Pace GW; Leaf CD
Research Triangle Pharmaceuticals, Durham, NC, USA.
Free Radic Biol Med Oct 1995, 19 (4) p523-8

Evidence has accumulated suggesting that HIV-infected patients are under chronic oxidative stress. Perturbations to the antioxidant defense system, including changes in levels of ascorbic acid, tocopherols, carotenoids, selenium, superoxide dismutase, and glutathione, have been observed in various tissues of these patients. Elevated serum levels of hydroperoxides and malondialdehyde also have been noted and are indicative of oxidative stress during HIV infection. Indications of oxidative stress are observed in asymptomatic HIV-infected patients early in the course of the disease. Oxidative stress may contribute to several aspects of HIV disease pathogenesis, including viral replication, inflammatory response, decreased immune cell proliferation, loss of immune function, apoptosis, chronic weight loss, and increased sensitivity to drug toxicities. Glutathione may play a role in these processes, and thus, agents that replete glutathione may offer a promising treatment for HIV-infected patients. Clinical studies are underway to evaluate the efficacy of the glutathione-repleting agents, L-2-oxothiazolidine-4-carboxy lic acid (OTC) and N-acetylcysteine (NAC), in HIV-infected patients. (93 Refs.)

Demling RH; DeBiasse MA
Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Crit Care Clin Jul 1995, 11 (3) p651-73
[published erratum appears in Crit Care Clin 1996 Oct;12(4):xi]

Micronutrients play a key role in many of the metabolic processes that promote survival from critical illness. For vitamins, these processes include oxidative phosphorylation, which is altered in the patient with systemic inflammation, and protection against mediators, in particular oxidants. Trace elements are essential for direct antioxidant activity as well as functioning as cofactors for a variety of antioxidant enzymes. Wound healing and immune function also depend on adequate levels of vitamins and trace elements (Table 6). Of extreme importance is the ease with which a deficiency state can develop in the critically ill because of decreased nutrient intakes and increased requirements. Daily intakes up to or exceeding many times the RDA usually are required. The enteral route is preferred, although, if not available, most of these agents can be given by the parenteral route. In that case, however, dose recommendations are less clear. Attention to micronutrients is paramount both in optimizing the nutritional management of the critically ill and in the overall management of these patients. It also is essential in promoting positive outcomes and decreasing complications. (40 Refs.)

Dubbels R; Reiter RJ; Klenke E; Goebel A; Schnakenberg E; Ehlers C; Schiwara HW; Schloot W
Center of Human Genetics and Genetic Counselling, University of Bremen, Germany.
J Pineal Res (Denmark) Jan 1995, 18 (1) p28-31

Melatonin, the chief hormone of the pineal gland in vertebrates, is widely distributed in the animal kingdom. Among many functions, melatonin synchronizes circadian and circannual rhythms, stimulates immune function, may increase life span, inhibits growth of cancer cells in vitro and cancer progression and promotion in vivo, and was recently shown to be a potent hydroxyl radical scavenger and antioxidant . Hydroxyl radicals are highly toxic by-products of oxygen metabolism that damage cellular DNA and other macromolecules. Herein we report that melatonin, in varying concentrations, is also found in a variety of plants. Melatonin concentrations, measured in nine different plants by radioimmunoassay, ranged from 0 to 862 pg melatonin/mg protein. The presence of melatonin was verified by gas chromatography/mass spectrometry. Our findings suggest that the consumption of plant materials that contain high levels of melatonin could alter blood melatonin levels of the indole as well as provide protection of macromolecules against oxidative damage.

Singh A; Failla ML; Deuster PA
Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814.
J Appl Physiol Jun 1994, 76 (6) p2298-303

To examine the effect of zinc (Zn) supplementation on exercise-induced changes in immune function, five male runners were randomly assigned in a double-blind crossover design to take a supplement (S; 25 mg of Zn and 1.5 mg of copper) or placebo (P) twice daily for 6 days. On morning 4 of each phase, 1 h after taking S or P, subjects ran on a treadmill at 70-75% of maximal oxygen uptake until exhaustion (approximately 2 h). Blood samples were obtained before (Pre), immediately after (Post), and 1 (Rec1) and 2 (Rec2) days after the run. [3H]thymidine incorporation by mitogen-treated mononuclear cell cultures was significantly lower (P < 0.05) Post than Pre, Rec1, or Rec2 for both S and P. Respiratory burst activity of isolated neutrophils was enhanced after exercise with P but not with S (P: Pre 12.0 +/- 1.1 vs. Post 17.6 +/- 2.3 nmol O2-/10(6) cells; S: Pre 11.7 +/- 0.3 vs. Post 12.1 +/- 1.2 nmol O2-/10(6) cells). Thus supplemental Zn blocked the exercise-induced increase in reactive oxygen species. Whether this antioxidant effect of Zn will benefit individuals exposed to chronic physical stress remains to be determined.

Fernandes G
Department of Medicine, University of Texas Health Science Center, San Antonio 78284-7874.
Clin Immunol Immunopathol Aug 1994, 72 (2) p193-7

In summary, it is well established that moderate calorie restriction or reduction in overall high calorie food intake prevents or forestalls the development of age-associated disease incidence such as breast cancer and renal disease in rodents. A similar approach could also readily be applied in humans for preventing the risk and rise of life-shortening diseases. Many age-associated diseases, particularly autoimmune diseases with viral etiology, appear to be exacerbated in the presence of adverse lipid intake such as an increased level of vegetable oils or trans-fatty acids from the usage of hydrogenated dietary oils. At present, nearly 35-40% of the total calories are from dietary fats and/or of lipid origin. Although usage of saturated fat, which increases cardiovascular disease, has been reduced to a large extent in the United States, consumption of both monounsaturated and polyunsaturated fats of omega-6 origin has either increased or simply been substituted in place of saturated fats. Further, for the past 50 years, a significant reduction in highly polyunsaturated fat consumption such as marine oil has also occurred specifically in the United States. The reduction in omega-3 lipids of marine or vegetable source occurs primarily because of short shelf life due to rancidity. However, the increased consumption of omega-6 or a vegetable source of oils and decreased omega-3 intake may increase in vivo the production of free radicals and higher proinflammatory cytokines. Our ongoing studies reveal that proinflammatory vegetable oil could increase autoimmune disease by increasing the free radical formation by decreasing the antioxidant enzyme mRNA levels, thereby further decreasing immune function, particularly the production of anti-inflammatory cytokines such as IL-2 and TGF beta mRNA levels. In contrast, omega-3 lipid intake in the presence of an antioxidant supplement appears to exert protection against autoimmunity by enhancing antioxidant enzymes and TGF beta mRNA levels and by preventing the rise in oncogene expression. However, detailed studies are required to establish the protective and deleterious role of different commonly consumed lipids or dietary oils by the general population, particularly during middle and aging years. Further, we also propose that combining nonsteroidal drug therapy along with moderate calorie reduction in the presence of more protective omega-3 dietary lipids of either marine or vegetable source and decreasing the levels of mono- and polyunsaturated lipids may provide additional protection against the age-associated rise in malignancy and autoimmune disorders. (43 Refs.)

Flescher E; Ledbetter JA; Schieven GL; Vela-Roch N; Fossum D; Dang H; Ogawa N; Talal N
Clinical Immunology Section, Audie L. Murphy Memorial Veterans Hospital, San Antonio, TX.
J Immunol Dec 1 1994, 153 (11) p4880-9

Products of polyamine oxidase activity, at micromolar levels and during a period of 2 to 3 days, down-regulate IL-2 mRNA levels and activity in human lymphocytes. We studied whether this suppression was associated with signal transduction abnormalities. We found that polyamine oxidase activity suppresses both anti-CD3-induced IL-2 production and protein tyrosine phosphorylation. Polyamine oxidase activity also caused a reduction in intracellular calcium mobilization after mitogenic stimulation. The most distal step of CD3-mediated signal transduction is dependent upon transcription factors that regulate a set of genes, including IL-2. We found that polyamine oxidase-treated cells exhibited very low DNA binding activity of two such factors: NFAT and NF-kappa B. On the other hand, AP-1 DNA binding activity was enhanced in polyamine oxidase-treated cells, suggesting a possible role for AP-1 in the human lymphocyte stress response. In accordance with the oxidation dependence of this suppressive mechanism, N-acetylcysteine (NAC; an antioxidant ) significantly reversed the polyamine oxidase effects on lymphokine production and signal transduction. These results suggest that NAC contributes, under oxidizing conditions, to the preservation of immune function . In summary, our data suggest that chronic low-level oxidative stress, via suppression of mitogen-induced transmembrane signaling (protein-tyrosine phosphorylation and calcium mobilization), causes a decrease in the DNA binding activity of transcription factors that regulate the IL-2 gene. This results in decreased IL-2 production.

Stahelin HB
Geriatric University Clinic, Kantonsspital, Basel, Switzerland.
Support Care Cancer (Germany) Nov 1993, 1 (6) p295-7

The potential of a high intake of fresh fruits and vegetables in cancer prevention is well established. Epidemiological studies support carotene, vitamins A, C, E and selenium as the active compounds. Antioxidant properties and direct effects (e.g. inhibition of N-nitrosamine formation or cell-to-cell interactions) are invoked. The role of other trace elements is less clear. The modulation of immune function by vitamins and trace elements remains important and affects survival. In established cancers, the site-specific differences in the diet/cancer relation require appropriate dietary changes, e.g. low fat (20% by energy) in breast cancer, or high vegetable or fruit intake in lung cancer. Single high-dose supplements (e.g. vitamin C) have proved to have no curative or life-prolonging effect. Chemotherapy and radiation increase the requirements for antioxidant compounds. Supplementation can diminish the damage induced by peroxidation. Carefully planned and monitored trials that establish the optimal intake of micronutrients as adjuvants in cancer patients are required. (18 Refs.)

Johnson K; Kligman EW
Dept. of Family and Community Medicine, University of Arizona College of Medicine, Tucson.
Geriatrics Nov 1992, 47 (11) p39-40, 45-9

Disease prevention through dietary management is a cost-effective approach to promoting healthy aging. Fats, cholesterol, soluble fiber, and the trace elements copper and chromium affect the morbidity and mortality of CHD. Decreasing sodium and increasing potassium intake improves control of hypertension. Calcium and magnesium may also have a role in controlling hypertension. The antioxidant vitamins A and beta-carotene, vitamin C, vitamin E, and the trace mineral selenium may protect against types of cancer. A decrease in simple carbohydrates and an increase in soluble dietary fiber may normalize moderately elevated blood glucose levels. Deficiencies of zinc or iron diminish immune function . Adequate levels of calcium and vitamin D can help prevent senile osteoporosis in both older men and women. (27 Refs.)

Jacob RA; Kelley DS; Pianalto FS; Swendseid ME; Henning SM; Zhang JZ; Ames BN; Fraga CG; Peters JH
Western Human Nutrition Research Center, USDA Agricultural Research Service, Presidio of San Francisco, CA 94129.
Am J Clin Nutr Dec 1991, 54 (6 Suppl) p1302S-1309S

To determine nonscorbutic effects of moderate vitamin C deficiency we measured immune function and oxidative damage in eight healthy men (25-43 y) who consumed 5-250 mg/d of ascorbic acid over 92 d on a metabolic unit. During ascorbic acid intakes of 5, 10, or 20 mg/d, subjects attained a state of moderate ascorbic acid deficiency as ascorbic acid concentrations in plasma, leucocytes, semen, and buccal cells dropped to less than 50% of baseline with no scorbutic symptoms observed. No changes in cell proliferation, erythrocyte antioxidant enzymes, and DNA strand breaks were observed; however, blood levels of glutathione and NAD(P) decreased during ascorbic acid deficiency, as did delayed hypersensitivity responsiveness. Concentrations of the oxidatively modified DNA base, 8-hydroxydeoxyguanosine in sperm DNA and fecapentaenes, ubiquitous fecal mutagens, were increased during ascorbic acid depletion. Moderate vitamin C deficiency, in the absence of scurvy, results in alteration of antioxidant chemistries and may permit increased oxidative damage.

Bendich A
Clinical Nutrition, Hoffmann La Roche Inc., Nutley, NJ 07110.
Basic Life Sci 1988, 49 p615-20

Vitamin E, the major lipid-soluble antioxidant present in all cellular membranes, is an important nutrient for optimal immune function . When animals are fed nutritionally complete diets lacking vitamin E, immune responses are adversely affected. Supplementation of these diets with higher than nutritionally adequate levels of vitamin E enhances immune responses. High levels of PUFA are immunosuppressive, and vitamin E can partially overcome this immunosuppression. High levels of vitamin C can protect tissue levels of vitamin E and may indirectly contribute to the immunoenhancement by vitamin E. Severe selenium deficiency is immunosuppressive. Vitamin E can protect some aspects of immune responses from the adverse effects of selenium deficiency. These data clearly indicate that nutrients that affect the overall antioxidant status have important effects on immune functions. In addition, antioxidant nutrient interactions can synergize to overcome the adverse effects of polyunsaturated fatty acids on immune functions (Fig 2). (26 Refs.)

Hornstra G.; Barth C.A.; Galli C.; Mensink R.P.; Mutanen M.; Riemersma R.A.; Roberfroid M.; Salminen K.; Vansant G.; Verschuren P.M.
Dr. G. Hornstra, Department of Human Biology, Maastricht University, PO Box 616, NL-6200 MD, Maastricht Netherlands
British Journal of Nutrition (United Kingdom), 1998, 80/Suppl. 1 (S113-S146)

Cardiovascular disease has a multifactorial aetiology, as is illustrated by the existence of numerous risk indicators, many of which can be influenced by dietary means. It should be recalled, however, that only after a cause-and-effect relationship has been established between the disease and a given risk indicator (called a risk factor in that case), can modifying this factor be expected to affect disease morbidity and mortality. In this paper, effects of diet on cardiovascular risk are reviewed, with special emphasis on modification of the plasma lipoprotein profile and of hypertension. In addition, dietary influences on arterial thrombotic processes, immunological interactions, insulin resistance and hyperhomocysteinaemia are discussed. Dietary lipids are able to affect lipoprotein metabolism in a significant way, thereby modifying the risk of cardiovascular disease. However, more research is required concerning the possible interactions between the various dietary fatty acids, and between fatty acids and dietary cholesterol. In addition, more studies are needed with respect to the possible importance of the postprandial state. Although in the aetiology of hypertension the genetic component is definitely stronger than environmental factors, some benefit in terms of the development and coronary complications of atherosclerosis in hypertensive patients can be expected from fatty acids such as alpha-linolenic acid, eicosapentaenoic acid and docosahexaenoic acid. This particularly holds for those subjects where the hypertensive mechanism involves the formation of thromboxane A2 and/or alpha1-adrenergic activities. However, large-scale trials are required to test this contention. Certain aspects of blood platelet function, blood coagulability, and fibrinolytic activity are associated with cardiovascular risk, but causality has been insufficiently proven. Nonetheless, well-designed intervention studies should be initiated to further evaluate such promising dietary components as the various n-3 and n-6 fatty acids and their combination, antioxidants, fibre, etc. for their effect on processes participating in arterial thrombus formation. Long-chain polyenes of the n-3 family and antioxidants can modify the activity of immunocompetent cells, but we are at an early stage of examining the role of immune function on the development of atherosclerotic plaques. Actually, there is little, if any, evidence that dietary modulation of immune system responses of cells participating in atherogenesis exerts beneficial effects. Although it seems feasible to modulate insulin sensitivity and subsequent cardiovascular risk factors by decreasing the total amount of dietary fat and increasing the proportion of polyunsaturated fatty acids, additional studies on the efficacy of specific fatty acids, dietary fibre, and low-energy diets, as well as on the mechanisms involved are required to understand the real function of these dietary components. Finally, dietary supplements containing folate and vitamins B6 and/or B12 should be tested for their potential to reduce cardiovascular risk by lowering the plasma level of homocysteine.

Yaqoob P.
P. Yaqoob, Division of Human Nutrition, School of Biological Sciences, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX United Kingdom
Brazilian Journal of Medical and Biological Research (Brazil), 1998, 31/4 (453-465)

Animal studies suggest that olive oil is capable of modulating functions of cells of the immune system in a manner similar to, albeit weaker than, fish oils. There is some evidence that the effects of olive oil on immune function in animal studies are due to oleic acid rather than to trace elements or antioxidants. Importantly, several studies have demonstrated effects of oleic acid-containing diets on in vivo immune responses. In contrast, consumption of a monounsaturated fatty acid (MUFA)-rich diet by humans does not appear to bring about a general suppression of immune cell functions. The effects of this diet in humans are limited to decreasing aspects of adhesion of peripheral blood mononuclear cells, although there are trends towards decreases in natural killer cell activity and proliferation. The lack of a clear effect of MUFA in humans may be attributable to the higher level of monounsaturated fat used in the animal studies, although it is ultimately of importance to examine the effects of intakes which are in no way extreme. The effects of MUFA on adhesion molecules are potentially important, since these molecules appear to have a role in the pathology of a number of diseases involving the immune system. This area clearly deserves further exploration.

Xiaoguang C.; Hongyan L.; Xiaohong L.; Zhaodi F.; Yan L.; Lihua T.; Rui H.
C. Xiaoguang, Department of Pharmacology, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050 China
Journal of Ethnopharmacology (Ireland), 1998, 60/1 (71-78)

Red ginseng extract A and B are the active components of Panax ginseng. Red ginseng is a classical traditional Chinese medicine. Among Chinese herbs, red ginseng has been considered as one of the tonics. Many studies indicated that red ginseng could enhance immune function of the human body. The effects of red ginseng extracts on transplantable tumors, proliferation of lymphocyte, two-stage model and rat liver lipid peroxidation were studied. In a two-stage model, red ginseng extracts had a significant cancer chemoprevention. At 50-400 mg/kg, they could inhibit DMBA/Croton oil-induced skin papilloma in mice, decrease the incidence of papilloma, prolong the latent period of tumor occurrence and reduce tumor number per mouse in a dose-dependent manner. Red ginseng extract B could effectively inhibit the Fe2+/cysteine-induced lipid peroxidation of rat liver microsome, suggesting that red ginseng extract B has a stronger antioxidative effect than that of extract A. The results indicated that red ginseng extracts (50 similar 400 mg/kg) could significantly inhibit the growth of transplantable mouse sarcoma S180 and melanoma B16. Red ginseng extracts A (0.5 mg/ml) and B (0.1 and 0.25 mg/ml) might effectively promote the transformation of T lymphocyte, but there was no influence on lymphocyte proliferation stimulated by concanavalin A. This suggests that red ginseng extracts have potent tumor therapeutic activity and improve the cell immune system.

Beisel W.R.
NAIDS, 8210 Ridgelea Court, Frederick, MD 21702-2938 USA
Journal of Nutrition (USA), 1996, 126/10 Suppl. (2611S-2615S)

Malnutrition can have adverse, even devastating effects on the antigen- specific arms of the immune system and on generalized host defensive mechanisms. Protein/energy malnutrition and/or deficiencies of single nutrients that assist in nucleic acid metabolism generally lead to atrophy of lymphoid tissues and dysfunctions of cell-mediated immunity. Deficiencies of single nutrients can impair production of key proteins. Trace element deficiencies are often multifactorial. Essential fatty acid deficiencies can reduce or perturb the synthesis of cytokine-induced eicosanoids. Arginine deficiency can diminish the production of nitric oxide, and deficiencies of antioxidant nutrients can allow increases in the damaging effects of free oxygen radicals. Humoral immunity continues to be maintained, although new primary responses to T-cell-dependent antigens are generally subnormal in both magnitude and quality. Immunological dysfunctions associated with malnutrition have been termed Nutritionally Acquired Immune Deficiency Syndromes (NAIDS). Infants and small children are at great risk because they possess only immature, inexperienced immune systems and very small protein reserves. The combination of NAIDS and common childhood infections is the leading cause of human mortality. NAIDS can generally be corrected by appropriate nutritional rehabilitation, but from a viewpoint highly important to this Workshop, AIDS and NAIDS are intensely synergistic. AIDS-induced malnutrition can lead to the secondary development of NAIDS, with its much broader array of additional immunological dysfunctions. The complex and far reaching insults to the immune system caused by NAIDS, and the synergistic combination of NAIDS and AIDS, thereby hasten the demise of many victims of AIDS. Aggressive nutritional support for children with HIV infections could delay, or lessen, the development of NAIDS and avoidance of NAIDS would improve both quality and length of life.

Liang B.; Watson R.R.
Prevention Center, University of Arizona, 1501 N. Campbell Avenue, Tucson, AZ 85724 USA
Expert Opinion on Investigational Drugs (United Kingdom), 1996, 5/9 (1221-1225)

Nutrition has a profound effect on immunity and health. Nutritional deficiencies impair immune responsiveness, thereby, increase morbidity and mortality. On the other hand, nutritional supplementation often enhances certain aspects of immune function . Vitamin E, as a potent antioxidant and immunostimulant, has recently received a great deal of attention because of its action on immunity and disease aetiology. We recently reviewed the interaction of vitamin E with the immune system, AIDS, circulatory system, and pulmonary system. This paper is a summary of several recent studies on the mechanisms by which vitamin E affects cancer resistance by immunomodulation via nuclear factor-kappaB (NF-kappaB) inhibition.

Traber M.G.; Sies H.
Department of Molecular/Cell Biology, University of California, Berkeley, CA 94720 USA
Annual Review of Nutrition (USA), 1996, 16/- (321-347)

How much vitamin E is enough? An established use of supplemental vitamin E in humans is in the prevention and therapy of deficiency symptoms. The cause of vitamin E deficiency, characterized by peripheral neuropathy and ataxia, is usually malabsorption-a result of fat malabsorption or genetic abnormalities in lipoprotein metabolism. Genetic abnormalities in the hepatic alpha-tocopherol transfer protein also cause vitamin E deficiency- defects in this protein cause an impairment in plasma vitamin E transport. Impaired delivery of vitamin E to tissues, thereby, results in deficiency symptoms. Also discussed is the use of supplemental vitamin E in chronic diseases such as ischemic heart disease, atherosclerosis, diabetes, cataracts, Parkinson's disease, Alzheimer's disease, and impared immune function, as well as in subjects receiving total parenterol nutrition. In healthy individuals, a daily intake of about 15-30 mg of alpha-tocopherol is recommended to obtain 'optimal plasma alpha-tocopherol concentrations' (30 microM or greater).

Liang B.; Lane L.; Watson R.R.
Department of Family Medicine, University of Arizona, Tucson, AZ 85724 USA
Expert Opinion on Investigational Drugs (United Kingdom), 1995, 4/3 (201-211)

As the most powerful and versatile biological defence mechanism of animals and man, the immune system identifies foreign substances and defends the body against their attack. The immune response is concerned not only with providing protection against disease-causing infectious agents, such as bacteria and viruses, that invade the body, but also in recognising and destroying pre-cancerous, tumour-forming cells that develop within the body. Recent evidence indicates that vitamin E is a vital link in optimal immune system functioning and can enhance resistance to disease. The interaction of vitamin E and immune systems, AIDS, oxidative stress, and circulatory and pulmonary system are reviewed in this paper.

Grant J.P.
Duke University Medical Center, Durham, NC 27710 USA
Ann. Surg. (USA), 1994, 220/5 (610-616)

Objective. The author reviews the newer nutritional substrates in use or under investigation for enteral and parenteral nutrition. Management of the critically ill patient remains a significant challenge to clinicians, and it is hoped that dietary manipulations, such as those outlined, may augment host barriers and immune function and improve survival.

Summary Background Data. The role of nutrition in patient well-being has long been recognized, but until the past 25 years, the technology to artificially provide nutrients when patients could not eat was not developed. With current, new methods for enteral and vascular access, patients can be fed nonvolitionally with little difficulty. Continued efforts have been directed toward identifying optimal feeding formulations, which have resulted in a multitude of commercially available products. In the past several years, attention has been turned to evaluation of four specialized nutrients and the use of other substrates as pharmacologic agents.

Methods. Pertinent laboratory and clinical data were reviewed to present the pros and cons for each nutritive substrate.

Conclusions. Medium-chain fatty acids, branched-chain amino acids, and glutamine have been shown to be of clinical benefit and should be in common use in the near future. Short-chain fatty acids still are under investigation. Albumin, vitamins E and C, arginine, glutamine, and omega-3 fatty acids show great promise as pharmacologic agents to manipulate the stress response. Nucleotides remain investigational. Contents Summary. The application of some new nutritional substrates for use in critically ill patients, both as caloric sources and as pharmacologic agents, are reviewed.

Huggins N.D.; Khaled M.A.; Cornwell P.E.; Alvarez J.O.
USA
Res. Common. Subst. Abuse (USA), 1991, 12/4 (209-215)

The plasma levels of some essential nutrients and the lymphocyte CD4 to CD8 ratio were measured in four groups of individuals that included: (a) cocaine and (b) heroin abusers, (c) methadone treated and (d) healthy subjects. Folate and B-carotene levels were lower in the three drug groups while vitamin C was lower in the methadone and heroin subjects. Vitamin E levels were borderline low in the methadone and cocaine groups. The methadone group also showed a significantly higher level of lipid peroxidation which correlated well with the low values observed for the antioxidant nutrients. Interestingly, the methadone group was the only one with a significantly reduced lymphocyte CD4/CD8 ratio.

Isoherranen K; Peltola V; Laurikainen L; Punnonen J; Laihia J; Ahotupa M; Punnonen K
Department of Clinical Chemistry, University of Turku, Finland.
kirsi.isoherranen@utu.fi
J Photochem Photobiol B (Switzerland) Oct 1997, 40 (3) p288-93

We have examined the effects of UVB irradiation, oxidative stress and cytokines on the antioxidant enzymes copper/zinc and manganese superoxide dismutase (CuZnSOD and MnSOD) in HeLa cells. A single dose of UVB irradiation regulated dose-dependently the expression of the 4 kb transcript of MnSOD although it did not have any significant effect on MnSOD enzymatic activity. In contrast, UVB irradiation reduced both the enzymatic activity and the expression of the 0.7 and 0.9 kb mRNA transcripts of CuZnSOD. The cytokines TNF-alpha (1 ng ml-1 and 10 ng ml-1) and IL-6 (100 U ml-1) induced MnSOD activity, and TNF-alpha also upregulated MnSOD mRNA expression. Interestingly, genistein, a soy isoflavone and a tyrosine kinase inhibitor, was able to inhibit the induction of Mn-SOD activity and mRNA expression by TNF-alpha. Enzymatic CuZnSOD activity was depressed by a high dose of H2O2 while IL-6 or TNF-alpha had no effect on CuZnSOD activity. Our results demonstrate that, in addition to enzyme activity level, UVB irradiation can regulate the superoxide dismutases at the mRNA level. We also suggest that UVB irradiation, oxidative stress and cytokines regulate differentially CuZnSOD and MnSOD, and that the activities and expression of these antioxidant enzymes are controlled by distinct mechanisms.

Beck FW; Prasad AS; Kaplan J; Fitzgerald JT; Brewer GJ
Department of Internal Medicine, Wayne State University School of Medicine, Detroit,
Am J Physiol Jun 1997, 272 (6 Pt 1) pE1002-7

We have utilized an experimental model of human zinc deficiency for study of cytokines production by TH1 and TH2 cells. Additionally, we determined ratios of CD4+ to CD8+ and CD4+ CD45RA+ to CD4+CD45RO+ cells and percentages of CD73+ T cytolytic cells in the CD8+ subset. The data were collected during baseline, at the end of the zinc -restricted period, and following zinc repletion. Our results showed that functions of TH1 cells, as evidenced by production of interferon-gamma, interleukin-2 (IL-2), and tumor necrosis factor-alpha, were decreased, whereas functions of TH2 cells (production of IL-4, IL-6, and IL-10) were unaffected by zinc deficiency. Thus an imbalance between TH1 and TH2 cells resulted because of zinc deficiency in humans. Our studies also showed that zinc may be required for regeneration of new CD4+ T lymphocytes and maintenance of T cytolytic cells. We conclude that an imbalance between TH1 and TH2 cells, decreased recruitment of T naive cells, and decreased percentage of T cytolytic cells may account for decreased cell-mediated immune functions in zinc -deficient subjects.

Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH
Department of Internal Medicine, Wayne State University School of Medicine, Detroit, MI
Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77

Cell-mediated immune dysfunctions and susceptibility to infections have been observed in zinc -deficient human subjects. In this study, we investigated the production of cytokines and characterized the T-cell subpopulations in three groups of mildly zinc -deficient subjects. These included head and neck cancer patients, healthy volunteers who were found to have a dietary deficiency of zinc, and healthy volunteers in whom we induced zinc deficiency experimentally by dietary means. We used cellular zinc criteria for the diagnosis of zinc deficiency. We assayed enzyme-linked immunosorbent assay the production of cytokines from phytohemagglutinin-stimulated peripheral blood mononuclear cells and assessed by flow cytometry the differences in T-cell subpopulations. Our studies showed that the cytokines produced by TH1 cells were particularly sensitive to zinc status, inasmuch as the production of interleukin-2 (IL-2) and interferon-gamma were decreased even though the deficiency of zinc was mild in our subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not affected by zinc deficiency. Natural killer cell lytic activity also was decreased in zinc -deficient subjects. Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+ CD11b-, precursors of cytolytic T cells, were decreased in mildly zinc -deficient subjects. An imbalance between the functions of TH1 and TH2 cells and changes in T-cell subpopulations are most probably responsible for cell-mediated immune dysfunctions in zinc deficiency.

Reinhold D.; Ansorge S.; Grungreiff K.
Dr. K. Grungreiff, Heydeckstr. 9, D-39104 Magdeburg Germany
Journal of Trace Elements in Experimental Medicine (USA), 1997, 10/1 (19-27)

Zinc (zinc ions and/or chelated zinc ) plays an important role in the maintenance of immune function. Patients with chronic liver disease, particularly liver cirrhosis, frequently have endotoxemia, increased serum concentrations of cytokines, e.g., interleukin-6 (IL-6), and reduced serum zinc levels. The aim of the present study was to investigate the effects of zinc (ZnCl2, ZnO, ZnSO4) on DNA synthesis and cytokine production (IL-2, IL-6, IL-10) in pokeweed mitogen (PWM)-stimulated peripheral blood mononuclear cells (PBMC). In addition, we examined the effect of long-term zinc supplementation ( zinc -hydrogen-aspartate; UNIZINK 50; 3 x 1 = 29.76 mg/day) on IL-6 and IL-10 serum levels in patients with chronic liver disease (n = 16), all with reduced serum zinc levels. It could be shown that zinc concentrations up to 0.1 mM stimulate DNA synthesis and cytokine production by PWM-stimulated PBMC, whereas higher concentrations (0.2-0.4 mM) have a strongly inhibitory effect. Zinc concentrations exceeding 0.5 mM were found to have a toxic effect on these immune cells. Interestingly, in most patients with chronic liver disease (n = 10), zinc supplementation decreased IL-6, and to a lesser extent, IL-10 serum levels, and normalized the serum zinc concentrations. We conclude that zinc plays a regulatory role in DNA synthesis and cytokine production by PBMC. The critical zinc concentration for immune cells lies in the range of 0.5 mM, which is equivalent to a daily dose of similar45 mg zinc salt. Furthermore, zinc supplementation in chronic liver disease with reduced serum zinc levels appears to normalize IL-6 and IL-10 production.

Fortes C; Forastiere F; Agabiti N; Fano V; Pacifici R; Virgili F; Piras G Guidi L; Bartoloni C; Tricerri A; Zuccaro P; Ebrahim S; Perucci CA
National Institute of Health, Rome, Italy.
J Am Geriatr Soc Jan 1998, 46 (1) p19-26

OBJECTIVE: To determine if either supplemental vitamin A, zinc, or both increases cell - mediated immune response in an older population.

DESIGN: A double-blind, randomized, controlled trial of supplementation with vitamin A and zinc.

SETTING: Casa Di Riposo Roma III, a public home for older people in Rome, Italy.

SUBJECTS: The health and nutritional status of 178 residents were evaluated. One hundred thirty-six residents agreed to participate in the trial and were randomized into four treatment groups, and 118 of these residents completed the trial.

INTERVENTION: The four treatments consisted of: (1) Vitamin A (800 micrograms retinol palmitate); (2) Zinc (25 mg as zinc sulfate); (3) Vitamin A and Zinc (800 micrograms retinol palmitate and 25 mg as zinc sulfate); (4) Placebo capsules containing starch.

MAIN OUTCOME MEASUREMENTS: Immune tests-counts of leucocytes, lymphocytes, T-cell subsets, and lymphocyte proliferative response to mitogens-were measured before and after supplementation.

RESULTS: Zinc increased the number of CD4 + DR + T-cells (P = .016) and cytotoxic T-lymphocytes (P = .005). Subjects treated with vitamin A experienced a reduction in the number of CD3 + T-cells (P = .012) and CD4 + T-cells (P = .012).

CONCLUSIONS: These data indicate that zinc supplementation improved cell - mediated immune response, whereas vitamin A had a deleterious effect in this older population. Further research is needed to clarify the clinical significance of these findings.

Grimble RF
Institute of Human Nutrition, University of Southampton, United Kingdom.
Nutrition Jul-Aug 1998, 14 (7-8) p634-40

The pro-inflammatory cytokines and oxidant molecules produced during the inflammatory response, which follows infection and injury, may be beneficial, or detrimental to the patient, depending on the amounts and contexts in which they are produced. Aberrant or excessive production has been implicated in inflammatory disease, and sepsis. The upregulation of cytokine production by NF kappa B and NFIL-6 activation by oxidants increases the likelihood of cytokine-induced mortality and morbidity. Complex systems exist for the control of cytokine production and oxidant actions. The former include the hormones of the hypothalamo-pituitary-adrenal axis, acute phase proteins, and endogenous inhibitors of interleukin (IL)-1 and tumor necrosis factor (TNF). The latter include endogenously synthesized antioxidants, such as glutathione and dietary antioxidants, such as tocopherols, ascorbates and cachectins. Nutrients change cytokine production and potency by influencing tissue concentrations of many of the molecules involved in cytokine biology. Monounsaturated fatty acids and omega-3 polyunsaturated fatty acids (PUFAs) suppress TNF and IL-1 production and actions, while n-6 PUFAs exert the opposite effect. Changes in eicosanoid production are more likely to underlie this effect than alterations in membrane fluidity. Low antioxidant intake results in enhanced cytokine production and effects. The anorexia that follows infection and injury, may be purposeful to permit release of substrate from endogenous sources to support and control the inflammatory process. Therefore, prior as well as concurrent nutrient intake are of importance in determining the outcome of the inflammatory response. (88 Refs.)

Santos MS; Gaziano JM; Leka LS; Beharka AA; Hennekens CH; Meydani SN
Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
Am J Clin Nutr Jul 1998, 68 (1) p164-70

We showed previously that natural killer (NK) cell activity is significantly greater in elderly men supplemented with beta -carotene than in those taking placebo. In an attempt to determine the mechanism of beta -carotene 's effect, we analyzed the production of NK cell-enhancing cytokines (interferon alpha, interferon gamma, and interleukin 12). Boston-area participants in the Physicians' Health Study (men aged 65-88 y; mean age, 73 y) who had been supplemented with beta -carotene (50 mg on alternate days) for an average of 12 y were enrolled in a randomized, placebo-controlled, double-blind study. Elderly subjects taking beta -carotene supplements had significantly greater plasma beta -carotene concentrations than those taking placebo. Beta -carotene -supplemented elderly men had significantly greater NK cell activity than did elderly men receiving placebo. Percentages of NK cells (CD16+CD56+) were not significantly different between the beta -carotene and placebo groups. Production of interleukin 12, interferon alpha, or concanavalin A-stimulated interferon gamma by cultured peripheral blood mononuclear cells was not significantly different between beta-carotene-supplemented elderly and those taking placebo. Our results indicate that beta -carotene -induced enhancement of NK cell activity is not mediated by changes in percentages of CD16+CD56+ NK cells nor through up-regulation of interleukin 12 or interferon alpha.

Spapen H; Zhang H; Demanet C; Vleminckx W; Vincent JL; Huyghens L
Department of Intensive Care, Academic Hospital, Vrije Universiteit, Brussels, Belgium.
Chest Jun 1998, 113 (6) p1616-24

STUDY OBJECTIVE: To assess the effects of adjunctive treatment with N-acetyl-L-cysteine (NAC) on hemodynamics, oxygen transport variables, and plasma levels of cytokines in patients with septic shock.

DESIGN: Prospective, randomized, double-blind, placebo-controlled study.

SETTING: A 24-bed medicosurgical ICU in a university hospital.

PATIENTS: Twenty-two patients included within 4 h of diagnosis of septic shock.

INTERVENTIONS: Patients were randomly allocated to receive either NAC (150 mg/kg bolus, followed by a continuous infusion of 50 mg/kg over 4 h; n= 12) or placebo (n=10) in addition to standard therapy.

MEASUREMENTS: Plasma concentrations of tumor necrosis factor-alpha (TNF), interleukin (IL)-6, IL-8, IL-10, and soluble tumor necrosis factor-alpha receptor-p55 (sTNFR-p55) were measured by sensitive immunoassays at 0, 2, 4, 6 and 24 h. Pulmonary artery catheter-derived hemodynamics, blood gases, hemoglobin, and arterial lactate were measured at baseline, after infusion (4 h), and at 24 h.

RESULTS: NAC improved oxygenation (PaO2/FIO2 ratio, 214+/-97 vs 123+/-86; p<0.05) and static lung compliance (44+/-11 vs 31+/-6 L/cm H2O; p<0.05) at 24 h. NAC had no significant effects on plasma TNF, IL-6, or IL-10 levels, but acutely decreased IL-8 and sTNFR-p55 levels. The administration of NAC had no significant effect on systemic and pulmonary hemodynamics, oxygen delivery, and oxygen consumption. Mortality was similar in both groups (control, 40%; NAC, 42%) but survivors who received NAC had shorter ventilator requirement (7+/-2 days vs 20+/-7 days; p<0.05) and were discharged earlier from the ICU (13+/-2 days vs 32+/-9 days; p<0.05).

CONCLUSION: In this small cohort of patients with early septic shock, short-term IV infusion of NAC was well-tolerated, improved respiratory function, and shortened ICU stay in survivors. The attenuated production of IL-8, a potential mediator of septic lung injury, may have contributed to the lung-protective effects of NAC.

Blok WL; Deslypere JP; Demacker PN; van der Ven-Jongekrijg J; Hectors MP; van der Meer JW; Katan MB
Department of General Internal Medicine, University Hospital Nijmegen, The Netherlands.
Eur J Clin Invest (England) Dec 1997, 27 (12) p1003-8

Dietary supplementation with n-3 fatty acids from fish oil alleviates inflammation in various chronic inflammatory disease states. Reductions in the production of pro-inflammatory cytokines interleukin 1 beta (IL-1 beta), tumour necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) have been seen in humans after short-term n-3 fatty acid supplementation. We investigated long-term effects of dietary n-3 fatty acids on circulating cytokine concentrations and on ex vivo stimulated whole-blood production of IL-1 beta, TNF-alpha and interleukin 1 receptor antagonist (IL-1Ra), the naturally occurring antagonist of IL-1. A total of 58 monks with a mean age of 56 years were randomized into four groups and their diets were supplemented with 0, 3, 6, or 9 g of fish oil, providing 0, 1.06, 2.13 or 3.19 g of n-3 fatty acids per day. Subjects received equal amounts of saturated fatty acids, vitamin E and cholesterol. Compliance was excellent and erythrocyte fatty acid profiles closely reflected the amounts of n-3 fatty acids ingested. In the group receiving 9 g of fish oil per day, no influence of n-3 fatty acids on circulating cytokine concentrations was observed relative to placebo. Endotoxin-stimulated whole-blood cytokine production was measured at 26 and 52 weeks after the start and at 4, 8 and 26 weeks after cessation of supplementation. In all groups, the production of IL-1 beta and IL-1Ra was higher during supplementation than afterwards. However, no differences in cytokine production were noted between the placebo group and the various treatment groups at any point in time. Our results suggest that long-term supplementation of fish oil does not affect ex vivo cytokine production in man.

Faruqi RM; Poptic EJ; Faruqi TR; De La Motte C; DiCorleto PE
Department of Cell Biology, Cleveland Clinic Foundation, Ohio 44195, USA.
Am J Physiol Aug 1997, 273 (2 Pt 2) pH817-26

We have examined the effects of N-acetyl-L- cysteine (NAC), a well-characterized, thiol-containing antioxidant, on agonist-induced monocytic cell adhesion to endothelial cells (EC). NAC inhibited interleukin-1 (IL-1 beta)-induced, but not basal, adhesion with 50% inhibition at approximately 20 mM. Monocytic cell adhesion to EC in response to tumor necrosis factor-alpha (TNF-alpha), lipopolysaccharide (LPS), alpha-thrombin, or phorbol 12-myristate 13-acetate (PMA) was similarly inhibited by NAC. Unlike published studies with pyrrolidinedithiocarbamate, which specifically inhibited vascular cell adhesion molecule 1 (VCAM-1), NAC inhibited IL-1 beta-induced mRNA and cell surface expression of both E-selectin and VCAM-1. NAC had no effect on the half-life of E-selectin or VCAM-1 mRNA. Although NAC reduced nuclear factor-kappa B (NF-kappa B) activation in EC as measured by gel-shift assays using an oligonucleotide probe corresponding to the consensus NF-kappa B binding sites of the VCAM-1 gene (VCAM-NF-kappa B), the antioxidant had no appreciable effect when an oligomer corresponding to the consensus NF-kappa B binding site of the E-selectin gene (E-selectin-NF-kappa B) was used. Because NF-kappa B has been reported to be redox sensitive, we studied the effects of NAC on the EC redox environment. NAC caused an expected dramatic increase in the reduced glutathione (GSH) levels in EC. In vitro studies demonstrated that whereas the binding affinity of NF-kappa B to the VCAM-NF-kappa B oligomer peaked at a GSH-to-oxidized glutathione (GSSG) ratio of approximately 200 and decreased at higher ratios, the binding to the E-selectin-NF-kappa B oligomer appeared relatively unaffected even at ratios > 400, i.e., those achieved in EC treated with 40 mM NAC. These results suggest that NF-kappa B binding to its consensus sequences in the VCAM-1 and E-selectin gene exhibits marked differences in redox sensitivity, allowing for differential gene expression regulated by the same transcription factor. Our data also demonstrate that NAC increases the GSH-to-GSSG ratio within the EC suggesting one possible mechanism through which this antioxidant inhibits agonist-induced monocyte adhesion to EC.

Mol MJ; de Rijke YB; Demacker PN; Stalenhoef AF
Department of Medicine, University Hospital Nijmegen, Netherlands.
Atherosclerosis (Ireland) Mar 21 1997, 129 (2) p169-76

To evaluate the role of both oxidation and inflammation in atherosclerosis, we compared LDL oxidizability, in vivo lipid and cholesterol oxidation, and basal and lipopolysaccharide (LPS)-stimulated production of various cytokines in normolipidemic patients with diabetes mellitus (DM: n = 11), cigarettes smokers (n = 14). In addition, the effects of vitamin E (600 I.U./day for 4 weeks) on these parameters were evaluated. Initial LDL oxidation characteristics before and after vitamin E were identical in the 3 groups. Plasma thiobarbituric acid reactive substances were higher in DM and smokers versus controls (0.77 +/- 0.22, 0.74 +/- 0.14 versus 0.62 +/- 0.10 mumol malondialdehyde equivalents/l, respectively; P versus controls < 0.05) and normalized after vitamin E supplementation. Total plasma oxysterols were higher in smokers versus controls (354 +/- 104 versus 265 +/- 66 nmol/l, P < 0.05) and unaffected by vitamin E. The basal and LPS-stimulated levels of interleukin-1 beta and tumour necrosis factor alpha (TNF alpha) and the basal level of interleukin-1-receptor antagonist (IL-1RA) were identical for the 3 groups. LPS-stimulated IL-1RA was higher in DM versus controls (10.7 +/- 2.0 versus 8.1 +/- 1.7 pmol/l, P < 0.05). After vitamin E, TNF alpha dropped in controls and smokers, and IL-1RA in smokers only. Results suggest increased in vivo oxidative stress and inflammation in DM and smoking, which is partly overcome by vitamin E.

Chuntrasakul C, Siltharm S, Sarasombath S, Sittapairochana C, Leowattana W, Chockvivatanavanit S, Bunnak A
Research Center for Nutritional Support, Siriraj Hospital.
J Med Assoc Thai 1998 May;81(5):334-43

To evaluate the nutritional, metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids (fish oil) supplementation in immunocompromised patients, we performed a prospective study on the effect of immune formula administered to 11 severe trauma patients (average ISS = 24), 10 burn patients (average % TBSA = 48) and 5 cancer patients. Daily calorie and protein administration were based on the patient's severity (Stress factor with the range of 35-50 kcal/kg/day and 1.5-2.5 g/kg/day, respectively) Starting with half concentration liquid immune formula through nasogastric tube by continuous drip at 30 ml/h and increasing to maximum level within 4 days. The additional energy and protein requirement will be given either by parenteral or oral nutritional support. Various nutritional, metabolic, immunologic and clinical parameters were observed on day 0 (baseline), day 3, 7, and 14. Analysis was performed by paired student-t test. Initial mean serum albumin and transferrin showed mild (trauma) to moderate (burn and cancer) degree of malnutrition. Significant improvement of nutritional parameters was seen at day 7 and 14 in trauma and burn patients. Significant increase of total lymphocyte count (day 7, P < 0.01), CD4 + count (day 7, p < 0.01), CD8 + count (day 7, p <0.0005 & day 14, p < 0.05), complement C3 (day 7, p < 0.005 day 14, p < 0.01), IgG (day 7, and 14, p < 0.0005), IgA (day 7, p < 0.0005 & day 14, p < 0.05), in all patients. C-reactive protein decreased significantly on day 7 (p < 0.0005) and day 14 (p < 0.005). 3 cases of burn wound infection, one case of UTI and one case of sepsis were observed. Two cases of hyperglycemia in burn, 3 cases of hyperbilirubinemia in trauma, 10 cases of elevated LFT (5 trauma/5 burn), and one case of hyponatremia in cancer patients were observed. Two cases of nausea, 4 cases of vomiting, 5 cases of diarrhea (< 3 times/day), 2 cases of abdominal cramp, 1 case of distension were observed. The feeding of IMMUNE FORMULA was well tolerated and significant improvement was observed in nutritional and immunologic parameters as in other immunoenhancing diets. Further clinical trials of prospective double-blind randomized design are necessary to address the so that the necessity of using immunonutrition in critically ill patients will be clarified.

Sayed-Ahmed MM; Shaarawy S; Shouman SA; Osman AM
Pharmacology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
Pharmacol Res, 39(4). 289-5 1999 Apr

Biopharmacological evaluations of the protective effects of L-carnitine (a naturally occurring quaternary ammonium compound) against doxorubicin-induced metabolic damage were carried out in isolated cardiac myocytes and in isolated rat heart mitochondria. Perfusion of the heart with DOX (0.5 mM) caused a significant 70% inhibition of palmitate oxidation in cardiac myocytes, while L-carnitine (5 mM) perfusion caused stimulation which accounted for 37%. Perfusion of the heart with L-carnitine after 10-min perfusion with DOX (0.5 mM) caused 88% reversal of DOX-induced inhibition of palmitate oxidation in cardiac cells. In rat heart mitochondria, DOX has no effect on either palmitate oxidation or acyl-CoA synthetase activity, whereas Enoximone (c-AMP-dependent phosphodiesterase inhibitor), caused a significant inhibition of palmitate oxidation and acyl-CoA activity (40 and 27%, respectively). The oxidation of palmitoyl-CoA, an index of carnitine palmitoyltransferse reaction was significantly inhibited by DOX as a function of DOX concentration. Preincubation of mitochondria with L-carnitine caused reversal of DOX-induced inhibition of palmitoyl-CoA oxidation depending on the concentration of L-carnitine. Moreover, L-carnitine treatment did not interfere with the cytotoxic effect of doxorubicin against the growth of solid Ehrlich carcinoma. The findings of this study may suggest that inhibition of fatty acid oxidation in the heart is at least a part of doxorubicin cardiotoxicity and that L-carnitine can be used to prevent the doxorubcin-induced cardiac metabolic damage without interfering with its antitumour activities. Copyright 1999 The Italian Pharmacological Society.

Continued on the next page...