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The regulation of prostaglandin E1 formation: a candidate for one of the fundamental mechanisms involved in the actions of vitamin C.

Vitamin C stimulates the formation of PGE1 in human platelets. The effect occurs over the physiologically relevant range of concentrations. PGE1 is required for T lymphocyte function and plays a major part in the regulation of immune responses. PGE1 is also important in the regulation of collagen and ground substance metabolism, in cholesterol metabolism and in regulation of responsiveness to insulin. It is proposed that defective formation of PGE1 could account for many of the features of scurvy and for many of the reported therapeutic effects of vitamin C. If correct, vitamin C will be of value only in conjunction with an adequate supply of dihomogammalinolenic acid, the precursor of PGE1. Essential fatty acids, pyridoxine and zinc are all required to achieve this.

Animals↗

Homo sapiens ascorbicus, a biochemically corrected robust human mutant.

Homo sapiens' gene pool contains a defective gene for the synthesis of the active enzyme protein, L-gulonolactone oxidase(GLO). The absence of GLO in the human liver blocks the normal mammalian conversion of blood sugar into ascorbate, leading to the potentially-fatal "inborn error of carbohydrate metabolism", the genetic disease, Hypoascorbemia (in the older nomenclature- scurvy). To survive, humans need exogenous sources of daily ascorbate. Most mammals have the intact gene for GLO synthesis and produce generous daily amounts of the liver metabolite, ascorbate; for instance, an unstressed 70 Kg goat is capable of producing over 13 grams of ascorbate daily and much more under stress. The recommended dietary allowance of 45 milligrams of ascorbate a day for human adults, now proposed and used by nutritionists, is grossly inadequate to restore Homo sapiens to a normal mammalian ascorbate physiology. To correct fully this human genetic defect and banish epidemic chronic subclinical scurvy requires daily intakes of ascorbate equivalent to, at least, the amounts synthesized by the other mammals. Humans kept on a long term regime of full correction of this birth defect show great salutary benefits in health maintenance, disease therapy and slowing of the aging process. This can be regarded as the creation of a new and more robust, longer-living, tough human sub-species, Homo sapiens ascorbicus, by the biochemical reversal of a primate mutation occurring some 60 million years ago. Some of the practical benefits and pathways of future clinical research are discussed.

Aging↗

Vitamin C: the nontoxic, nonrate-limited, antioxidant free radical scavenger.

The amount of oral ascorbic acid that a patient can tolerate without diarrhea, increases somewhat proportionately to the "toxicity" of his disease. Clinically, in a disease ameliorated by ascorbate, there is a suppression of symptoms only with very high doses and approximately to that extent which a nonrate-limited, antioxidant free radical scavenger, might be expected to affect that disease process if all harmful free radicals and highly reactive oxidizing substances were quenched. In most pathologic processes, the rate at which free radicals and highly reactive oxidants are produced, exceeds the rate at which the ordinary rate-limited antioxidant free radical scavenging mechanisms can quench those free radicals and oxidants. When ascorbate acts as a scavenger, dehydroascorbate is formed; but if the ascorbate/dehydroascorbate (AA/DHA) ratio is kept high (the redox potential kept reducing) until the unstable dehydroascorbate undergoes hydrolysis or can be reduced back to ascorbate, the dehydroascorbate will do no harm. Since even at very high doses, ascorbate is virtually nontoxic, it may be given in the enormous doses necessary to quench almost all unwanted free radicals and oxidants. The wide spectrum of infectious diseases ameliorated by massive doses of ascorbate indicates some common pathologic processes in these diseases.

Acquired Immunodeficiency Syndrome↗

Essential fatty acid metabolism in diseases of connective tissue with special reference to scleroderma and to Sjogren's syndrome.

Drugs which modify the conversion of essential fatty acids to prostaglandins and leukotrienes are the mainstays of treatment in rheumatology. Yet these drugs have little or no action in scleroderma or Sjogren's syndrome and under some circumstances may have adverse effects. Patients with scleroderma have been shown to have very high levels of circulating prostaglandins, coupled with depletion of the prostaglandin precursors, dihomogammalinolenic acid and arachidonic acid. Levels of the metabolites of arachidonic acid, 22:4n-6 and 22:5n-6, which have major roles in maintaining normal cell membrane characteristics were exceptionally low in both plasma and red cell membranes. Others have observed that various functions are highly resistant to normal actions of PGs in scleroderma. This raises the possibility that the high rate of PG formation in scleroderma may be beneficial, in compensation, and that clinical symptoms develop when PG precursors begin to be depleted. Red cell membrane fatty acids patterns in Sjogren's syndrome are almost identical to those in scleroderma. Placebo-controlled trials of supplementation with essential fatty acids have been found to be beneficial in both scleroderma and Sjogren's syndrome.

Animals↗

The GI T-lymphocyte theory of schizophrenia: some new observations.

Schizophrenic patients have low concentrations of PGE-1, n-6 fatty acids, vitamin C and zinc, elevated brain levels of dopamine and high plasma levels of interleukin-2 receptors (IL-2R). IL-2R plasma titers can be raised in celiac patients by administering wheat. These findings are both consistent with and supportive of the GI T-lymphocyte theory of schizophrenia.

Ascorbic Acid Deficiency↗

Ascorbate status and xerostomia.

Xerostomia, the subjective feeling of dry mouth, affects millions of people particularly the elderly. It is invariably associated with hypofunction of the salivary glands. The amount, rate of secretion, and composition of saliva are regulated by both sympathetic and parasympathetic receptor systems whose stimulation transmits signals through intracellular messengers (cations, nucleotides, phospholipid derivatives) to structures and enzymes within the cell. Salivary glands express a variety of cell-surface receptors including adrenergic (alpha and beta), muscarinic-cholinergic, substance P, vasoactive intestinal peptide hormone, and ATP receptors. Ascorbate which is present in salivary acinar cells in relatively high concentrations, is closely involved in many cellular functions including the metabolism of pyrimidines, intracellular calcium, the catecholamines and other neurotransmitters which regulate salivary gland exocytosis. Ascorbate-dependent carboxyl-terminal peptide alpha-amidation enzyme similar to the pituitary peptidyl-glycine alpha-amidating monooxygase, is also present in salivary glands. It is therefore not fortuitous that the seemingly unrelated numerous factors like aging, drug ingestion, pregnancy, smoking, ionizing radiation, stress, and various pathological states such as cancer, autoimmune disorders, diabetes mellitus, and hypertension often implicated in the causation of xerostomia, all promote increased tissue requirement for and/or depletion of ascorbate.

Ascorbic Acid↗

Vitamin C treatment reduces transcapillary escape rate of albumin in type 1 diabetes.

BACKGROUND: Latent tissue scurvy in clinical and experimental ascorbic acid (AA) deficiency resembles diabetic microangiopathy as reflected in capillary hyperperfusion and increased transcapillary escape rate (TER), von Willebrand factor (vWf), and capillary fragility (CF). We aimed to investigate the possible clinical impact of the low plasma AA level observed in type 1 diabetes mellitus. METHODS: Twenty normoalbuminuric patients with retinopathy were included in a randomized, double-blinded, placebo-controlled 6-month study with AA (6 g/day; n=10, mean age+/-S.D. 35.3+/-8.5 years, diabetes duration 17.2+/-3.3 years) or placebo (n=10; mean age 37.8+/-6.6 years, diabetes duration 18.4+/-1.7 years). RESULTS: An inverse correlation between log plasma AA (HPLC method) and TER of (125)I-labelled albumin was found (r=-0.66, p=0.002). TER decreased in the AA-treated group from 6.8+/-1.0 to 5.4+/-1.5%/h compared to the unchanged placebo group (from 5.6+/-1.5 to 5.9+/-1.1%/h; p=0.031). The CF (capillary resistance test) decreased in the AA group compared to the placebo group (p=0.028), while vWf, fibrinogen and fibronectin levels, and glomerular filtration rate (clearance of (125)I-iothalamate) remained unchanged. CONCLUSIONS: The results suggest that a low plasma AA level might be associated (pathogenetic?) with development of microangiopathy in type 1 diabetes mellitus and points to a possible treatment modality.

Journal Article↗

Testing the feasibility and initial effects of iron and vitamin C to enhance nursing home residents' immune status following an influenza vaccine.

Influenza infections pose a serious threat to residents living in nursing homes and are a major cause of morbidity and mortality in older adults. It is estimated that influenza vaccination is only 30%-40% effective in the frail elderly. This 2-group experimental design study examined the efficacy of giving iron supplements to nursing home residents aged 65 and older to improve immune response following influenza vaccination. Specific aims of the study were to test study procedures and explore initial immune response. A number of barriers were encountered during the recruitment and consent phase limiting subject recruitment. Only serum transferrin was significantly different following the 30-day administration of iron supplementation. It was concluded that to achieve sufficient power to examine the effect of the intervention on immune response and infection rates, aggressive recruiting strategies at multiple sites are necessary.

Aged↗

Musculoskeletal manifestations of scurvy.

Scurvy occurs in individuals who eat inadequate amounts of fresh fruit or vegetables, often because of dietary imbalances related to advanced age or homelessness. Asthenia, vascular purpura, bleeding, and gum abnormalities are the main symptoms. In 80% of cases, the manifestations of scurvy include musculoskeletal symptoms consisting of arthralgia, myalgia, hemarthrosis, and muscular hematomas. Vitamin C depletion is responsible for structural collagen alterations, defective osteoid matrix formation, and increased bone resorption. Imaging studies may show osteolysis, joint space loss, osteonecrosis, osteopenia, and/or periosteal proliferation. Trabecular and cortical osteoporosis is common. Children experience severe lower limb pain related to subperiosteal bleeding. Laboratory tests show nonspecific abnormalities including anemia and low levels of cholesterol and albumin. The finding of a serum ascorbic acid level lower than 2.5 mg/l confirms the diagnosis. Vitamin C supplementation ensures prompt resolution of the symptoms.

Ascorbic Acid Deficiency↗

Age-dependent change in Vitamin C status: a phenomenon of maturation rather than of ageing.

Several reports have shown that Vitamin C is depleted in animals with age. Based mainly on comparisons between young animals that have not yet reached maturity and old animals, it appears to be the general assumption that the change in Vitamin C status occurs at a late stage in life and that this phenomenon may either contribute to or result from the ageing process. In the present study, young (3 months old, n = 8) and old (36 months old, n = 8) female guinea pigs were followed for 6 months with monthly blood samplings and monitored for Vitamin C status as measured by plasma ascorbate and erythrocyte ascorbate recycling capacity after which the animals were euthanized. While remaining unchanged in the old animals, plasma Vitamin C status of the young animals significantly declined to that of the old animals within 3 months. During the following 3 months, the Vitamin C status of the young animals remained unchanged. Furthermore, post mortem Vitamin C analyses of the animals now aged 9 and 42 months, respectively, showed no effect of age on Vitamin C in plasma, liver, kidney, heart and brain between the groups while concentrations were significantly increased in cerebrospinal fluid and lung with age (p < 0.05). Moreover, a significantly elevated ascorbic acid oxidation ratio was observed in young compared to old animals (p < 0.05). The present data suggest that the decline in Vitamin C status with age occur early in life and is a phenomenon of maturation rather than of ageing. Data from other species and humans are discussed.

Age Factors↗

Low brain glutathione and ascorbic acid associated with dopamine uptake inhibition during rat's development induce long-term cognitive deficit: relevance to schizophrenia.

Schizophrenia is associated with a cerebral glutathione deficit, which may leave the brain susceptible to oxidants. To study the consequences of a glutathione deficit, we treated developing rats with L-buthionine-(S,R)-sulfoximine (BSO), an inhibitor of glutathione synthesis, and later investigated their behaviour until adulthood. Since rodents may in some occasions compensate for a glutathione deficit by ascorbic acid (AA), we used Osteogenic Disorder Shionogi (ODS) mutant rats, which like humans, cannot synthetize ascorbic acid. Moreover, as hyperactivity of the dopaminergic system may be associated with schizophrenia, some rats were treated with the dopamine uptake inhibitor GBR 12909. Whereas ODS rats treated with either BSO or GBR 12909 alone had normal behaviour, rats treated with both BSO and GBR 12909 failed to discriminate between familiar and novel objects although other behaviours proved to be normal. In contrast, nonmutant rats were not affected by treatment with BSO and GBR 12909. Our results suggest that low brain glutathione and ascorbic acid levels associated with a perturbation of the dopaminergic system actively participate in the development of some cognitive deficits affecting schizophrenic patients.

Animals↗

Iron deficiency with normal ferritin levels in restless legs syndrome.

This report describes a patient with iron deficiency in bone marrow examination and iron-responsive restless legs syndrome (RLS), in whom serum ferritin levels were well above the conventional cutoff for considering iron deficiency. The predictive value of serum ferritin for iron deficiency in RLS depends on the cutoff employed, on the pre-test likelihood of iron deficiency and on coexisting inflammatory conditions. Bone marrow examination is helpful when ferritin levels are equivocal.

Aged↗

Stability of ascorbic acid in commercially available orange juices.

OBJECTIVE: To compare the vitamin C content of reconstituted frozen orange juice concentrates at preparation to that of ready-to-drink orange juices purchased 4 to 5 weeks from expiration. DESIGN: Juices were unsealed and analyzed for reduced and oxidized vitamin C content at the time of purchase and reanalyzed 3 times weekly for 4 to 5 weeks. Same-lot samples of the ready-to-drink juices remained sealed after purchase and were opened for analyses at 3, 2, 1, or 0 weeks before expiration. SAMPLES/SETTING: Orange juices were reconstituted frozen concentrates, ready-to-drink juice packaged in resealable, screw-top containers, or ready-to-drink juice packaged in nonresealable containers. Juices were obtained from local retailers and stored at 4 degrees C in their original containers when appropriate. STATISTICAL ANALYSES PERFORMED: The reduced vitamin C content of juices analyzed repeatedly, 3 times weekly for 4 weeks, were compared using repeated measures analysis of variance. Linear regression lines were computed for reduced vitamin C in each juice over time, and differences between slopes were analyzed by oneway analysis of variance. RESULTS: The orange juices from frozen concentrates contained 86 mg reduced vitamin C per fluid cup at initial preparation and 39 to 46 mg/c after 4 weeks of storage. Ready-to-drink juices averaged significantly lower reduced vitamin C: 27 to 65 mg/c at opening and 0 to 25 mg/c at expiration 4 weeks later. Ready-to-drink orange juices had twofold to threefold higher concentrations of oxidized vitamin C vs the orange juices reconstituted from frozen, and the decomposition rate of reduced vitamin C was similar for all juices, about 2% per day once opened. APPLICATIONS: Ready-to-drink orange juices should be purchased 3 to 4 weeks before expiration date and consumed within 1 week of opening.

Ascorbic Acid↗