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Biomedical subjects

W Pierpaoli

Publications and source records attributed to W Pierpaoli.

At least 19 recordsLinked to original sources
PubMed2001

Effects of melatonin in perimenopausal and menopausal women: a randomized and placebo controlled study.

In aging humans, night levels of melatonin (MEL) decline progressively. Also thyroid and gonadal functions decline during aging while gonadotropins (luteotropic hormone (LH) and follicle stimulating hormone (FSH)) steadily increase. A desynchronization of pineal circadian cyclicity as expressed by the progressive decrease of the MEL night peak may be permissively linked to the onset and progression of menopause. We studied the effects of exogenous, evening administration of MEL on the level of hormones which are known to be involved in the genesis and progression of menopause. Perimenopausal and menopausal women from 42 to 62years of age with no pathology or medication were selected. MEL was measured in saliva to divide them into low, medium and high-MEL patients. Half of them took 3mg MEL and half of them Placebo at bedtime (10-12p.m.) in a fully randomized and double-blind fashion. Three and six months later blood was taken for determination of pituitary (LH, FSH), ovarian, and thyroid hormones I(T3 and T4). All women taking MEL with low basal level of MEL and/or Placebo for three and six months showed a significant increase in levels of thyroid hormones. Before initiation of the study, a negative correlation was found in all women between LH, FSH and basal MEL levels. Within six months of treatment, MEL produced a significant diminution of LH in the younger women (43 to 49year-old), while no effect was seen in the older women (50-62years old). A decrement of FSH was observed in MEL-treated women with low basal MEL levels. In addition, most MEL-treated women reported a general improvement of mood and a significant mitigation of depression. MEL decline during aging may thus signal the derangement of pineal and pituitary-controlled ovarian cyclicity and the progressive quenching of fertility in women. These findings seem to show a recovery of pituitary and thyroid functions in MEL-treated women, towards a more juvenile pattern of regulation.

Adult↗
PubMed2000

The pineal gland and cancer. I. Pinealectomy corrects congenital hormonal dysfunctions and prolongs life of cancer-prone C3H/He mice.

Hormonal derangements almost invariably anticipate and signal the onset of tumors. Chronic, nocturnal melatonin administration delays aging in normal strains of mice. On the contrary it promotes and accelerates the onset of tumors in the cancer-prone strain of C3H/He mice. Grafting of a young pineal gland into aging mice prolongs their longevity and maintains juvenile circadian hormonal functions while pinealectomy (Px) does the opposite. We investigated if Px in C3H/He mice would modify their congenitally deranged pituitary function and affect their longevity. It was found that contrarily to Px in normal mice, Px in C3H/He mice remarkably maintains juvenile night levels of thyroid hormones and lipids, preserves a cell-mediated immune response and significantly prolongs their life. The pineal gland and its pathology may be the key for understanding, not only the causes of metabolic aging, but also the origin of those congenital or progressive aging-related hormonal alterations preceding onset of all tumors and thus allow preventive corrective interventions with pineal-derived agents.

Aging↗
PubMed2000

Transferrin treatment corrects aging-related immunologic and hormonal decay in old mice.

Experiments were conducted to study the effect of heterologous plasma transferrins separated and purified from human plasma pools on endocrine and immune functions of old, aging mice. Two similar experiments have shown that parenteral treatment with iron and zinc-free human transferrins produces a significant improvement of immunological and endocrine functions in the aging mice toward more juvenile values. Those changes occur in the thymus and its cell subsets, in peripheral blood lymphocytes, in the restoration of juvenile levels of thyroxine, in the increase of testis weight, and in the normalization of plasma zinc levels. These totally unsuspected effects of transferrin in aging mice suggest a most important role of endogenous transferrins in the maintenance of neuroendocrine and immune functions. The mechanism remains unexplained although the basic immunoenhancing and anti-apoptotic effect of transferrin-vehiculated zinc may be relevant.

Adrenal Glands↗
PubMed2000

Upregulation of interleukin-10 and inhibition of alloantigen responses by transferrin and transferrin-derived glycans.

Previous studies have shown that critically timed administration of transferrin (Tf) facilitates induction of immunologic unresponsiveness. Here, we determined in mixed leukocyte culture (MLC) and in concanavalin A (ConA)-driven cultures the effect of exogenous Tf and Tf-derived glycans (Tf-Gly) on lymphocyte proliferation. In cultures of human blood lymphocytes, Tf inhibited selectively alloantigen-driven proliferation in MLC, but not ConA-stimulated lymphocyte proliferation. Deglycosylation of Tf abrogated the inhibitory effect of Tf on alloantigen-induced lymphocyte proliferation, and, consistent with a role for glycans, an effect qualitatively and quantitatively similar to Tf was exerted by purified Tf-Gly. Glycans isolated from other proteins, for example, immunoglobulin G (IgG) or fibrinogen, failed to inhibit alloantigen-induced proliferation selectively. Rather, they suppressed lymphocyte proliferation in a non-specific manner. Determination of cytokines in MLC supernatant showed a downregulation of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), IL-2, and IL-12 (p40), along with an upregulation of IL-10, a pattern entirely consistent with the observed effects of Tf and Tf-Gly on alloantigen-induced lymphocyte proliferation. The effect of Tf on MLC was directly IL-10-dependent. IL-10 levels were inversely correlated with lymphocyte proliferation and CD86 expression. Neutralization of IL-10 by anti-IL-10 monoclonal antibody (mAb) blocked the effect of Tf. The MLC-modulating effect of Tf (or Tf-Gly) was not dependent upon the Tf receptor CD71 but appeared to be mediated by a Gly-responsive receptor. These data suggest a role of Tf, and, in particular, Tf-Gly, in allo-interactions that is independent from the role of Tf in iron metabolism, and appears to involve co-stimulatory signals.

Antibodies, Monoclonal↗
PubMed1998

Neuroimmunomodulation of aging. A program in the pineal gland.

We have investigated for 35 years the relationship between the neuroendocrine and the thymo-lymphatic, immune system. In the last decade we have shown that the pineal gland is a main adapter and fine synchronizer of environmental variables and endogenous messages into physiological modifications of basic functions. In particular the pineal gland itself seems to regulate, via circadian, night secretion of melatonin, all basic hormonal functions and also immunity. We have shown with several in vivo models that this fundamental role of the pineal gland decays during aging. Aging itself seems to be a strictly pineal-programmed event similar to growth and puberty. The continuation of our interventions with melatonin against the typical degenerative diseases of aging must be based on an accurate evaluation of its mechanisms of action. Melatonin being a ubiquitous molecule in nature, we suggest that it has acquired during evolution of the species numerous levels of activities. In fact, melatonin can be found in a large variety of cells and tissues, and bindings sites and "receptors" have been identified in many tissues and cells of the neuroendocrine and immune system. Therefore, the progressive understanding of the aging-programming role of the pineal gland also depends on studies of melatonin and its basic regulatory function. Our present studies will be described.

Aging↗
PubMed1997

Theoretical considerations on the nature of the pineal 'ageing clock'.

The models developed in our laboratory demonstrate that ageing initiates and progresses in the pineal gland. However, the ageing postponing effects of pineal grafting into older recipients cannot be explained by a simple maintenance and/or normalization of the night melatonin synthesis and release. We propose here that the pineal gland monitors and regulates, via its control of neuroendocrine function, the maintenance of 'self-identity' and the capacity of the immune system to recognize and react against any noxious, endogenous or exogenous agent. Senescence is characterized by the extinction of this central pineal function. The progressive decline of the self-recognition capacity distinguishes the typical diseases of ageing expressed as emergence of peripheral desynchronization and autoimmune, anaplastic, neoplastic and degenerative processes. Our approaches aim at a prevention and/or restoration of central pineal functions.

Aging↗
PubMed1996

Facilitation of DLA-incompatible marrow grafts by donor-specific serum transferrin?

Studies in mice have shown that donor-specific plasma transferrin (TF) given to the recipient in the peritransplant period facilitates engraftment of marrow from histoincompatible donors. Dogs given 920 cGy of total body irradiation (TBI) and infused with marrow from an unrelated major histocompatibility complex (DLA) different donor generally fail to engraft; only approximately 20% of dogs achieve sustained engraftment. We have now investigated in this model whether the infusion of donor-specific plasma TF would facilitate engraftment. Ten dogs were given TBI, followed at 23 h by an intravenous dose of TF, at 24 h by marrow from the same donor, and another dose of TF at 48 h; six dogs also received postgrafting methotrexate (MTX). Seven dogs (three of four without MTX, four of six with MTX) had sustained engraftment, and three dogs failed to engraft. A single dog given third-party TF failed to engraft. Among five dogs not given TF two achieved sustained engraftment. This pilot study suggests that donor-specific TF facilitates engraftment of DLA-incompatible marrow. Further studies are warranted.

Animals↗
PubMed1996

Unresponsiveness to human leukocytes in immunosuppressed mice by combined donor-derived human transferrin and antigens.

Previous work on the facilitation of xenogeneic and allogeneic bone marrow engraftment in irradiated mice and dogs with transferrins allowed the development of a model for induction of an apparently durable state of immunological unresponsiveness or 'tolerance' in chemically immunosuppressed mice. The system is based on the simultaneous and combined administration of donor-derived cell antigens, namely human leukocytes, and specific donor-derived or plasma pool human transferrin into BALB/c or C57BL/6 mice previously treated with prednisolone and cyclophosphamide on day 0 and day 1 of the experiment. A properly timed presentation of both donor-specific or plasma pool transferrin and leukocyte antigens into the mice on day 3 and day 16 of the experiment, in the course of initial restoration of their lymphohaemopoietic tissues and cells after severe immunosuppression, results 1-3 months later, in their inability to 'recognize' human donor lymphocytes and to mount an immediate or a delayed-type immune response against human antigens. This durable state of unresponsiveness was evaluated by a complement-mediated cytotoxicity assay, with a mixed lymphocyte culture method and confirmed by the abrogation of the humoral (antibody response to human erythrocytes) and of the cell-mediated (popliteal lymph node test) immune responses in vivo. Our findings demonstrate the capacity of human plasma-derived transferrins to induce a state of durable unresponsiveness (xenogeneic tolerance?) in mice when administered with human antigens in the course of regeneration of stem cells in the bone marrow and lymphatic organs.

Animals↗
PubMed1996

The zinc pool is involved in the immune-reconstituting effect of melatonin in pinealectomized mice.

Melatonin (MEL) affects the immune system by direct or indirect mechanisms. An involvement of the zinc pool in the immune-reconstituting effect of MEL in old mice has recently been documented. An altered zinc turnover and impaired immune functions are also evident in pinealectomized (px) mice. The present work investigates further the effect of "physiological" doses of MEL on the zinc pool and on thymic and peripheral immune functions in px mice. Daily injections of MEL (100 micrograms/mouse) for 1 month in px mice restored the crude zinc balance from negative to positive values. Thymic and peripheral immune functions, including plasma levels of interleukin-2, also recovered. The nontoxic effect of MEL on immune functions was observed in sham-operated mice. Because the half-life of MEL is very short (12 min), interruption of MEL treatment in px mice resulted, after 1 month, in a renewed negative crude zinc balance and a regression of immune functions. Both the zinc pool and immunological parameters were restored by 30 further days of MEL treatment. The existence of a significant correlation between zinc and thymic hormone after both cycles of MEL treatment clearly shows an involvement of the zinc pool in the immunoenhancing effects of MEL and thus suggests an inter-relationship between zinc and MEL in px mice. Moreover, the existence of significant positive correlations between zinc or thymulin and interleukin-2 suggests that interleukin-2 may participate in the action of MEL, via zinc, on thymic functions in px MEL-treated mice.

Analysis of Variance↗
PubMed1996

Donor-derived plasma transferrin facilitates the engraftment of xenogeneic (rat) bone marrow in irradiated mice.

Endogenous factors originally found in the bone marrow (BM) and facilitating the engraftment of xenogeneic (rat) BM in lethally irradiated mice have been recently identified as transferrins (Tf). Tf have been separated and purified from plasma pools of inbred Rii/2 rats and injected in lethally irradiated BALB/c and C57BL/6 mice 1 h before the infusion of BM and for several days after BM transplantation. Other groups of irradiated mice have been similarly treated with human Tf, Tf from other strains of rats different from the BM donors and with human or rat serum albumin. A remarkable facilitation of BM engraftment and a durable graft-versus-host disease (GVHD)-free hemopoietic chimerism have been achieved in the irradiated mice when a combination of BM and Tf from the same donor rat (Rii/2) strain was used for transplantation. Durable survival and persistent chimerism were not observed in the control groups. It seems that donor Tf profoundly affects the outcome of BM transplantation when combined with donor BM. These results indicate that the mechanism by which Tf promotes engraftment of xenogeneic BM deserves investigation in order to improve this novel procedure and to extend it to other species and possibly to man.

Animals↗
PubMed1994

Pineal cross-transplantation (old-to-young and vice versa) as evidence for an endogenous "aging clock".

Circadian (night), chronic administration of melatonin and young-to-old pineal grafting into the thymus have provided evidence for the existence of an endogenous, primary and central "aging clock" in the pineal gland. The new model described here serves to definitely demonstrate that the replacement of the pineal gland of an old mouse with the pineal from a young, syngeneic donor mouse remarkably prolongs its life and, conversely, the "old" pineal transplanted into a younger mouse will considerably shorten its life span. Pineal cross-transplantation thus provides clear-cut evidence for the central role of the pineal gland in the initiation and progression of senescence. It offers a novel basis for interventions in the aging process.

Aging↗
PubMed1994

Pineal control of aging: effect of melatonin and pineal grafting on aging mice.

Dark-cycle, night administration of the pineal hormone melatonin in drinking water to aging mice (15 months of age) prolongs survival of BALB/c females from 23.8 to 28.1 months and preserves aspects of their youthful state. Similar results were seen in New Zealand Black females beginning at 5 months and C57BL/6 males beginning at 19 months. As melatonin is produced in circadian fashion from the pineal, we grafted pineals from young 3- to 4-month-old donors into the thymus of 20-month-old syngeneic C57BL/6 male recipients, and a 12% increase in survival was induced. Prolongation of survival was also seen on pineal transplant to the thymus in C57BL/6, BALB/cJ, and hybrid female mice at 16, 19, and 22 months. In all studies, the endogenous pineal of grafted mice was left in situ. Pineal grafted aged mice display a remarkable maintenance of thymic structure and cellularity. Preservation of T-cell-mediated function, despite age, as measured by response to oxazolone is seen. Other evidence suggests that melatonin and/or pineal-related factors could produce their effects through an influence on thyroid function. These data indicate that pineal influences have a place in the physiologic regulation of aging.

Aging↗