acid inhibited bacterial adhesion, due to its ability to modulate cellular aggregation and attachment.47 , 48 Glycoconjugate sugars display anti-viral activity because of their ability to stimulate macrophages to release interferon, and they also inhibit glycosylation of the viral envelope and thereby interfere with normal viral function (discussion of immune system activities follow). Considerable scientific evidence also suggests that FM/CFS is related to immune system dysfunction, based on measurements of various immune markers in patients with the disorders. Although this does not imply causality, it supports the hypothesis that the immune system is a pathogenetic mechanism for FM/CFS.49 For example, the activity/activation of natural killer lymphocytes (NK), which participate in the immune defense system against a wide range of pathogens, especially viral infections, is decreased in CFS patients.50 , 51 , 52 Cytokines, which are believed to play a role in the fatigue and depression of CFS via their effects on the central nervous system, pituitary, and gonadal hormones, are increased in CFS. For example, production of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) increased and IL-10 decreased in CFS.53 , 54 There was also increased IL-1 activity by cells from CFS patients, that were sensitive to the female hormones, estradiol and progesterone,55 coincident with a greater frequency of FM/CFS in females. Interestingly, the symptoms of CFS are similar to the reactions observed in humans following infusion of TNF-alpha and IL-1.56 A high frequency of autoantibodies have also been reported in CFS patients, suggesting that the disorder may have an autoimmune basis.57 However, other investigators have been unable to detect consistent or predictive changes in anti-muscle or anti-CNS circulating antibodies in CFS.58 , 59 Unfortunately, serum markers of immune activation are of limited diagnostic use in the evaluation of FM/CFS patients,60 and some clinicians have been unable to find any important associations between clinical status, treatment response, and immunological status.61 The reasons for these discrepancies may be that there are subsets of patients with different types of immune dysfunction. For example, when patients were subgrouped by type of disease onset (gradual or sudden) or by how well they were feeling on the day of testing, more pronounced differences were seen in various measures of immune function.4 Since one of the most important biological activities of the necessary glycoconjugate sugars and complex carbohydrates is immune system modulation,14 any role that the immune system might play in FM/CFS would logically be influenced by these particular nutritional elements. In this regard, mannose stimulates the migration of macrophages, immune system cells that orchestrate the release of various bioactive substances that modulate the immune response and tissue inflammation and phagocytize bacteria and cell debris.62 Acemannan, an acetylated mannose polysaccharide, also enhances killing of Candida albicans by macrophages.18 In one of the few studies in which possible effects have actually been measured, FM/CFS patients who consumed a nutritional supplement containing freeze-dried aloe vera extract, which is rich in acetylated mannans, reported significant improvement in their symptoms.63 A host of other immune-modulating effects are part of the activities of glycoconjugate sugars. Mannose-containing glycopeptides can also directly inhibit antigen-driven T-cell responses.64 Galactose-containing glycoproteins induce prostaglandin synthesis and directly stimulate IL-1, which are involved in regulating mammalian inflammatory responses.65 A galactose-containing polymer stimulates macrophages and other immune system activities important in resolving inflammation and in wound healing.62 , 66 In experimental animal studies, galactose conjugated to protein decreases experimentally induced necrotizing gastritis to a greater extent than antacids.67 Fucose stimulates rabbit macrophages62 and inhibits neutrophil and macrophage chemotactive factors, which are also important immunomodulatory activities. If sialic acid residues are removed from peripheral blood mononuclear cells, the multiplication of HIV-1 is increased in vitro, possibly due to decreased interferon secretion.68 Secondary FM has also been documented in patients with rheumatoid arthritis, osteoarthritis, sleep apnea, irritable bowel syndrome, and menstrual dysfunction.3 With regard to rheumatoid arthritis, immunoglobulin-G in some patients has fewer galactosyl residues; the reduction of residues worsens with disease severity69 and reverses during symptomatic remission.70 Since FM/CFS is considered to have a strong psychological component, it is important to consider how the CNS can also modulate the immune response and influence the expression of latent viruses, and how cytokine synthesis, NK cell activity, and T-lymphocyte function relate to FM/CFS. These relationships have been aptly described by Drs. R. Glaser and J.K. Kiecolt-Glaser35 as follows: Psychological stress can stimulate release of corticotropin-releasing hormone (CRH) from the hypothalamus, which leads to production of adrenocorticotropic hormone (ACTH). ACTH stimulates the adrenal cortex to increase levels of glucocorticoid hormones, which suppress the immune response and can reactivate latent viruses. Glucocorticoid hormones, ACTH and CRH have also been shown to enhance viral replication in vitro. Other "stress" hormones, such as prolactin and growth hormone, can act as immune enhancers. Communication between the CNS and immune system is bidirectional. For example, IL-1 can influence the hypothalamus to modulate CRH production, and lymphocytes can synthesize hormones such as ACTH, prolactin, and growth hormone. The release of ACTH and cortisol (glucocorticoid) was also found to be decreased in a group of CFS patients, suggesting that other factors may also be important in the pathogenesis of the disorder.71 Conclusion Regardless of the precise mechanism(s) of pathogenesis for FM/CFS, it should be clear from this review of the most recent scientific and medical literature that the immune (eg. cytokines, lymphocytes, virus infection), endocrine (eg. hormones), nervous (eg. neurotransmitters, sleep pathways, psychological stress) and muscular (eg. tender points, cardiovascular deconditioning) systems of the body are all intimately involved in the FM/CFS syndrome. It should also be apparent that the necessary glycoconjugate sugars and complex carbohydrates all play important roles in maintaining the health and normal functioning of these systems. Moreover, dietary mannose (and, perhaps, other necessary glycoconjugate sugars) has been shown to be well absorbed and preferentially utilized for biosynthesis of glycoproteins in humans.72 Maintenance of body health also seems particularly important, considering the major medical and pharmaceutical challenges of diagnosis and therapy of FM/CFS and the long-term difficulties facing FM/CFS patients. Certainly, the complex pathogenesis of FM/CFS and variations in symptoms among individual patients combine to challenge the medical understanding of these debilitating syndromes. Date last modified: June 03, 2000
GLYCONUTRITIONALS: IMPLICATIONS IN ANTIMICROBIAL ACTIVITYAuthor(s): Stanley S. Lefkowitz, PhD, and Doris L. Lefkowitz, PhD PDF of this article
Author biographies
Abstract We are all under attack by microorganisms that inhabit our environment. Many of these microorganisms are beneficial and necessary for our well-being. However, some microorganisms cause disease. Both our cells and microorganisms have carbohydrates on their surface. Through the interactions of these surface carbohydrates, which act as cell-cell communication signals, microorganisms can gain access to our body, start to multiply, and cause disease. Various carbohydrates, such as mannose, have been shown to participate in this process. Glyconutritional supplements, which contain various saccharides including mannose, can supply carbohydrates that assist in the maintenance of good health by interfering with the infectious process. This may be accomplished by at least two mechanisms: 1) by hindering pathogen colonization and 2) by stimulating immune cell function. We live in a world where we are painfully outnumbered by numerous microorganisms. While some microorganisms, such as the bacteria that colonize the gut, are beneficial to human health, many other microorganisms are particularly adept at out maneuvering our immune system and subsequently causing disease. Before these microorganisms can cause disease, they must gain access to our bodies. With respect to bacteria, these microorganisms have carbohydrate-binding proteins which are receptors called adhesins. Adhesins bind to carbohydrates on the surface of the host cells.1 Bacteria utilize binding to our cell surface sugars as the first step towards infection. Conversely, our cells also express various receptors that bind mannose or other sugars expressed on the surface of other cells or bacteria. Bacteria that have been shown to express carbohydrates on their surface include: Escherichia coli, Neisseria gonorrhoeae,2 Mycobacterium tuberculosis,3 as well as certain Salmonella and Staphylococci.2 Fungi are also capable of causing disease; however, fungal interactions with host cell receptors have not been studied as extensively as have such interactions with bacteria. Candida albicans, which causes an array of diseases from asymptomatic to life-threatening, interacts with the host receptors through the mannose-containing proteins expressed on the yeast's cell surface. Because of the ability of macrophages to bind mannose on the surface of Candida, experiments were done in vitro to determine if macrophages exposed to glyconutrients would exhibit enhanced candidicidal activity compared to control cultures.4 , 5 Macrophages incubated with glyconutrients for 60 minutes were significantly more candidicidal than those not exposed to glyconutrients. In other studies, investigators reported that saccharides protected mice against gastrointestinal colonization by C. albicans.6 Other types of infectious agents also require carbohydrate-mediated adherence for infection. The amoebal parasite Acanthamoeba, which can cause serious eye infections, requires binding to mannose receptors on host cells. It has been demonstrated that mannose-containing saccharides, as well as N-acetyl-d-glucosamine, can inhibit amoeba-induced cytopathology of isolated cells.7 Even viruses have glycoproteins on their surface that are involved in their entry into a host cell. It has been recognized for decades that sialic acid residues on the surface of cells represent part of the receptor for the influenza virus.8 Furthermore, sialic acid containing receptors in the sera can block binding of the virus glycoprotein to cells in vitro.8 One of the most extensively studied viral glycoproteins is the glycoprotein (gp120) on the surface of HIV, the virus that causes AIDS. Numerous investigators are currently attempting to develop a vaccine against this glycoprotein in order to prevent AIDS. Once again, communication between the invading pathogen and the host cell is through carbohydrate interactions at the pathogen-host interface. Our bodies have adapted to the invasion of these microbes by a series of non- specific, as well as specific, highly specialized defense maneuvers.9 For example, many host cells are coated with mucins, which are primarily carbohydrate in nature. Mucins form a protective barrier between us and the invaders. Other substances in our bodies are capable of binding to bacteria or other microorganisms, making them more susceptible to engulfment and destruction by phagocytic leukocytes. These substances include surfactant, which is a carbohydrate-containing substance found in lungs, and mannose binding lectin, which is found throughout the body. Mannose-binding lectin binds to repeating sugar arrays on microbial surfaces and may result in enhanced uptake and destruction of microorganisms.10 , 11 Specific immune responses, which develop in response to an invader, develop after the initial carbohydrate-receptor interactions described above. These specific responses are the product of highly specialized cells.9 In addition, the importance of these carbohydrate-receptor interactions is apparent from reports that genetic defects in cellular adhesion molecules which contain carbohydrates can result in a higher incidence of infection.12 The macrophage represents one of the first lines of defense against microbial attack. Initial recognition between a microorganism and this cell is through carbohydrate-receptor interactions. One of the most studied receptors involved in carbohydrate recognition is on the macrophage cell surface. This receptor is known as the macrophage mannose receptor and it recognizes and preferentially binds various substances containing either mannose or fucose. This receptor can also bind other sugars with a somewhat lower affinity. It has been proposed that the macrophage mannose receptor is a part of a "primitive" immune recognition system that is based on carbohydrate-specific interactions.13 There are, however, other receptors on the surface of the macrophage which also bind mannose and other sugars. These receptors have recently been discovered and the role they play in clearing an infection is not clearly defined.14 Numerous studies have looked at the effects of Acemannan, which is a beta-1,4-linked acetylated mannan, and beta-1,3-glucan on various immune functions.15 Both substances have been shown both experimentally and clinically, in various studies, to have immunoenhancing properties.15 Acemannan is currently licensed to treat fibrosarcomas in dogs and cats.15 With regard to its anti-microbial properties, this substance was also shown to inhibit binding of Pseudomonas aeruginosa to epithelial cells.16 Studies by the present authors have demonstrated that certain carbohydrates and or glyconutrients can activate macrophages, resulting in increased microbicidal activity. Studies using Acemannan have demonstrated that this material, when incubated with murine peritoneal macrophages in vitro, results in their activation with enhanced killing of C. albicans.17 Killing of these microorganisms was both time- and dose-dependent. Additional studies by these researchers have demonstrated similar activity for a glyconutrient mixture of eight saccharides (fucose, galactose, glucose, mannose, N-acetylglucosamine, N-acetylgalactosamine, N-acetylneuraminic acid, xylose).4 , 5 , 18 As with Acemannan, a dose- and time-dependent enhanced killing of these same microorganisms was demonstrated. In addition to the above interactions, it should be noted that host immune cells require signals that involved carbohydrate interactions to initiate their migration into a site of pathogen invasion. Upon stimulation, endothelial cells that comprise the wall of the capillaries express certain carbohydrates. These carbohydrates function as cell-cell communication signals, in that the carbohydrate-cell interactions indicate to the cells of the immune system where to leave the bloodstream and migrate into the tissues.12 Without these interactions, we are not able to clear invading pathogens and a common bacterial infection could become a life-threatening event. The fact that various cellular receptors are glycoproteins and that specific sugars present on the surface of microorganisms react with them suggests a possible target for prevention of disease. That is, specific sugars could interfere with some of a microorganism's initial interactions necessary for the disease process. This concept has already been supported by studies in which sugars, or other synthetic receptor analogs blocked binding of microorganisms to cells, subsequently preventing microbial invasion.19 , 20 , 21 , 22 In fact, oligosaccharides and glycoconjugates, which are natural components of breast milk, may prevent intestinal attachment of pathogens by acting as receptors that bind bacteria, ultimately resulting in a reduction of infectivity.23 Figure C illustrates how a glyconutrient could be used to prevent disease. Therefore, from the above information it can be surmised that carbohydrate-receptor interactions are vital for both the invading pathogen and the host. Without these interactions, the pathogen cannot cause disease. Likewise, without these interactions the host cannot defend itself against the pathogen. With the rise of numerous antibiotic-resistant strains of bacteria, scientists are searching for new treatment modalities for which pathogens have not developed escape mechanisms. The administration of carbohydrates can benefit the host through at least two possible mechanisms: (1) through its hindrance of pathogen colonization and (2) potentiation of immune cell function.4 , 5 , 24 . Thus, utilization of glyconutrients could represent a new weapon in the never ending battle between us and the microbial world. Date last modified: June 17, 2000
www.glycoscience.orgCopyright 2000-2004 Mannatech™ Incorporated. All Rights Reserved.This site is provided by Mannatech™ Incorporated as an educational site for use in the United States. Specific handling of printed documents from this site is covered in detail under Legal Notices and Terms of Use.Email Webmaster
Glyconutritionals and Glycoconjugates: Implications in Failure-to-Thrive SyndromeBy Tom Gardiner, PhD PDF of this article
Author biographies
The sugars present in glycoconjugates and the glycoconjugates themselves (mainly in the form of glycoproteins) are necessary for normal body functions that become dysfunctional in failure-to-thrive (FTT) syndrome. For example, glucose transporters, which are glycoproteins, can malfunction, resulting in deprivation of an essential energy source. Defects in glycoconjugate sugar and glycoprotein metabolism can also occur, resulting in specific sugar deficiencies in key glycoproteins that result in muscular, nervous, and GI dysfunction. Cytokines are important modulators of the general wasting syndrome (cachexia) of various disorders, and may play a similar role in FTT. Due to the immune system modulation activity of glycoconjugate sugars and their associated glycoconjugates, which includes modulation of cytokines, it is possible that dietary glyconutritional supplements may have a protective or reparative role in FTT. In fact, a pilot study in FTT children has provided evidence that certain glyconutritional substances can significantly reduce some wasting symptoms of FTT. Introduction Failure-to-thrive (FTT) is a clinical syndrome of body wasting and weight loss. It can occur during development in infants and young children,1 or it can occur in adults as part of the cachectic (tissue wasting) process in diseases such as cancer and acquired immune deficiency syndrome (AIDS).2 Neurological and gastrointestinal (GI) symptoms, characteristic of poor development and function, are also often present in FTT patients. For example, FTT infants frequently have seizures and microcephaly.3 ,4 GI symptoms include diarrhea, bowel inflammation and malabsorption, which further interfere with the utilization of dietary nutrients, resulting in additional tissue wasting and weight loss. Although the cause(s) of FTT are not clearly understood, primarily because of the complexity of the symptoms involved, in simple terms, FTT results from an imbalance between the supply of food substances to the body and the ability of the body to utilize the nutrients found in these foods.5 This can occur when there is general undernutrition that may result from poverty, neglect, or other environmental factors.6 It can also occur as a result of more specific conditions such as disease, genetic disorders, or impairment of functions that are necessary for adequate absorption or conversion of nutrients so that they may be used by the body.5 ,7 Since glycoforms play key roles in the maintenance of normal health and function of the muscular, neurological, and gastrointestinal systems of the body that are involved in the FTT syndrome,8 it is not surprising that various glycoconjugate sugars and glycoproteins may be important in the prevention, modulation, and resolution of FTT symptoms. For example, defects in glycoconjugate sugar metabolism and absorption,9 or malfunction of transporters which carry glucose (i.e., source of energy) and galactose across the placenta or into the brain of developing fetuses, can result in severe FTT symptoms in developing children. Additionally, certain cytokines, which are immune system glycoprotein "messengers", can produce a cachectic response when given to experimental animals. The possibilities for altering these responses through dietary supplementation with glyconutritional substances have obvious implications for improved health. In fact, a recent study in FTT children demonstrated that supplementation of their diets with glyconutritional substances, including some that act as immune system modulators, resulted in definite improvement of their FTT symptoms.1 The present review will attempt to summarize the current scientific literature concerning the glycobiology of the FTT syndrome. Defects in absorption and metabolism of key glycoconjugate sugars that result in altered synthesis and malfunction of various glycoproteins critical to normal growth and development will be reviewed. The major FTT symptoms of tissue wasting, neurological impairment, and gastrointestinal (GI) dysfunction will be discussed with regard to specific glycoproteins. Finally, conclusions will be drawn concerning the importance of the nutritional availability of glycoconjugate sugars and associated glycoproteins. Glucose Transporter Malfunction One of the more direct causes of FTT symptoms is malfunction of glucose transporters (which are glycoproteins) in placenta, blood-brain barrier, and muscle cells that results in decreased cellular availability of this important energy source.10 For example, impaired glucose transport across brain tissue barriers, due to malfunction of the facilitative glucose transporter GLUT1, causes infantile seizures, developmental delay, and microcephaly as a result of a decreased glucose energy supply. In these patients, glucose levels in cerebrospinal fluid (CSF), which bathes nerve cells, are much lower than normal since less glucose is being transported from blood to CSF.3 ,4 ,11 In cases of fetal intrauterine growth retardation (IUGR), the glucose transporters GLUT3 and GLUT4 are reduced in the human placenta, which correlates with decreased birth weight.12 GLUT1 densities in term and pre-term placentas of human fetuses with IUGR are unaltered,13 suggesting a specificity for glucose transporters. In animal studies, fetal growth is reduced when sheep placental GLUT114 or mice placental GLUT315 expression are decreased. However, when intrauterine growth is restricted in pregnant rats by uterine artery ligation, placental expression of GLUT1 and GLUT3 is unchanged,16 suggesting species differences as well in glucose transporter specificity. Interestingly, in a separate study using this same rat model for IUGR, fetal brain and skeletal muscle GLUT1 (but not GLUT3) was increased, suggestive of a protective effect against glucose deprivation in developing brain and skeletal muscle cells.17 Although results with GLUT1 were not reproduced in two other studies with this same rat IUGR model,18 ,19 it was concluded by the authors that maintenance of normal transporter function and expression in brain may play a role in sparing its growth under IUGR conditions. Finally, when glucose and galactose cannot be absorbed properly from the intestines, which occurs when there is a defect in the glucose-galactose transporter, an osmotic diarrhea results, which also leads to FTT and severe malnutrition in children.20 Interestingly, exposure to the toxic chemical dioxin results in severe metabolic imbalances, leading to a wasting syndrome in both experimental animals and humans. In a dioxin toxicity study in guinea pigs, it was concluded that reduction of glucose transporters in various tissues was one of the major causes of dioxin-induced tissue wasting.21 Defects in Glycoconjugate Sugar and Glycoprotein Metabolism Mannose FTT and its various symptoms can also result from an inability of the body to adequately metabolize glycoconjugate sugars and incorporate them into glycoproteins that are necessary for normal cell development and function. For example, carbohydrate-deficient glycoprotein syndrome (CDGS), an autosomal recessive genetic disease, appears to result from a deficiency in key enzymes that are required to produce a metabolically activated form of the glycoconjugate sugar mannose, which can be incorporated into glycoproteins necessary for proper function of various body systems.22 ,23 ,24 CDGS patients generally have symptoms which include failure to thrive,13 ,24 ,25 ,26 ,27 gastrointestinal (GI) dysfunction (e.g., vomiting, diarrhea),24 marked delay in psychomotor development, mental retardation,22 ,23 ,28 neurological dysfunction (e.g., psychomotor disturbance),22 cerebellar atrophy,25 ,27 cardiomyopathy,26 and retinopathy.29 The degree of severity of these symptoms appears to depend, in part, on the specific type of CDGS 23 and the age of the patient.24 Interestingly, addition of mannose to culture media containing fibroblasts from CDGS patients with mannose-deficient oligosaccharides resulted in correction of the deficiency in vitro,23 ,30 consistent with the direct utilization of mannose by fibroblasts for the synthesis of mannose-containing glycoproteins.31 Other studies in humans have shown that dietary mannose is preferentially utilized to synthesize glycoproteins,32 which has definite therapeutic implications for CDGS patients.33 Galactose Galactose, another glycoconjugate sugar, and certain associated proteins also play important roles in supporting normal growth and development. For example, galactose appears to regulate the proliferation and differentiation of epithelial cells after birth, since a deficiency in the (-1,4-galactosyltransferase enzyme that transfers galactose to N-glycans in the Golgi apparatus of cells results in intestinal epithelial cell abnormalities and growth retardation in mice.34 Interestingly, a relatively rare metabolic disorder caused by a deficiency in the enzyme galactose-1-phosphate uridyltransferase (GalPUT) results in the inability to metabolize galactose, causing it to accumulate in the blood to extremely high levels, which also results in FTT, liver dysfunction, sepsis, and cataracts.35 ,36 ,37 Obviously, it would be important for these rare individuals to limit galactose in their diets. Sialic Acid The glycoconjugate sugar N-acetylneuraminic acid (sialic acid) also appears to be important in preventing the neurological disorders that are associated with FTT resulting from either malnutrition or defects in glycoprotein metabolism. With regard to malnutrition, intrauterine and postnatal undernutrition adversely affects brain development, in part, by limiting the availability of glyconutrients needed to synthesize nervous system glycolipids, such as gangliosides.38 ,39 For example, in studies conducted in rats,39 when mothers were undernourished throughout pregnancy and lactation and their litters were assessed for learning behavior, there was a significant reduction in learning when the pups were tested in a Y maze. When these same litters were given daily injections of sialic acid during postnatal days 7-21, they learned the Y maze more quickly than control pups given placebo injections of saline. In fact, rat pups from mothers receiving normal nutrition behaved "super-normally" when similarly injected with sialic acid. When the brains of these rats were analyzed, the increased learning behavior of the sialic acid-treated pups was associated with an increase in brain ganglioside and glycoprotein sialic acid levels. Injection of radiolabeled sialic acid resulted in its localization in glycoproteins mainly in synaptosomes (structures associated with nerve impulse transmission). This latter finding was consistent with another study in rats in which sialic acid incorporation into synaptic plasma membrane glycoproteins was altered in developing offspring from nutritionally stressed mothers.40 It also appears that sialic acid availability is most important during early brain development, as seen in the rat studies, since plasma sialic acid concentrations were not reduced in malnourished children at a late-stage time in their brain development.41 With regard to FTT due to defects in sialic acid metabolism, a condition known as disialotransferrin developmental deficiency (DDD) syndrome,41 ,42 ,43 a form of CDGS, 44 ,45 has been described. FTT, psychomotor retardation, and heart and liver abnormalities are signs commonly exhibited by these patients. The metabolic defect involves an inherited inability to transfer sialic acid, galactose, and N-acetylglucosamine to the secretory glycoprotein, transferrin, probably due to a specific glycosyltransferase enzyme deficiency. 45 Sialic acid incorporation into other secretory glycoproteins is also reduced in the presence of growth retardation. For example, the sialic acid content of the surfactant layer of lung is reduced in intrauterine growth-retarded rat fetuses.46 Finally, with regard to sialic acid, it is noteworthy that a relatively rare autosomal recessive heritable condition, known as sialic acid storage disease, has been associated with severe growth and psychomotor retardation.47 ,48 ,49 In this disease there is a deficiency in neuraminidase, an enzyme that liberates sialic acid from glycoconjugates. This deficiency leads to excessive intracellular accumulation of sialic acid, and/or an increased excretion of extremely high levels of sialic acid in the urine. Fucose Fucose is another glycoconjugate sugar that is important in the normal development of the nervous system, and a defect in its metabolism could contribute to FTT.40 ,50 For example, approximately 85% of synaptic plasma membrane (SPM) glycoproteins, which are involved in synaptic adhesion and conductivity and are components of neurotransmitter receptors, contain fucose. In rats, developing brains of offspring from undernourished mothers had as much as a 50% deficiency of SPM glycoproteins; this effect was reversible if nutritional rehabilitation was instituted on the 21st postnatal day.40 In humans, a condition of severe hypofucosylation of glycoconjugates, known as leukocyte adhesion deficiency II syndrome, has been described in two children with FTT and considerable psychomotor retardation.50 In these subjects, there was an absence of fucose in different glycosidic linkages on multiple glycans, suggesting a more general defect in fucose metabolism, which would probably have developmental effects beyond the nervous system. Enterokinase FTT has also been linked to a defect in the metabolism of the digestive enzyme enterokinase (EK). EK is a glycoprotein in the intestinal mucosa that activates the pancreatic proenzyme trypsinogen, converting it to trypsin, an intestinal enzyme that digests protein. EK sugar residues include fucose, mannose, galactose, glucosamine, and galactosamine. Congenital EK deficiency is a disorder characterized by malabsorption of protein, resulting in FTT and diarrhea.51 General Wasting Syndrome (Cachexia) Cachexia is characterized by loss of adipose tissue and skeletal muscle mass and frequently occurs in cancer and AIDS patients or following certain types of infection. Since the general tissue wasting that occurs in this syndrome is similar to that seen in FTT,52 it is important to consider how glycoconjugates are involved in cachexia. In this regard, complex polysaccharides and certain glycoconjugates are biologically active as modulators of the immune system,8 and cytokines ("communicators" of the immune system) have been proposed as mediators of the cachectic process.52 A number of cytokines, including tumor necrosis factor (TNF)-alpha, interleukins (IL)- 1 and -6, and interferon (IFN)-gamma have been postulated to play a role in the etiology of cachexia in cancer,53 human immunodeficiency virus infection,54 ,55 ,56 ,57 rheumatoid arthritis,58 and uremia.59 Similar roles have been demonstrated in animal models for infection-induced cachexia, such as visceral Leishmaniasis in hamsters,60 ,61 Trypanosoma cruzi infection in mice,62 Mycobacterium paratuberculosis infection in cattle,63 and bacterial lipopolysaccharide feeding in rats.64 TNF-alpha has been one of the more widely studied cytokines, and excellent reviews are available.65 ,66 ,67 In this regard, continual administration of TNF-alpha for several days to laboratory animals induces a state of cachexia, with anorexia and depletion of adipose tissue and lean body mass.68 ,69 ,70 ,71 ,72 ,73 The catabolic effect of TNF-alpha in amounts that by itself does not influence muscle breakdown was potentiated in rats continually infused with TNF-alpha and corticosterone.74 In in vitro studies, exposure of cultured cells to TNF-alpha results in inhibition of protein synthesis in human myoblasts,75 inhibition of collagen synthesis in rat osteoblasts,76 and inhibition of human adipose tissue lipoprotein lipase.77 TNF-alpha also may modulate cachexia by stimulating an increase in serum leptin, a hormone believed to regulate body weight by decreasing appetite.78 Additionally, both TNF-alpha and IL-1 act to reduce the availability of insulin-like growth factor (IGF), which stimulates protein synthesis by increasing IGF binding protein.79 In animal models of cachexia, administration of substances that either decrease TNF-alpha levels (such as pentoxifylline,80 TNF-alpha antibody,81 ,82 ,83 and soluble TNF-alpha receptor-containing copolymer84 ) or inhibit the oxidative stress produced by TNF-alpha, 85 partially prevent anorexia and loss of body weight and skeletal muscle protein. In summary, TNF-alpha administration can cause weight loss in experimental animals, mainly by decreasing appetite, and it appears to be an important component of cachexia. But other cytokines are also involved in the cachectic response, and in humans, the extent of cachexia does not always correlate with the level of circulating TNF-alpha.86 ,87 In fact, studies in animals demonstrate that, regardless of serum levels, TNF-( produced locally in brain influences both the rate of development of wasting and its net metabolic effects.88 A potential role for IL-6 in the development of cancer cachexia has also been demonstrated in mouse models for both colon89 and cervical90 cancers. In these models, IL-6 was produced by the tumor cells and appeared to act as a mediator of cachexia. Additionally, the administration of anti-mouse IL-6 monoclonal antibody attenuated the development of weight loss and other parameters of cachexia in mice with colon cancer. In another study, when the drug suramin inhibited receptor cell binding of IL-6 in a mouse colon cancer model, cancer-associated tissue wasting was decreased by 60%.91 In human studies, an elevated level of serum IL-6 has also been reported in cancer patients with the cachexia syndrome.92 Furthermore, administration of IL-1 to rats produced weight loss and skeletal muscle breakdown,73 and injection of a mixture of IL-1 and TNF-alpha in rats showed a synergistic effect.93 Weight loss in mice with lung cancer is associated with IFN-gamma production. Administration of an anti-IFN-gamma antibody reduced the depletion of body fat in tumor-bearing mice.52 Possible Roles of Dietary Glyconutritional Supplements in FTT Since certain glycoconjugate sugars and their associated glycoconjugates are biologically important in many aspects of functions related to FTT, it is understandable that dietary supplementation with glyconutritional substances might be important in maintaining health and preventing malfunction of the body systems involved in the FTT syndrome. In this regard, it is again important to highlight the recent study cited earlier in which a glyconutritional supplement given to FTT children resulted in significant reduction of FTT symptoms.1 The glyconutritional supplement contained glycoconjugate sugars needed to build glycoconjugates necessary for proper cell function as well as polysaccharides with potent immune system modulatory activity. Regarding the possible mechanism(s) for a proposed protective or reparative role for glycoconjugate sugars and associated glycoconjugates in FTT, it is of value to review briefly relevant biological activities of these substances.8 For example, it is interesting to speculate that possible mechanisms might include inhibition of the secretion of TNF-alpha and other pro-inflammatory cytokines by down-regulation of the immune system; attachment to cytokine glycoprotein receptors resulting in inhibition of a cytokine-induced response; stimulation of anti-inflammatory responses that would counter the adverse GI symptoms of FTT; increasing availability of glycoconjugate sugars used in the synthesis of glycoproteins and glycolipids needed for proper development and function of the nervous system; interference with oxidative or other detrimental processes that result in tissue destruction; and support of metabolic systems needed for protein and fat synthesis rather than breakdown. Although it is easy to see how these biological activities could benefit FTT patients, it should be noted that there are rare instances where a deficiency in an enzyme necessary for the overall metabolism of a specific glycoconjugate sugar (e.g., GalPUT or neuraminidase) might lead to an excess level of that sugar in the body. These rare individuals might be adversely affected by dietary supplementation with that specific sugar. Conclusions Glycoconjugate sugars and their associated glycoconjugates are necessary for normal body functions. Malfunction of glucose transporters results in deprivation of an essential nutrient source. Defects in glycoconjugate sugar and glycoprotein metabolism can also occur, resulting in deficiencies of key glycoproteins that cause muscular, nervous, and GI system dysfunctions seen in the FTT syndrome. Cytokines are important modulators of the general wasting syndrome (cachexia) of various disorders, and may play a similar role in FTT. Due to the immune system modulation activity of glycoconjugate sugars and their associated glycoconjugates, it is possible that dietary glyconutritional supplements may play important roles in the prevention and repair of dysfunctional processes involved in the FTT syndrome. In fact, a pilot study in FTT children has provided evidence that certain glyconutritional substances can significantly reduce some of the signs and symptoms of wasting found in FTT. Date last modified: March 12, 2001
www.glycoscience.orgCopyright 2000-2004 Mannatech™ Incorporated. All Rights Reserved.This site is provided by Mannatech™ Incorporated as an educational site for use in the United States. Specific handling of printed documents from this site is covered in detail under Legal Notices and Terms of Use.Email Webmaster
Glyconutritionals: Implications for Recovery from Viral InfectionsBy Charles J. Gauntt, PhD; Bill H. McAnalley, PhD; H. Reginald McDaniel, MD PDF of this article
Author biographies
Most coxsackieviral infections are subclinical in humans, but among the estimated 10 million people annually infected by these viruses, those with nutrient-deficient diets are at highest risk for developing diseases. This review discusses several studies that were performed to assess potential benefits of two glyconutrients on coxsackievirus B3 (CVB3)-induced models of myocarditis or pancreatitis. Nutritional supplementation in the form of Aloe polymannose (AP) significantly increased titers of anti-viral antibodies in mice challenged with a CVB3 strain that is both cardiovirulent and pancreatovirulent, but this dietary intervention had no effect on the virus-induced myocarditis in mice. In contrast, administration of a glyconutritional complex (GC), composed of additional sugars required for cellular glycoconjugate synthesis, to mice challenged with the same CVB3 strain did provide significant benefits over a period of 8 months to most animals in reversing virus-induced pancreatitis. Another study of rat hepatocytes showed that GC could block chemical depletion of free reduced glutathione, a major cellular antioxidant. These studies suggest a role for AP in stimulating the humoral immune system to produce antiviral antibodies and a role for GC in restoring the antioxidant potential of cells. Both glyconutrients may offer improved health to individuals who may or may not be infected by a virus that could subsequently cause disease. Viruses, viral diseases, and the coxsackieviruses group B3 (CVB3) Viruses are incredibly efficient parasites that require living cells in which they replicate, or reproduce, in large numbers.1 During replication, a virus takes command of the host cell and converts some or all of the cellular metabolic processes, those normally required to maintain the health of the cell, toward synthesis of viral component parts and then assembly of these components into new infectious virus particles. During the virus takeover of a cell, some to all essential daily cellular growth and repair processes may not be performed, and this virus-induced irreversible damage can lead to a reduction in function or death of the infected host cell. In addition to directly inducing death of the infected cell(s), viruses can also exert a number of other effects (Table 1). When a sufficient number of cells become damaged, major organs such as the heart, liver or lungs that contain the infected cells may not function well. Serious debilitating disease, or organ failure and death may follow. More than 400 viruses are known to infect humans.2 Animal viruses are classified into 23 families on the basis of nucleic acid type (RNA or DNA), genome structure (single-or double-stranded, continuous or segmented, polarity and arrangement of genes), and architecture of infectious virus particles (presence or absence of an envelope, capsid symmetry and size). Among these virus families, the Picornaviridae are small (~33 nm) nonenveloped RNA genome viruses that are quite stable in nature. Within the Picornaviridae are classified the enteroviruses, a group of etiologic agents responsible for a long list of human diseases.1 ,3 ,4 ,5 The enteroviruses consist of the three polioviruses, twenty-three coxsackieviruses group A, six coxsackieviruses group B (CVB), thirty echoviruses, and four enteroviruses.3 If we focus on the CVB, this small group of viruses causes a wide range of health problems,2 ,4 ,6 ,5 from noisome common colds, muscle aches, and severe pharyngitis to serious diseases such as aseptic meningitis,5 pancreatitis,6 ,7 ,8 myocarditis,6 ,7 ,9 ,10 infant death,2 ,4 likely some cases of diabetes mellitus type I1 ,4 ,6 and amyotrophic lateral sclerosis (Lou Gehrig's disease).11 There are excellent animal models of several human diseases caused by the CVB. Most of these models involve inbred mouse strains and CVB3 or CVB4.12 CVB3-murine models of inflammatory diseases of the heart muscle (myocarditis) or the pancreas (pancreatitis) have been well characterized over the past three to four decades.4 ,6 ,7 ,8 ,9 ,13 These studies document the importance of the host genetic background upon the outcome and severity of CVB3 disease induced in the heart or pancreas, and a role for the virus-induced cell-mediated immune system's noxious attack on host tissues (autoimmunity), to contribute to chronic diseases of either organ.9 ,10 The similarities between pathologic alterations found in hearts and pancreata of the CVB3-murine models and in cases of human diseases6 ,14 have suggested that the models would be useful in assessing interventional strategies that might improve some clinical sign(s) or speed the recovery of animals (or humans) from either disease. Host status influences viral infection susceptibility Viral activities can result in both acute and chronic episodes of disease, the outcome and severity reflecting the health status and genetic background of the host.1 ,2 A compromised host is one in which one or more resistance mechanisms are either inactive or not at an optimum response level, thereby increasing the probability of infection.14 Conditions that contribute to a compromised state include numerous stressors that include hospital procedures, organ transplantation, smoking, excessive consumption of alcohol, intravenous drug abuse, sleep deprivation, a concurrent infection, and inadequate nutrition.14 The major host factor that influences the outcome of a microbial infection, particularly a viral infection, is the immunological status of an individual at the time of infection.5 Stress and inadequate nutritional status are two factors that can depress the immune systems,15 , 16 , 17 particularly those of the neonate, where both development and function can be compromised.18 Individuals who are immunodepressed or immunocompromised can suffer more grave consequences from a viral disease than people with competent immune systems.19 Thus, people whose diets provide insufficient or excessive amounts of required nutrients may develop far more serious consequences from viral infections than people who experience similar viral infections, but maintain healthier diets.19 , 20 , 21 , 22 , 23 For example, a major nutritional problem in some parts of the world is vitamin A deficiency, which can significantly impair the immune systems24 and significantly contributes to the deaths of millions of children each year who acquire a measles virus infection. In contrast, excess iron in the diet of individuals infected with hepatitis C virus exacerbates severity of infection and destruction of the liver.19 Nonimmune (e.g., nonspecific or innate) defense factors of resistance come into play against viruses and other infectious microorganisms long before immune responses are functional. The general factors of nonspecific resistance fall into two broad categories, innate host barriers to infection and genetically mediated resistance (within families or strains of animals). Innate host barriers include skin, epithelial cilia in the respiratory tract that sweep materials upward for discharge, acidity of the stomach fluids, fever, and anti-microbial activities of macrophages and natural killer cells.1 Optimal nutrition can obviously play a major role in establishing and maintaining these barriers of resistance. The genetic basis for resistance is not well understood at the molecular level. However, genetic deficiencies among individuals in some families show that loss of a function can have severe consequences for individuals who experience subsequent infections by microorganisms. It is known that nasopharyngeal carcinoma caused by an Epstein-Barr herpesvirus is influenced by host genetic background.1 Studies examining the effects of glyconutrients on CVB3 infections It is well-known that some viruses have profound effects on the nutritional status of the host16 and that the undernourished host often experiences more severe diseases from viral infection.25 It is less well known that there are substances in ingested foods that can reduce or block virus replication, e.g., lactoferrin, leptin and feed-induced lectins.25 While not found in most foods (with the exception of colostrum and breast milk), IgA is very important in recovery from viral infections at the mucosal surface; these antibodies neutralize viruses outside and inside cells and can participate in a non-cytolytic (via interferons) clearance of virus from cells.26 In previous studies from other labs, Aloe polymannose (AP), a high mannose biological response modifier (BRM), significantly enhanced anti-viral antibody titers in chickens inoculated with several enveloped viruses.27 AP also exhibited antiviral properties against both the human immunodeficiency virus type 1 and a herpesvirus.28 ,29 Over the past half dozen years, we performed several studies to determine whether nontoxic doses of glyconutrients (AP or GC) can provide health benefits to mice developing CVB3-induced myocarditis or pancreatitis.6 ,30 ,31 ,32 Our initial study of AP was performed in numerous experiments conducted over several years to determine whether this BRM could enhance anti-CVB3 antibody titers in mice. Because there are no licensed antivirals for any of the enteroviruses (including the coxsackieviruses), we also wanted to ascertain if AP could ameliorate the myocarditis induced in these mice by a highly cardiovirulent CVB3. The data from this study showed that intraperitoneally (IP)-administered AP significantly stimulated production of antibody titers against CVB3 and also increased the number of mice able to produce high titers of anti-CVB3 antibodies. AP was administered into the peritoneal cavity of mice to achieve efficacious levels in the blood. In humans, efficacious levels of AP (or other bioactive compounds) can be achieved in the blood by ingestion; if mice ingest these compounds, they are immediately converted into energy. Administration of one or several doses of AP, either at the same time of, or within 2 days of virus challenge, was effective in enhancing antiviral antibody titers. No dose of AP was found that could either reduce the severity of myocarditis induced by CVB3, or reduce titers of virus in heart tissues.32 However, with the exception of interferon (which must be administered within a day of virus challenge), no drugs or natural substances have been found that can reduce the severity of CVB3-induced myocarditis in mice.33 An 8-month study was performed to evaluate the efficacy of GC in alleviating the destructive effects of CVB3 replication on acinar cells in the pancreas of male mice of a semi-inbred strain (CD-1).31 We also wished to determine whether GC, like AP, could stimulate antibodies against CVB3. Pancreatic acinar cells produce a large number of digestive enzymes that are released via pancreatic ductules into the small intestine for breakdown of food into useable nutrients by the body. These mice were chosen to represent the genetic variability one could expect in the normal human population. This cardiovirulent CVB3 strain generally induces both an acute myocarditis that is resolved, as well as a mild to severe pancreatitis characterized by destruction of pancreatic acinar cells.8 This infection does not cause death nor induce hyperglycemia, a marker of increased glucose levels typically found in diabetes mellitus type I. A major clinical outcome of intraperitoneal administration of GC was to reduce the severity of pancreatitis induced in virus-challenged mice, as shown by significant reductions in percentages of acinar cells destroyed, compared to virus-infected mice not treated with GC. When the extent of pathologic alterations induced by CVB3 in the pancreas was statistically analyzed between the group that received GC versus the untreated virus control group, the data on over 80 mice from the 8-month study showed that GC significantly contributed to recovery of the pancreatic acinar cell population in virus-infected mice.(Table 2) The mechanism which effected this recovery remains elusive, but GC did not stimulate production of anti-CVB3 antibody titers. Studies examining the antioxidant effects of glyconutrients One potential mechanism that might explain the acinar cell recovery promoted by GC was found in studies of antioxidant levels of free intracellular reduced glutathione in macrophages/monocytes taken from the spleens of CVB3-infected mice that were or were not treated with GC.31 ,30 Increased glutathione levels provide cellular protection from oxidative stress. Macrophages/monocytes were chosen for study because they represent a primary line of defense against microbial infections, including viruses. They also served as indicator cells of free reduced glutathione levels. The technique used in assessing these levels permitted analyses of over 100 measurements in cells from most groups of mice under study. We used cell-imaging analyses with a laser-activated fluorescent probe and a scanning confocal microscope to detect glutathione levels in individual cells in situ.6 Data from these triple-blind studies showed that whereas macrophages/monocytes from mice challenged with CVB3 showed significant reductions in free glutathione levels at the majority of times tested (compared to levels in cells taken from normal mice). GC treatment of virus-infected mice restored the relative levels of free reduced glutathione in the splenic cells to those levels found in normal mice. Splenic cell populations from normal mice treated with GC showed similar levels of free reduced glutathione as those found in splenic cells from normal mice. An initial technical problem resulted in approximately 50-fold lower values for all day 28 measurements. However, the relative virus-induced decrease in free GSH was found, as was restoration of GSH levels in GC treated virus challenged group of mice. Overall, GC treatment appeared to hasten restoration of acinar cells in pancreata of mice whose acinar cells had been destroyed by a CVB3 infection.(Table 3) One potential mechanism to explain this recovery may be the capacity of GC to increase levels of reduced glutathione in cells. In another series of studies,34 mice fed selenium or vitamin E-deficient diets developed significant internal oxidative stress that in some unknown manner promoted the selection of cardiovirulent CVB3 variants from the non-cardiovirulent challenge inoculum of CVB3. This highly oxidative milieu in mouse heart tissue then promoted production of the cardiovirulent virus variants to high titers and these variants then induced severe heart disease. Mice fed a standard diet developed normal levels of antioxidants; they did not select and promote replication of cardiovirulent CVB3 variants and thus did not develop heart disease. These studies were the first to show that diet could significantly influence metabolic homeostasis in mice and promote selection and production of virulent viruses found as minor contaminants in a virus inoculum or promote mutation to cardiovirulence. These data are of particular clinical concern because any amount of virus passed among people is a collection of nonvirulent and virulent (for one or more organs) viruses. The conclusions from the studies of Levander suggest for the first time that a host's inadequate nutritional status could significantly influence the outcome of a viral infection, favoring selection and replication of the more virulent variants in the population with induction of disease and potential passage to other susceptible hosts.34 Our 8-month study also suggested that the majority of mice, but not all, derived health-promoting benefits from GC.31 In a clinical study, some subjects with either form of diabetes also failed to derive any apparent health benefits from dietary glyconutritional supplements,35 although most patients showed significant improvement in subjective analyses of several parameters of well-being. Subtle, unidentified genetic background differences in both mice and humans could differentiate those individuals who can receive health benefits from dietary glyconutritionals versus those individuals who cannot benefit. Data derived from deciphering the human, and ultimately the murine, genomes may one day provide a genetic explanation for this phenomenon. In a companion study on the effects of GC at the cellular level, rat hepatocytes in culture were exposed to patulin, a sulfhydryl-reactive mycotoxin that depletes cells of glutathione.30 Using the same free glutathione fluorescent probe and detection by laser scanning cell imaging as described above, it was found that exposure of hepatocytes for at least three hours prevented the patulin-induced depletion of glutathione. Normal hepatocytes treated with GC had relatively twice the level of glutathione found in normal untreated hepatocytes.(Figure 1) These data show that GC can also protect cells from a chemically-initiated depletion of free intracellular reduced glutathione. Both vitamin E and glutathione can reduce oxidative stress and pancreatic cellular injury.36 These antioxidants are believed to retard or prevent onset of several diseases that, as a group, may be characterized by cellular injury, dysfunction or death, resulting from stress due to oxidative and other reactive chemicals. Dietary supplementation with a number of antioxidants such as vitamins C and E or alpha-lipoic acid has provided significant health benefits to humans for many years. Patients with non-insulin-dependent diabetes mellitus who reduced their dietary intake of glucose and ingested supplemental vitamin E were found to have increased levels of total glutathione.30 A role for antioxidants in prevention or reducing incidence of cancer or coronary heart disease, however, may be overstated, and other nutrients, phytochemicals and dietary fiber may likely have a more significant protective role.37 CONCLUSIONS Two glyconutrients have been found to have biological roles that can provide some protection against viral infections, enhancement of the production of anti-viral antibodies and the amelioration of virus-induced pancreatitis. These studies, conducted in mice, serve as excellent animal models of some cases of human heart disease and pancreatitis due to the ubiquitous coxsackieviruses group B. The ameliorative effect of GC on acute pancreatitis needs to be examined further, as some cases of this disease can be fatal.38 More research is also needed to focus on a role for these glyconutrients in the treatment of diabetes mellitus Type I using a recently developed, naturally-occurring variant of CVB3 of human origin. Acknowledgments Dr. Gauntt is a professor in the Department of Microbiology, University of Texas Health Science Center at San Antonio, Texas. Dr. McAnalley is Chief Science Officer and Vice President, Research and Product Development at Mannatech(, Inc. Dr. McDaniel is the Medical Director at Mannatech. The glyconutritional complex (GC) used in these studies was Ambrotose( complex, provided by Mannatech. Date last modified: January 26, 2001
www.glycoscience.orgCopyright 2000-2004 Mannatech™ Incorporated. All Rights Reserved.This site is provided by Mannatech™ Incorporated as an educational site for use in the United States. Specific handling of printed documents from this site is covered in detail under Legal Notices and Terms of Use.Email Webmaster
Post a Comment