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Biomedical subjects

G Fernandes

Publications and source records attributed to G Fernandes.

At least 73 records · Page 4Linked to original sources
PubMed1990

Studies on membrane lipid peroxidation in omega-3 fatty acid-fed autoimmune mice: effect of vitamin E supplementation.

Enzyme-dependent and non-enzymatic in vitro lipid peroxidation was studied in autoimmune prone B/W mice fed diets containing high levels of dietary corn oil (CO) or menhaden fish oil (FO) as lipid source since weaning. Lipid analysis revealed that FO-fed mouse liver mitochondrial and microsomal membrane fractions incorporated 20:5 omega 3 and 22:6 omega 3 in replacement of 18:2 omega 6 and 20:4 omega 6 found in corn oil (CO) fed control animals reflecting the composition of the dietary oils. Lower concentrations of vitamin E were found in the FO-fed mouse membranes and serum than those of CO-fed mice when diets were supplemented with a standard 75 I.U. alpha-tocopheryl acetate/kg diet. The rate and extent of membrane lipid peroxidation was greatly increased in FO-fed, vitamin-E-depleted membranes. Full repletion of membrane vitamin E levels by supplementation with 500 I.U./kg of FO diet for 30 days significantly decreased lipid peroxidation and showed that in FO-fed mice, membrane peroxidation is inversely proportional to vitamin E content. However, due to a lower ratio of vitamin E and highly unsaturated fatty acids, FO-fed mouse membranes were more sensitive to pro-oxidant stimulus than were those from CO-fed mice. These findings illustrate the action of vitamin E against membrane lipid peroxidation and stress the importance of adequate supplementation of antioxidant with high omega-3 fatty acids intake.

Animals↗
PubMed1990

Modulation of gene expression in autoimmune disease and aging by food restriction and dietary lipids.

Several recent observations carried out by many investigators have offered some clues in understanding the mechanism of how food restriction (FR) acts in the prolongation of life-span, but the precise mechanisms involved in modulating the immune system have not been clearly understood. Our own ongoing studies indicate that FR may act at the molecular level and may extend the life-span by modulating functional activities of several genes in various target tissues. For instance, while cytochrome P-450 IIB1 and IIB2 expression is known to decline with age in ad libitum-fed rats, FR prevented the loss of (drug-inducible) P-450 enzymes in liver tissues. In addition, both alpha 2u-globulin and senescence marker protein 2 expressions, which are regulated by hormones, were also modulated during aging by FR in Fischer 344 male rats. In short-lived autoimmune-prone mice, both FR and omega-3 (n-3) fatty acids diet lowered the severity of autoimmune disease both in lupus-prone (NZB x NZW)F1 mice and in mice prone to develop lymphoproliferative and renal diseases, whereas saturated (n-9) and polyunsaturated (n-6) dietary lipids not only exacerbated autoimmune disease, but also significantly enhanced expression of several oncogenes in lymphoid tissues. FR and omega-3 fatty acids decreased the expression of certain oncogenes. Both FR and omega-3 fatty acids may modulate the aging and autoimmune disease processes by not only altering the fatty acid composition, membrane fluidity, and signal transduction, but also by modulating the lymphokine hormone receptors and their functions and thereby modulating expression of several genes in various tissues during the aging process.

Aging↗
PubMed1990

Food restriction prevents the loss of isosafrole inducible cytochrome P-450 mRNA and enzyme levels in aging rats.

The influence of food restriction (FR) on the drug-inducible capacity of liver microsomal cytochrome P-450s IA1, IA2 and IIB1 and IIB2 was studied in 20-month-old male Fischer-344 rats. ELISA and Western Blotting revealed that the induction of the cytochrome P-450-IA1/IA2 and P-450-IIB1/IIB2 enzymes was considerably higher in the liver microsomes of FR rats than in their ad libitum (AL) fed counterparts. In order to determine whether the higher P-450 enzyme levels in FR rats were a reflection of an increased synthesis rate or a stabilization of these enzymes, hybridization studies were performed with a cDNA probe for P-450-IIB1/IIB2. These studies show markedly higher levels of P-450-IIB1/IIB2 mRNAs in the livers of FR rats as compared to AL animals. These results suggest that it is possible to prevent the age-dependent loss of drug-induced cytochrome P-450s by 40% dietary restriction which suggest FR may improve the drug-metabolizing capacity during aging.

Aging↗
PubMed1990

Effect of blood transfusions on immune function. Part VI. Effect on immunologic response to tumor.

Transfusions are reported to increase the incidence of tumor metastasis in clinical studies and primary tumor growth in animal studies. We evaluated the effect of transfusions on immunologic response to primary and metastatic tumors in multiple rat models. One half of the animals were administered lactated Ringer's solution and one half ACI rat blood at the time of tumor challenge. In 80 rats a slow-growing colon tumor was implanted subcutaneously. At 4 months there were no significant differences in tumor size or leukocyte infiltration of the tumor. Similar results were obtained with a rapidly growing colon cancer. Analysis of T-lymphocyte subpopulations in both groups showed no differences. Rats transfused at the time of intravenous challenge with a suspension of 1 x 10(6) tumor cells had a mean survival time of 38.3 +/- 0.8 days and the control group had a mean survival time of 41.1 +/- 0.8 days (p = 0.016). One week after transfusion, natural killer cell lysis of tumor cells at a 100:1 effector/target cell ratio was 18.0% +/- 1.8% in the transfusion group and 23.0% +/- 1.3% in the control group (p = 0.034). In conclusion, transfusions in multiple rat cancer models did not affect primary tumor growth or the host's immunologic response to it but did significantly impair natural killer cell function and survival with tumor metastases.

Adenocarcinoma↗
PubMed1989

Immunological functions in food-restricted rats: enhanced expression of high-affinity interleukin-2 receptors on splenic T cells.

Several immunological functions of B and T cells including IL-2 receptor expression on T cells were measured in 12-month-old Fisher-344 male rats maintained from 6 weeks of age on an ad libitum (AL) or a 40% food-restricted (FR) diet. Direct anti-SRBC plaque-forming cell (PFC) assays revealed a higher response in FR rats than in AL rats when splenocytes were cultured with or without recombinant interleukin-2 (rIL-2). B cell functions were studied by using nylon wool-purified splenic B cells stimulated either with rIL-2, lipopolysaccharide (LPS), or Salmonella typhimurium mitogen (STM) as a thymus-independent antigen. Reserve plaque assay showed no difference between FR and AL rats in the secretion of anti-IgM and anti-IgG antibodies. In addition, no difference was found in proliferation of B cells stimulated by LPS, STM mitogens or rIL-2. Although purified splenic T cells demonstrated an equally proliferative response in FR and AL rats when cultured with concanavalin A (Con A) or phytohemagglutinin (PHA), T cells in FR rats developed higher responses when stimulated with an alloantigen and rIL-2. Time-course studies carried out to measure high-affinity (HA) IL-2 receptor (R) molecules by using purified T cells with rIL-2 and 125I-labeled IL-2 revealed a higher expression of IL-2R molecules on T cells of FR rats than on T cells of AL rats at 72 h after culturing with Con A.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

The influence of diet and environment.

I have reviewed a small fraction of the vast literature on the influence of diet, food antigens, and environment on the immune response and would like to emphasize three points. Excess dietary lipid is thought to have a crucial role in inducing obesity and many age-related diseases including cardiovascular disease, malignancy and autoimmune diseases. Micronutrients are involved in protecting the functional integrity of the immune system, particularly to overcome the anti-oxidant deficiency present in refined diet components. Finally, environmental influences such as UV radiation or air pollutants may have an adverse effect in the modification of immune functions when combined with dietary and nutritional factors. It appears that future studies should be directed to understanding the overall interactions of diet and environmental factors, including those of food and viral antigens, and the impact that these have on the maintenance and gene expression of an active and vigorous immune system in healthy and diseased states.

Air Pollutants↗
PubMed1989

Calorie restriction delays age-dependent loss in androgen responsiveness of the rat liver.

We have shown that restricted calorie intake retards age-associated loss in androgen responsiveness of the rat liver. Sustained androgen receptivity delays age-dependent decline in the synthesis of the androgen-inducible alpha 2u globulin and derepression of the androgen-repressible senescence marker protein (SMP-2). Quantitation of mRNAs for alpha 2u globulin and SMP-2 in the liver of animals of various ages maintained on either ad libitum or restricted diets revealed that, although the 27-month-old ad libitum-fed rat had only 5% as much alpha 2u mRNA as the 6-month-old rat, the mRNA level was as high as 45% in the 27-month-old food-restricted rat. Conversely, the 27-month-old food-restricted rat had a much reduced amount (45%) of SMP-2 mRNA compared to the age-matched control that was allowed unlimited access to food. Furthermore, we have correlated the effect of dietary restriction on age-dependent changes in specific gene expression with the hepatic level of the immunoreactive cytoplasmic androgen-binding (CAB) protein. We observed that senescence in the male causes a substantial decrease in the circulating level of testosterone. However, dietary restriction does not retard the rate of decline in the plasma level of the male hormone during aging. These results indicate that age-dependent changes in the expression of androgen-responsive genes (alpha 2u globulin and SMP-2) reflect changing androgen sensitivity and that food restriction may directly influence the androgen receptivity of the liver.

Aging↗
PubMed1989

Strain differences in the early development of the thymus-dependent cells: precocity of T lineage cells in AKR mice as compared to those in C3H mice.

Early development of T lineage cells were compared between AKR and C3H mice by using two experimental strategies--neonatal thymectomy (NTx) and bone marrow transplantation (BMT)--between these two strains of mice. After NTx, AKR mice developed less wasting disease and showed better maintenance of several T cell functions. In addition, the response of neonatal spleen cells to PHA and ConA was much greater in AKR mice than in C3H mice. Further, when AKR mice were used as recipients of BMT, cell numbers recovered from thymuses between 2 and 7 weeks after reconstitution were consistently much greater (about 10 times greater) than those from chimeras where C3H mice were used as recipients, regardless of the donor strains of bone marrow cells. However, 4 weeks after BMT the proliferative responses to ConA were consistently higher in the donor-derived thymocytes from chimeras where AKR mice were used as bone marrow donors than in those from chimeras in which C3H were donors. The present findings suggest that these differences may be attributed to characteristics of recipient microenvironment (e.g., thymic stroma) which maintain developing thymocytes and supply them to the peripheral lymphoid tissue. Alternatively the differences may to some degree also be attributable to characteristics of the thymic progenitors themselves, which may determine the rates of maturation of thymocyte functions.

Animals↗
PubMed1987

Effect of age and dietary restriction on the expression of alpha 2u-globulin.

The effect of aging on the expression of alpha 2u-globulin was studied in liver tissue from 6-30-month-old male Fischer F344 rats. The synthesis of alpha 2u-globulin by suspensions of isolated hepatocytes decreased 90% between 6 and 22 months of age. The levels of alpha 2u-globulin mRNA and the transcription of alpha 2u-globulin genes by isolated liver nuclei decreased 80-85% between 5 and 24 months of age. Because alpha 2u-globulin has been suggested to be a "senescence marker protein," the expression of alpha 2u-globulin was measured in rats fed a diet restricted in calories. This dietary restriction procedure has been shown to increase significantly the longevity of rodents. The expression of alpha 2u-globulin was compared in liver tissue from 18-month-old rats fed ad libitum and a restricted diet (40% restriction of total calories). The synthesis, mRNA levels, and transcription of alpha 2u-globulin were 1.8-3-fold higher for liver tissue from restricted rats compared to liver tissue from rats fed ad libitum. Therefore, dietary restriction alters the age-related change in the expression of alpha 2u-globulin. Our results demonstrate that the changes in alpha 2u-globulin expression that arise during aging or dietary restriction are regulated at the level of transcription.

Aging↗
PubMed1987

Enhancement of natural killer-cell activity in young and old mice treated with cyclophosphamide on a circadian basis.

Several recent studies have revealed a significant circadian variation in immunological functions including natural killer (NK)-cell activity against tumor target cells both in rodents and in man. We have previously reported circadian changes in antibody-forming cells as well as NK-cell activity in mice and rats. The present study was undertaken to determine the effect of high and low doses of cyclophosphamide on circadian NK-cell activity in young (8-week-old) and old (8-month-old) female C57BL/6 (B/6) mice. The results revealed that, in general, young animals had higher NK activity than old animals. In both young and old mice, the high dose of cyclophosphamide depressed NK activity. In contrast, the low dose of cyclophosphamide showed significantly increased NK activity, which was proportionately greater in old mice than in young mice. Cyclophosphamide-enhanced NK activity was found to be higher during the resting period than during periods of activity. Apparently, high NK activity can be induced with a circadian-based immunotherapy regime using low-dose cyclophosphamide in both young and old animals. It is presently not clear if increased NK activity caused by cyclophosphamide is due to a decrease in activity of immunoregulatory cells, such as T cells, B cells, or macrophages. More studies are required to determine the basis of increased NK activity caused by treatment with low dosages of cyclophosphamide in mice.

Age Factors↗
PubMed1986

Studies of immune responses in mice prone to autoimmune disorders. II. Decreased down-regulation by auto-anti-idiotype antibody in autoimmune-prone mice.

Three lines of evidence are presented which suggest that autoimmune-prone mice are deficient in the production of auto-anti-idiotype antibody during their immune response to trinitrophenylated Ficoll (TNP-F). NZB, MRL lpr/lpr and older BXSB male mice have no hapten-augmentable plaque-forming cells (PFC). Hapten-augmentable PFC have been previously shown to be cells whose secretion of antibody has been inhibited by the binding of auto-anti-idiotype antibody to cell surface idiotype. Sera from TNP-F immunized NZB mice lack PFC inhibiting activity (anti-idiotype antibody). Spleen cells from TNP-F immune NZB mice fail to transfer anti-idiotype antibody-mediated suppression to naive mice as do spleen cells from immune non-autoimmune-prone mice. Taken together these data suggest that autoimmune-prone mice are deficient in auto-anti-idiotype antibody-mediated downward regulation of their immune responses. It was further shown that the immune response of NZB mice to TNP-F shows a slower decline in splenic PFC and a greater heterogeneity of PFC affinity than do the responses of non-autoimmune-prone strains. Since athymic (nude) mice, which were previously shown to be defective in the production of auto-anti-idiotype antibody, also show a slower decline in splenic PFC and an increased heterogeneity of PFC affinity, it is suggested that these peculiarities of the immune responses of autoimmune-prone and athymic mice are also the consequences of the lack of auto-anti-idiotype antibody-mediated down-regulation.

Animals↗
PubMed1986

Augmentation of natural killer cytotoxicity by alpha or gamma natural and recombinant interferons and interferon inducers. Effect of monocytes.

We investigated the effect of human peripheral blood monocytes on the augmentation of natural killer cytotoxicity by alpha or gamma natural and recombinant interferons (IFN) and certain interferon inducers. We observed that: (1) in the majority of the donors examined (75%) human peripheral blood monocytes do not affect natural killer cytotoxicity, determined by a 4-hour chromium-51 release assay, against target cells from hemopoietic human tumor cell lines. (2) Monocytes are not required and do not affect the augmentation of natural killer cytotoxicity by Escherichia coli-derived IFN-gamma, natural human IFN-gamma, E. Coli-derived IFN-alpha 2 or natural human IFN-alpha. E. Coli-derived IFN-gamma and natural human IFN-gamma have been reported to activate monocyte cytotoxicity determined in 72-hour assay. (3) Monocytes are not required for the augmentation of natural killer cytotoxicity against target cells from hemopoietic tumor cell lines by polyinosinic acid-polycytidylic acid or staphylococcal enterotoxin A.

Cells, Cultured↗
PubMed1986

Reduction of blood pressure and restoration of T-cell immune function in spontaneously hypertensive rats by food restriction and/or by treadmill exercise.

The studies were carried out to compare the effects of food restriction and/or treadmill exercise on the development of high blood pressure and to compare immune function in spontaneously hypertensive rats (SHR). The results demonstrate that moderate food restriction from weaning or a regular treadmill exercise not only maintains significantly lower blood pressure, but also increases T-cell proliferative response against mitogens which is found to be significantly depressed in SHR fed ad libitum. A significant loss of T-cell subpopulation such as W3/25+ T helper cells and OX8+ non-helper T-cells occurring in mice fed ad libitum were restored to normal levels, including IL-2 response, in food-restricted SHR. Our results suggest that both food restriction and/or physical exercise is effective in modulating the blood pressure and increasing T-cell immune functions in SHR.

Animals↗
PubMed1985

DNA and RNA analysis by flow cytometry of the leukemia in AKR mice.

The development of the leukemia-lymphoma complex was studied in AKR/J (H-2k) mice using flow cytometry and staining with acridine orange. Investigation of cytokinetics and of cellular RNA content showed that during the neonatal period all mice had a significant increase of S phase cells in the thymus, bone marrow, lymph nodes and spleen reflecting extramedullary hematopoiesis. Concomitantly, G0/G1 cells were significantly reduced in the thymus, lymph nodes and spleen when compared to 6-week old mice of the same strain. No changes in the cell cycle or in RNA content were observed until 10 months of age in congeneic AKR (H-2b) mice, which do not develop leukemia during the first year of life. In leukemia-prone AKR/J (H-2k) mice, however, it was shown that the first appearance of a leukemic process may be recognized in the thymus by a significant increase of cells in G1 phase of the cell cycle which have a high RNA content. These changes were first seen at 5 months of age before the increased expression of MuLV antigen signals preleukemic alterations at 6 months of age and long before morphological changes appear (8-10 months). Furthermore, at 6 months these mice showed a significant elevation of cells in S phase which always appeared initially in the thymus. By 10 months of age, when the mice were overtly leukemic, these changes had progressed in all lymphoid organs and in the peripheral blood. At the same time a unique population of cells was observed that was characterized by cells in S and G2M with very low RNA content. The method used is applicable to further analysis of the precise locus of development of leukemia in the thymus of AKR/J (H-2k) mice, analysis of the nature of the earliest malignant cells, and investigation of the influence of viruses in the pathogenesis of AKR leukemia.

Animals↗
PubMed1985

Alterations in immunological reactivity in encephalomyocarditis virus-induced murine diabetes. I. Defective primary IgM plaque forming cell responses to sheep erythrocytes: correction by islet cell transplantation.

Increasing data suggest a possible viral aetiology of juvenile onset, insulin-dependent diabetes mellitus. The M variant of the encephalomyocarditis (EMC) virus infects murine pancreatic beta cells and causes a diabetes like syndrome in susceptible strains of mice. Abnormalities in immunological function have been documented in patients with diabetes mellitus and in spontaneous, streptozotocin-induced and alloxan-induced diabetes in animals. The present study documents a significant impairment of the ability of mice with EMC virus (M variant)-induced diabetes to generate a direct, IgM PFC response after in vivo immunization with sheep erythrocytes. This abnormality appears to be a direct consequence of the diabetic state and not EMC virus infection, per se, since mice infected with EMC virus that do not become diabetic have normal direct PFC responses and islet cell transplantation, which cures the diabetes, corrects the defect in PFC responsiveness.

Animals↗