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Biomedical subjects

C Franceschi

Publications and source records attributed to C Franceschi.

At least 145 records · Page 8Linked to original sources
PubMed1998

Thyroid autoimmunity and aging.

Aging is associated with the appearance of several serum autoantibodies, including thyroid autoantibodies. The biological and clinical significance of this phenomenon is still unknown, because, with the exception of primary myxedema, the prevalence of clinically overt thyroid autoimmune diseases is not increased in the elderly. The peculiar link between autoimmune thyroid failure and aging is also underscored by the high prevalence of subclinical hypothyroidism in elderly subjects with positive serum thyroid autoantibodies, and could be the consequence of preferential age-dependent expression of destructive effector mechanisms and/or increased target gland susceptibility. Thyroid autoimmunity and subclinical hypothyroidism have been also implicated in the pathogenesis of other age-associated disorders, in particular coronary heart disease. Interestingly, recent data from our laboratories showed that thyroid autoantibodies are rare in healthy centenarians and in other highly selected aged populations, while they are frequently observed in unselected or hospitalized elderly. Taken together, these data suggest that thyroid autoimmune phenomena are not the consequence of the aging process itself, but rather might be related to age-associated disease.

Aging↗
PubMed1998

A new theory on the common evolutionary origin of natural immunity, inflammation and stress response: the invertebrate phagocytic immunocyte as an eye-witness.

Data in favor of the hypothesis of the common evolutionary origin of natural immunity inflammation and stress response are presented. These phenomena seem to be mediated by a common pool of molecules (POMC-derived peptides, cytokines, biogenic amines, glucocorticoids, and nitric oxide). Macrophages are able to release all the above mentioned molecules. They play a primary role in defence mechanisms. Thus, we argue that this cell can be considered the eye-witness of the common evolutionary origin of the immune and neuroendocrine systems.

Animals↗
PubMed1998

Presence of immunoreactive corticotropin-releasing hormone and cortisol molecules in invertebrate haemocytes and lower and higher vertebrate thymus.

Corticotropin-releasing hormone- and cortisol-like molecules are present in the haemocytes of different molluscan species and in the epithelial cells, interdigitating cells and macrophages - but not in the lymphocytes - of fish, frog, chicken and rat thymus. Taking into account the fact that other pro-opiomelanocortin-derived peptides, such as adrenocorticotropin hormone, are present in the haemocytes and thymus of the same species, these results complete the list of stress mediators present in molluscan haemocytes and further support the hypothesis that, although the prototype stress response we have demonstrated in invertebrates is concentrated in a single cell, i.e. the haemocyte, it is similar to the response seen in vertebrates. Moreover, the data presented here are compatible with the hypothesis that an evolutionary, conserved stress response can occur locally with a single organ, e.g. the thymus, in which all the main mediators of this biological response, such as corticotropin-releasing hormone, adrenocorticotropin hormone and glucocorticoids, are present. The implications of these findings for the physiology of thymus and stress response may be far reaching.

Animals↗
PubMed1998

Age-related changes of the 3'APOB-VNTR genotype pool in ageing cohorts.

The analysis of seven different age cohorts (697 individuals from 10 to 109 years old) revealed age-related changes in the 3'APOB-VNTR genotype pool. By recoding the 3'APOB-VNTR alleles into three size-classes (small, S, 26-34 repeats; medium, M, 35-39 repeats; large, L, 41-55 repeats), an age-related convex trajectory of the frequency of SS homozygotes was found. The frequency of SS in the genotype pool increased from the group aged 10-19 years (3.06 +/- 1.74%) to that aged 40-49 years (8.51 +/- 4.07%). Then it declined reaching the minimum value in centenarians (1.58 +/- 0.90%). The observed trajectory is in agreement with that expected by assuming crossing of mortality curves relevant to subgroups of individuals having different genotypes.

Adolescent↗
PubMed1998

Lipoprotein(a) and lipoprotein profile in healthy centenarians: a reappraisal of vascular risk factors.

In this study we assessed whether widely accepted risk factors for atherosclerotic vascular diseases such as lipoprotein(a) [Lp(a)], a cholesterol-rich lipoprotein under strict genetical control, and other lipid parameters change with age. The variations of blood levels and the pathophysiological role of Lp(a) in old people, and particularly in the oldest old, are unknown. Accordingly, we measured Lp(a) levels as well as total, LDL, and HDL cholesterol (CT), and triglycerides (TG) in sera from 75 healthy centenarians, 114 randomly selected subjects under 65 years, 73 randomly selected elderly people, and 30 healthy selected elderly people. The results showed that Lp(a) serum levels did not vary by age group, including centenarians. Remarkably, one-quarter of the centenarians had high Lp(a) serum levels even though they never suffered from atherosclerosis-related diseases. At variance with young and aged people, centenarians with high Lp(a) serum levels also had high plasma concentrations of the proinflammatory cytokine IL-6, suggesting that genetic control of the Lp(a) serum level may attenuate with age and that environmental factors such as chronic subclinical inflammatory processes may play a role. We also showed that most centenarians are paradoxically characterized by low HDL-CT and relatively high TG levels, which together are considered to be strong risk factors for coronary heart disease. On the whole, these data support the hypothesis that a continuous and complex reshaping of lipid metabolism occurs in physiological aging, likely contributing to successful aging.

Aged↗
PubMed1997

The A3 adenosine receptor mediates cell spreading, reorganization of actin cytoskeleton, and distribution of Bcl-XL: studies in human astroglioma cells.

The pathophysiological role of the adenosine A3 receptor in the central nervous system is largely unknown. We have investigated the effects of the selective A3 receptor agonist 2-chloro-N6-(3-iodobenzyl)-adenosine, Cl-IB-MECA, in cells of the astroglial lineage (human astrocytoma ADF cells). A marked reorganization of the cytoskeleton, with appearance of stress fibers and numerous cell protrusions, was found following exposure of cells to low (nM) concentrations of Cl-IB-MECA. These "trophic" effects were accompanied by induction of the expression of Rho, a small GTP-binding protein, which was virtually absent in control cells, and by changes of the intracellular distribution of the antiapoptotic protein Bcl-XL, that, in agonist-exposed cells, became specifically associated to cell protrusions. This is the first demonstration that the intracellular organization of Bcl-XL can be modulated by the activation of a G-protein-coupled membrane receptor, such as the A3 adenosine receptor. Moreover, modulation of the astrocytic cytoskeleton by adenosine may have intriguing implications in both nervous system development and in the response of the brain to trauma and ischemia.

Actins↗
PubMed1997

Actin cytoskeleton as a target for 2-chloro adenosine: evidence for induction of apoptosis in C2C12 myoblastic cells.

Recent results for various cell types have shown that adenosine is capable of inducing relevant cytophatological alterations which can eventually lead to apoptosis. No data are available regarding the involvement of adenosine in apoptosis of muscle cells. In this work, we studied the effect of the relatively hydrolysis-resistant adenosine analog 2-chloro adenosine on a cultured myogenic cell line, C2C12, which is able to differentiate in vitro, leading to the formation of syncythia, giant multinucleated cells called myotubes. Results indicated that 2-chloro adenosine induces apoptotic cell death in both myoblasts and myotubes; this was preceded by a derangement of actin microfilaments, which represent the main cytoskeletal component and play a pivotal role in the physiology of such cell line. The time-dependency of cytoskeletal alterations suggested a causal relationship between these changes and the induction of apoptosis. These results implicate adenosine as an endogenous regulator of apoptosis in muscle cells and validate this cell model system as a useful tool for studying human muscle cell pathologies.

2-Chloroadenosine↗
PubMed1997

JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess delta psi changes in intact cells: implications for studies on mitochondrial functionality during apoptosis.

The sensitivity and specificity of three fluorescent probes used for cytofluorimetric analysis of mitochondrial membrane potential (delta psi) were studied in the U937 human cell line. First, the role of plasmamembrane in influencing the binding of the probes to mitochondria has been investigated. The depolarization of plasmamembrane with high doses of extracellular KCl had no immediate effects on the loading of JC-1, DiOC6(3) and rhodamine 123 (R123). However, after a few hours of culture in the presence of KCl, significant changes were observed only in cells stained with DiOC6(3). Second, a comparative study was performed concerning the effects of agents capable of collapsing deltapsi. While adding FCCP to cell cultures resulted in consistent changes in the fluorescence emission of both JC-1 and DiOC6(3) - but not of R123 - only cells stained with JC-1 responded to valinomycin. On the whole, our data indicate that JC-1 is a reliable probe for analyzing delta psi changes with flow cytometry, while the others show a lower sensitivity (R123), or a non-coherent behaviour, due to a high sensitivity to changes in plasmamembrane potential [DiOC6(3)]. These data cast some doubts on those studies that, using fluorescent probes that have a low sensitivity to delta psi, hypothesized that the fall in delta psi is one of the early events, if not one of the main causes, of apoptosis.

Apoptosis↗
PubMed1997

Resistance to apoptosis in Fanconi's anaemia. An ex vivo study in peripheral blood mononuclear cells.

Fanconi's anaemia (FA) is a rare autosomal recessive disease characterised by progressive pancytopoenia, a diverse assortment of congenital malformations, an increased sensitivity to reactive oxygen species and a predisposition to the development of malignancies. In the present study, we assessed the propensity to undergo apoptosis of peripheral blood mononuclear cells (PBMC) from Italian FA patients. Cells were challenged by 2-deoxy-D-ribose (dRib) or TNF-alpha plus cycloheximide as agents that induce apoptosis by interfering with cell redox status and mitochondrial membrane potential (MMP), and PBMC from FA patients resulted to be less prone to die than those from healthy subjects. The decreased susceptibility of FA cells to undergo apoptosis was also evident when another parameter highly correlated with the apoptotic process, i.e. MMP, was measured. Moreover, when N-acetylcysteine was added to dRib-treated PBMC, a strong protection was evident either in PBMC from control subjects or from FA patients. These data indicate that an alteration of unknown nature of the mechanisms favouring apoptosis is present in freshly collected cells from FA patients, and that such alteration could contribute to the pathogenesis of the disease, and particularly to the increased susceptibility to cancer.

Adolescent↗
PubMed1997

Cytometric analysis of immunosenescence.

We have been studying the immune system of healthy centenarians for many years, and they provide the best example of successful aging. They are people who have escaped major age-related diseases and reached the extreme limit of human life in good clinical condition. In most cases, histories of centenarians reveal them to be free of cancer, dementia, diabetes, cardiovascular diseases, and cataracts. Moreover, in order to reach such an advanced age, they should be equipped with well preserved and efficient immuno- and defense mechanisms, and optimal combinations of an appropriate lifestyle and genetic background. Using this approach, several paradoxes emerged as far as the immune system of centenarians is concerned, regarding: i) humoral immunity (increase in plasma immunoglobulins and nonorgan-specific autoantibodies, decrease in B cell number and lack of organ-specific autoantibodies); ii) cellular immunity (well preserved number of "virgin" T cells, a relatively intact T cell repertoire despite a thymus involuting since puberty, increased number of cells with markers of NK activity); iii) decreased peripheral blood lymphocyte tendency to programmed cell death, associated with a well preserved mitochondria functionality and intracellular bcl-2 levels. An age-related increase in the levels of adhesion molecule present on lymphocyte plasma-membrane, accompanied by a complex reshaping of the cytokine network, must be added to this scenario. All our data fit the hypothesis that a complex, unpredicted remodeling of the immune system occurs with age. In the present review it is underlined how flow cytometry has been used to study most of the above mentioned aspects of immunosenescence, and to establish new age-related reference values.

Adult↗
PubMed1997

Resistance to apoptosis in CTLL-2 cells constitutively expressing c-Myb is associated with induction of BCL-2 expression and Myb-dependent regulation of bcl-2 promoter activity.

c-Myb, the cellular homologue of the transforming gene of the avian myeloblastosis virus, is preferentially expressed in all hematopoietic lineages, including T and B lymphocyte lineages. In T lymphocytes, c-Myb expression appears to be required for cell cycle progression and proliferation. To further investigate the role of c-Myb in T cell proliferation and survival, interleukin (IL) 2-dependent CTLL-2 cells were transfected with a constitutively active c-myb or with a c-myb antisense construct able to down-regulate endogenous Myb levels, and the transfectants were assessed for proliferation and survival in low concentrations of IL-2 and for susceptibility to dexamethasone-induced apoptosis. Compared with control cells, CTLL-2 cells constitutively expressing c-Myb proliferate in low concentrations of IL-2 and are less susceptible to apoptosis induced by IL-2 deprivation or treatment with dexamethasone. In contrast, cells transfected with an antisense c-myb construct do not proliferate in low concentrations of IL-2 and undergo apoptosis upon IL-2 deprivation or dexamethasone treatment more rapidly than parental cells. Overexpression of c-Myb was accompanied by up-regulation of BCL-2 expression. In transient transfection assays, the murine bcl-2 promoter was efficiently transactivated by c-Myb, but such effect was observed also in cells transfected with a DNA binding-deficient c-myb construct. Moreover, in gel retardation assays, a 38-bp oligomer in the shortest bcl-2 promoter segment regulated by c-Myb formed a specific complex with nuclear extracts from c-Myb-transfected CTLL-2 cells. Thus, these results strongly suggest that c-Myb, in addition to regulating T cell proliferation, protects T lymphocytes from apoptosis by induction of BCL-2 expression, which involves a c-Myb-dependent mechanism of promoter regulation.

Animals↗
PubMed1997

Different pathways of apoptosis revealed by 2-chloro-adenosine and deoxy-D-ribose in mammalian astroglial cells.

Both the adenosine analogue 2-chloro-adenosine (2-CA) and the reducing sugar deoxy-D-ribose (dRib) induce apoptosis of astroglial cells in rat brain primary cultures (Abbracchio et al.: Biochem Biophys Res Commun 213:908-915, 1995). The present study was undertaken to elucidate by both morphological and cytofluorimetric analyses the intracellular mechanism(s) involved in induction of apoptosis by these two agents. The poly(ADP-ribose)polymerase (PARP) inhibitor 3-aminobenzamide did not prevent either 2-CA- or dRib-induced cell death, suggesting that activation of PARP is not critically important for induction of apoptosis in astrocytes. The radical scavenger N-acetyl-cysteine (NAC) strongly inhibited dRib- but not 2-CA-induced cell death, suggesting a differential role for radical formation in apoptosis by these two agents. A time-dependent increase of cells with depolarized mitochondria was observed in dRib-, and to a lesser extent, in 2-CA-treated cultures. NAC also prevented dRib- but not 2-CA-induced mitochondrial changes. We conclude that, in mammalian astrocytes, apoptosis can proceed through diverse and multiple pathways, depending upon the apoptotic stimulus. For dRib, apoptosis likely proceeds through generation of radicals and mitochondrial involvement. An adenosine extracellular receptor linked to an as yet unidentified signaling pathway may instead mediate 2-CA-induced cell death, which may have intriguing implications for both nervous system development and brain response to trauma and ischemia.

2-Chloroadenosine↗
PubMed1997

Antisense inhibition of c-fes proto-oncogene blocks PMA-induced macrophage differentiation in HL60 and in FDC-P1/MAC-11 cells.

To gain some insight into the role of c-fes in macrophage differentiation, we have analyzed the ability of HL60 leukemic promyelocytic cells and FDC-P1/MAC-11 murine myeloid precursor cells to differentiate in response to phorbol esters after inhibition of c-fes function. Fes inactivation has been obtained by using oligodeoxynucleotides (ODN) complementary to the 5' region of c-fes mRNA and to 5' splice junctions of c-fes primary transcript. After 5 days (d) in culture, in several separate experiments performed with different ODN preparations, a complete inhibition of c-fes expression was observed in HL60 and in FDC-P1/MAC-11 cells. No perturbation of cell growth was evident in our experimental conditions in both cell lines after c-fes inhibition. Furthermore, in HL60 cells lacking c-fes product, an almost complete downregulation of the alpha 4 beta 1 fibronectin receptor occurred. However, in both cell lines, the induction of macrophage differentiation by phorbol esters resulted in an almost complete maturation arrest as evaluated by morphological, cytochemical, immunological criteria, and by the cytofluorimetric cell cycle analysis. A loss of the adhesion capacity of both myeloid cell lines, when compared to terminally differentiated macrophages, was also observed. These results suggest that HL60 and FDC-P1/MAC-11 cells, when treated with phorbol 12-myristate 13-acetate, require c-fes protein expression to activate the genetic program underlying macrophage differentiation.

Animals↗