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LE Magazine October 2000

Continued from Medical Abstracts, October 2000

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Effects of orally administered bovine lactoferrin on the immune system of healthy volunteers

A protective effect of bovine lactoferrin (Lf) during lethal bacteraemia has been reported in mice. Also, protective effects of orally administered bovine Lf have been reported in cases of intractable stomatitis in cats and Cryptocaryon irritans infection in red sea bream. In this study, we examined the effects of orally administered bovine Lf on the immune system of healthy volunteers. Ten healthy male volunteers (age range of 31 to 55 years old) were given bovine Lf (2 g/body/day) for 4 weeks. Blood samples were drawn before, during and after administration of Lf. Phagocytic activity and superoxide production activity of polymorphonuclear leukocytes (PMN) were evaluated from the number of PMN phagocytizing polymer particles and by the dichlorofluorescein (DCFH) oxidation assay, respectively. The expression levels of CD11b, CD16 and CD56 molecules on leukocytes were quantified using flow cytometry. The phagocytic activity of PMN increased during the period of Lf administration in 3 of the 10 volunteers. In 2 of the 3 volunteers in which the phagocytic activity increased, PMN expressed CD16 at higher levels corresponding to the increase in 3 of the 10 volunteers, whereas the CD11b+ lymphocytes and CD56+ lymphocytes increased in 4 volunteers including the same 3 volunteers who showed an increase in CD16+. These results suggest that the proportion of natural killer (NK) cells among the lymphocytes might have increased in these subjects. It was demonstrated that the phagocytic activity or superoxide production activity of PMN or the proportions of CD11b+, CD16+ and CD56+ in lymphocytes was influenced by Lf administration in 7 of the 10 volunteers, while the effects of Lf on the immune system differed in individual cases. These results suggest that Lf administration may influence primary activation of the host defense system.

Adv Exp Med Biol 1998;443:261-5

The gut-a key metabolic organ protected by lactoferrin during experimental systemic inflammation in mice

The gastrointestinal tract may be viewed as an ecologic system in which a balance between the host and bacterial flora exists. Two major host components appear to be involved in maintaining this balance. The first is a non-specific structural barrier provided by the epithelial layer of the gastrointestinal mucosae. The second component involves functional immunological elements found in the mucosal and submucosal compartments, e.g., gut associated lymphoid tissue. When gut integrity is disrupted by invasive pathogens or by trauma, a myriad of pro-inflammatory mediators are released from cells in the gut wall that exert actions in the tissue or gut lumen. One of these mediators is lactoferrin, and iron binding protein found in high concentration in most human exocrine secretions. Despite controversies on its physiological role, evidence is emerging that lactoferrin plays an important role in host defense against toxic metabolites and antigenic components of potential pathogens2-4. This manuscript is intended to provide an overview of work related to lactoferrin's modulatory roles in inflammation, and to present observations from experimental studies on the preservation of intestinal structure and function by lactoferrin during intestinal inflammation. The possibility that lactoferrin limits the autodestructive inflammatory responses presents a new alternative for the future management of systemic inflammation.

Adv Exp Med Biol 1998;443:167-73

Impairment of circulating lactoferrin in HIV-1 infection

Levels of plasma lactoferrin are decreased in HIV-1-infected patients in relation to the progression of the disease. Plasma lactoferrin concentrations were determined using a specific and sensitive enzyme immunoassay. 97 plasma were studied (22 asymptomatic, 45 symptomatic patients compared to 30 healthy controls) and the results showed a highly significant decrease (p < 0.001) of the level of lactoferrin in HIV-1-infected patients (respectively 2.79 +/- 1.2 and 0.68 +/- 0.22 micrograms/ml) compared to controls (4.37 +/- 0.83 micrograms/ml). Since it is well established that plasma lactoferrin level could be influenced by the number of neutrophils, the experiments were reproduced in neutropenic patients who represent 10% of recruitment (6 among 45 symptomatic patients). The plasma from neutropenic symptomatic patients (neutrophils < or = 1,300/mm3) showed their mean lactoferrin level at 0.36 micrograms/ml still far above the normal values. In view of the different reported biological effects of lactoferrin that are of great importance in the non-specific defences, the real biological place of the lack of such a molecule could be one important component of the multifactorial nature of HIV-1 infection.

Cell Mol Biol (Noisy-le-grand) 1995 May;41(3):417-21

Antiviral effect of bovine lactoferrin saturated with metal ions on early steps of human immunodeficiency virus type 1 infection

Lactoferrin is a mammalian iron-binding glycoprotein present in many biological secretions, such as milk, tears, semen and plasma and a major component of the specific granules of polymorphonuclear leucocytes. The effect of bovine lactoferrin (BLf) in apo-form or saturated with ferric, manganese or zinc ions, on human immunodeficiency virus type 1 (HIV-1) infection in the C8166 T-cell line was studied. Both HIV-1 replication and syncytium formation were efficiently inhibited, in a dose-dependent manner, by lactoferrins. BLf in apo and saturated forms markedly inhibited HIV-1 replication when added prior to HIV infection or during the virus adsorption step, thus suggesting a mechanism of action on the HIV binding to or entry into C8166 cells. Likewise, the addition of Fe3+BLf prior to HIV infection and during the attachment step resulted in a marked reduction of the HIV-1 DNA in C8166 cells 20 h after infection. The potent antiviral effect and the high selectivity index exhibited by BLf suggest for this protein, in apo or saturated forms, an important role in inhibiting the early HIV-cell interaction, even though a post adsorption effect cannot be ruled out.

Int J Biochem Cell Biol 1998 Sep;30(9):1055-62

Inhibitory effects of bovine lactoferrin on intestinal polyposis in the Apc(Min) mouse

Chemopreventive effects of bovine lactoferrin (bLF), previously shown to strongly inhibit intestinal carcinogenesis in rats (K. Sekine, E. Watanabe, J. Nakamura, N. Takasuka, D.J. Kim, M. Asamoto, V. Krutovskikh, T.H. Baba, T. Ota, M.A. Moore, M. Masuda, H. Sugimoto, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of azoxymethane-initiated colon tumor by bovine lactoferrin administration in F344 rats, Jpn. J. Cancer Res. 88 (1997) 523-526; K. Sekine, Y. Ushida, T. Kuhara, M. Iigo, H. Baba-Toriyama, M.A. Moore, M. Murakoshi, Y. Satomi, H. Nishino, T. Kakizoe, H. Tsuda, Inhibition of initiation and early stage development of aberrant crypt foci and enhanced natural killer activity in male rats administered bovine lactoferrin concomitantly with azoxymethane, Cancer Lett. 121 (1997) 211-216), on spontaneous intestinal polyp development were assessed in the ApcMin mouse, a model for both familial adenomatous polyposis and sporadic colon cancers. In the experiment, 54 mice at 6 weeks of age were given 2% bLF (15 mice), 0.2% bLF (15 mice) and AIN-93G (24 mice) as basal diet ad libitum for 8 weeks. An overall tendency for a reduction in the total number of polyps in the small intestine was evident in the bLF-treated animals, along with significant suppression in the jejunum at the 2% dose (P < 0.05, 68% of the control). In addition, body growth suppression, presumed to be due to anemia and/or intussusception as a consequence of numerous polyps in the intestine, was alleviated. No toxic effects were observed in the intestinal epithelium. Although not as obvious as observed for the rat case, the data suggest that bLF may be a chemopreventor of intestinal polyposis.

Cancer Lett 1998 Dec 25;134(2):141-5

Antiviral activity of lactoferrin

A series of native and chemically derivatized lactoferrins (Lfs) purified from milk and colostrum were assayed in vitro for their anti-HIV and anti-HCMV-cytopathic effects in MT4 cells and fibroblasts respectively. All Lfs from bovine and human milk or colostrum were able to completely block HCMV replication as well as inhibited HIV-1 induced cytopathic effects. Through acylation of the amino function of the lysine residues in Lf, using anhydrides of succinic acid or cis-aconitic acid, negatively charged Lf derivatives were obtained that all showed a strong antiviral activity against the HIV-1 in vitro. Acylated-Lf exhibited a 4-fold stronger antiviral effect on HIV-1 than the parent compound but the activity on HCMV was abolished. Peptide scanning studies indicated that the native Lf as well as acylated Lf strongly bind to the V3 domain of the HIV envelope protein gp120, with Kd values in the same concentration range as the in vitro IC50. Therefore, shielding of this domain, resulting in inhibition of the virus-cell fusion and entry of the virus in MT4 cells is the likely mechanism underlying the anti-HIV activity. In contrast, addition of positive charges to Lf through amination of the proteins resulted in an increased anti-HCMV activity and a loss of anti-HIV activity, with anti-HCMV IC50 values in the low micromolar concentration range. The N-terminal portion of LF appeared essential to this anti-HCMV effect. The specific distribution of positively and negatively charged domains in the molecule appears to be important in both the anti-HIV and anti-HCMV effects.

Adv Exp Med Biol 1998;443:205-13

Nonspecific oral immunity in individuals with HIV infection

Lactoferrin, lysozyme, interferon, and neopterin levels were determined in parotid saliva from 44 individuals with different clinical stages of human immunodeficiency virus (HIV) infection and 19 HIV-seronegative controls. The secretory output of individual components was calculated according to the fluid flow rate. No parotid interferon activity was found in any of the HIV-infected subjects or controls, and no significant differences in parotid lysozyme or neopterin outputs were observed. The lactoferrin output was significantly decreased in HIV-seropositive subjects in parallel with their markedly reduced parotid secretory IgA output. This combined deficiency of parotid lactoferrin and secretory IgA may well contribute to the frequent oral infections seen in subjects with HIV infection.

J Acquir Immune Defic Syndr 1992;5(1):46-51


Insulin exposure and unifying aging

BACKGROUND: Absence of a widely agreed upon central paradigm for mammalian aging. OBJECTIVE: Detailed elaboration of a proposed mammalian aging paradigm. METHODS: Elaboration of a new theoretical model. RESULTS: Hormonal imbalance-growth factor exposure theory (HI-GFE theory) can account for two major aging phenomena: (1) decline in mammalian 'reserve capacity' and consequent rise of diseases of maintenance, and (2) rise then peaking of most age-associated proliferative diseases. Reserve capacity decline via gradual decline in mitochondrial maximal energy production (state 3) accounts for the gradual redirection of declined maximal energy production toward survival functions like ion pumping to the relative detriment of RNA and protein synthesis as seen in lesser synthetic rates and slower turnover with consequent gradual cellular impairment. Developmental program triggered, and over-ample nutritionally driven, growth factor exposure in youth to middle age encourages promotional events that lead to proliferative diseases that rise coincident to rapidly declining reserve capacity and cumulative increased mutational status of age. CONCLUSIONS: Declining mitochondrial state 3 aging energy production status is easily and safely reversible with probable consequences of greatly postponing the decline in overall 'reserve capacity' which may also improve insulin: growth hormone balance and result in lower overall growth factor exposure and consequent longer healthy life of a potentially greater magnitude increase in life spans than that seen in calorie-restricted animals.

Gerontology 1999 May-Jun;45(3):121-35

Physiologic changes in humans subjected to severe, selective calorie restriction for two years in biosphere 2: health, aging, and toxicological perspectives

Biosphere 2 is a closed ecological space of 7-million cubic feet near Tucson, AZ, containing 7 biomes: rain forest, Savannah, ocean, marsh, desert, agricultural station, and habitat for humans and domestic animals. Sealed inside, 4 men and 4 women maintained themselves and the various systems for 2 years. All organic material, all water, and nearly all air was recycled, and virtually all food was grown inside. On the low calorie but nutrient-dense diet available, the men sustained 18% and the women 10% weight loss, mostly within the first 6 to 9 months. The nature of the diet duplicated rodent diets that had been shown to enhance health, lower disease incidence, and retard aging. Using blood specimens frozen at different points during and after the 2 years, determinations were made of a number of biochemical parameters judged to be pertinent based on past studies of rodents and monkeys on similar diets. These included blood lipids, glucose, insulin, glycosylated hemoglobin, renin, and others. The results clearly suggest that humans react to such a nutritional regime similarly to other vertebrates. In addition to these studies, and because this was a tightly closed, isolated environment, the levels of insecticides or pollutants or their derivatives were determined in the sera of 2 crew members. It was found that levels of the lipophilic toxicant DDE and the “total PCB” load increased with the loss of body fat during the first 12-18 months inside Biosphere 2, then decreased.

Toxicol Sci 1999 Dec;52(2 Suppl):61-5

Beneficial effect of a moderately energy-restricted diet on fibrinolytic factors in non-obese men

Impaired fibrinolytic activity has been reported in the elderly and is thought to play a role in the etiology of cardiovascular disease, one of the leading causes of death in most Western countries. Since restriction of energy intake has been demonstrated to act beneficially on the aging process in a variety of species, we studied the effect of a 10-week moderately energy-restricted (ER) regimen (80% of habitual) on plasminogen activator inhibitor (PAI) activity, PAI-1 antigen, tissue plasminogen activator (tPA) activity, and tPA antigen in non-obese, middle-aged men. Moreover, the relationship between these fibrinolytic markers and glucose tolerance was investigated. Weight loss in the ER group (n = 16) was considerable (-7.4 +/- 1.7 kg, P < .001). Subjects in the control group (n = 8) also lost some weight (-2.1 +/- 1.5 kg, P < .01). Fasting glucose levels decreased in the ER group (-0.31 +/- 0.48 mmol/L, P < .05), which was correlated with the extent of weight loss (P < .01). Baseline insulin levels at 2 hours after an oral glucose load correlated with baseline PAI activity (P < .001) and PAI-1 antigen levels (P < .001). PAI activity decreased in the ER group (-2.94 +/- 2.90 IU/mL, P < .001), particularly in subjects with a high baseline PAI activity (> 9 IU/mL). Furthermore, energy restriction led to decreased PAI-1 antigen concentration (P < .05), a nonsignificant increase in tPA activity, and a decrease in tPA antigen concentration (P < .001). All these changes were more clear in subjects with a high baseline PAI activity. These results suggest that 10 weeks of moderate energy- restriction has a profibrinolytic effect in non-obese, middle-aged men, at least in subjects with higher baseline PAI activity (> 9 IU/mL). Moreover, in line with the suggestion that high PAI activity goes together with insulin resistance, a relationship between insulin concentration after a glucose load and PAI activity was found.

Metabolism 1995 Dec;44(12):1548-52

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