Biomedical subjects

D Monti

Publications and source records attributed to D Monti.

At least 37 records · Page 2Linked to original sources

PubMed2001

Polymorphisms of drug-metabolizing enzymes in healthy nonagenarians and centenarians: difference at GSTT1 locus.

Drug metabolizing enzymes are involved in the detoxification of several drugs, environmental substances, and carcinogenic compounds, and their polymorphisms have been associated with risk for a variety of cancer. In this paper, we compared the frequency of polymorphisms in cytochrome P450-1A1 gene (CYP1A1), a phase 1 gene (oxidation, activation), and of two polymorphisms of glutathione S-transferase enzymes (GSTM1, GSTT1), two phase 2 genes (conjugation, detoxification). Two groups were studied and compared, i.e., 94 nonagenarians and centenarians and 418 control subjects of younger age. A significant difference in the proportion of nonagenarians and centenarians homozygotes for a GSTT1 deletion (28%) was observed in comparison to control subjects (19%, P = 0.03). The distribution of the other gene polymorphisms did not differ in the two groups. These findings on phase 2 drug-metabolizing enzyme gene polymorphisms may help in disentangling gene-environmental interactions which can have a role in successful aging and longevity, as well as in cancer incidence in the oldest old.

Adolescent↗

PubMed2001

Regioselective enzymatic glycosylation of natural polyhydroxylated compounds: galactosylation and glucosylation of protopanaxatriol ginsenosides.

Ginsenoside Rg1 (1), the most representative Ginsenoside from Panax Ginseng C.A. Meyer belonging to the protopanaxatriol family, has been galactosylated by action of the beta-(1,4)-galactosyltransferase (GalT) from bovine colostrum, using UDP-galactose as an activated sugar donor. The enzyme showed the well-known specificity for the formation of a beta-linkage with the C-4 OH of the glucose acceptor, but it was not able to discriminate between the two glucose moieties of 1, giving a mixture of mono- and digalactosylated derivatives. Other natural Rg1-analogues such as F1, Rh1, Re, as well as the synthetic derivative 6'-O-acetyl-Rg1 have been also galactosylated, giving monolactosyl derivatives. GalT was also able to accept UDP-glucose as an activated sugar donor, giving rise to cellobiosyl derivatives of Rg1.

Carbohydrate Sequence↗

PubMed2001

A gender--dependent genetic predisposition to produce high levels of IL-6 is detrimental for longevity.

Current literature indicates that elevated IL-6 serum levels are associated with diseases, disability and mortality in the elderly. In this paper, we studied the IL-6 promoter genetic variability at -174 C/G locus and its effect on IL-6 serum levels in a total of 700 people from 60 to 110 years of age, including 323 centenarians. We found that the proportion of homozygotes for the G allele at -174 locus decreases in centenarian males, but not in centenarian females. Moreover, we found that, only among males, homozygotes for the G allele at -174 locus have higher IL-6 serum levels in comparison with carriers of the C allele. On the whole, our data suggest that those individuals who are genetically predisposed to produce high levels of IL-6 during aging, i.e. -174 locus GG homozygous men, are disadvantaged for longevity.

Aged↗

PubMed2001

Neuroinflammation and the genetics of Alzheimer's disease: the search for a pro-inflammatory phenotype.

The role of interleukin 1 (IL-1) and interleukin 6 (IL-6) in the pathogenesis of Alzheimer's disease (AD) is reviewed within the framework of "inflamm-aging", i.e., the characteristic chronic pro-inflammatory status which develops in old age, and neuroinflammation, i.e., the peculiar inflammatory process which is present in the brain of AD patients. In particular, the data suggesting that several IL-1 and IL-6 gene polymorphisms can contribute to the risk of developing AD are reviewed. The possibility as well as the difficulty in identifying a pro-inflammatory phenotype, and its importance for the prevention, diagnosis and therapy of AD and other age-related pathologies are discussed.

Aged↗

PubMed2001

Evidence of melatonin involvement in pindolol-induced suppression of REM sleep.

The effects of pindolol, melatonin, and the melatonin receptor agonist agomelatine were studied in rats implanted for chronic sleep procedures. Administration of pindolol (1.0-4.0 mg/kg) during the light phase induced a significant reduction of rapid-eye-movement sleep (REMS) and an increase of waking (W). In the rats recorded after receiving 1.0-6.0 mg/kg melatonin no significant differences were found in sleep or W compared with controls. Agomelatine (1.0-6.0 mg/kg) induced a significant increase of light sleep during the first 3 h of the recording period. Pretreatment with melatonin partly prevented the pindolol-induced suppression of REMS. However, agomelatine was ineffective in this respect. Overall, these data suggest that the decreased production of melatonin could play a role in REMS suppression related to pindolol administration.

Acetamides↗

PubMed2001

Ultrastructural characteristics, biological activity and pharmacological relevance of synthetic malaria pigment (beta-haematin).

Malaria pigment (haemozoin, HZ) is the detoxification product of haemoglobin-derived haem of intraerythrocytic malaria parasites. At schizont rupture, haemozoin accumulates inside host phagocytic cells. The chemical structure and the spectroscopic characteristics of haemozoin are identical to those of beta-haematin (BH), a synthetic pigment obtained from Ferriprotoporphyrin IX (Fe (III) PPIX) in acidic conditions. The process of BH formation is the target of quinoline antimalarials. Here, we summarise the results of our studies on the ultrastructural characteristics, biological and pharmacological relevance of synthetic vs. native haemozoin. 1) By electron microscopy, native HZ and synthetic BH appear as dark brown crystals, morphologically indistinguishable and are internalised by phagocytes at the same extent. 2) Both HZ and BH modulate the production of cytokines (TNF and NO) and increase the susceptibility to lipid peroxidation of mouse or human phagocytes. The antioxidant status of the phagocytes regulates the susceptibility to BH/HZ-mediated effects. 3) The process of BH formation from Fe(III)PPIX, hence haem detoxification, can be inhibited by electrochemically-reduced, Fe(II)PPIX molecules. Maintaining iron in the reduced state can thus be considered a new pharmacological target. This was confirmed by the observation that thiol-reducing agents (NAC, cystein) were able to inhibit BH formation and were toxic to parasites in vitro.

Animals↗

PubMed2000

Chemokines, sTNF-Rs and sCD30 serum levels in healthy aged people and centenarians.

Several lines of evidence point to a profound remodelling of the cytokine network in healthy elderly subjects, with decreased type-1 cytokine production (IL 2) and a shift to type 0 and 2. We have also observed an increase of proinflammatory cytokines (IL-1, IL-6, TNF-alpha) in vitro, and an increase of circulating stem cell factor in vivo. In this setting, we studied changes of chemokines (MCP-1 and RANTES) with aging, as well as other molecules, namely, sTNF-RI and sTNF-RII, and the soluble form of the CD30 molecule (sCD30), involved in the pro- and antiinflammatory cytokine balance. The subjects enrolled in the study belonged to three different selected healthy groups of young, aged and centenarians. The presence of rheumatoid factor (RF) and antinuclear antibodies (ANA) was simultaneously assessed. The results show that MCP-1 serum levels were higher in the healthy aged and lowest in the young, while RANTES increased exclusively in centenarians. Only centenarians had autoantibodies (ANA and RF). sTNF-RI and sTNF-RII were significantly elevated in healthy old subjects compared to the young, and even higher in selected centenarians compared to the other age groups. sCD30 serum levels were significantly raised in centenarians compared to the young, despite absence of circulating CD30+ cells in the peripheral blood of the whole study population. No relationship among serum values of these different members of the TNF-R family was found, despite a strong correlation for sTNF-RI and sTNF-RII in all groups. We hypothesize that the increased chemokine levels in aged people, and raised sCD30 levels in centenarians, may reflect a general shift towards type 0/2 cytokines in normal aging, which may be responsible, at least in part, for the appearance of circulating autoantibodies without definite clinical consequences at advanced age.

Adult↗

PubMed2000

Decreased susceptibility to oxidative stress-induced apoptosis of peripheral blood mononuclear cells from healthy elderly and centenarians.

The susceptibility to undergo apoptosis of fresh human peripheral blood mononuclear cells (PBMCs) from three groups of healthy donors of different ages: young people (19-40 years), old people (65-85 years) and centenarians was assessed. Apoptosis was induced by 2-deoxy-D-ribose (dRib), an agent which induces apoptosis in quiescent PBMCs by interfering with cell redox status and mitochondrial membrane potential (MMP). Our major finding is that an inverse correlation emerged between the age of the donors and the propensity of their PBMCs to undergo dRib-induced apoptosis. PBMCs from old people and centenarians also showed an increased resistance to dRib-induced glutathione depletion and a decreased tendency to lose MMP. The anti-apoptotic molecule Bcl-2 was similarly expressed in PBMCs from the three age groups. Moreover, the plasma level of the stable product of transglutaminase, epsilon(gamma-glutamyl)lysine isodipeptide, a marker of total body apoptotic rate, was decreased in centenarians compared to young and elderly people. On the whole, these findings suggest that physiological aging is characterised by a decreased tendency to undergo apoptosis, a phenomenon likely resulting from adaptation to lifelong exposure to damaging agents, such as reactive oxygen species, and may contribute to one of the major phenomena of immunosenescence, i.e. the progressive accumulation of memory/effector T cells.

Acetylcysteine↗

PubMed2000

Conventional and power spectrum analysis of the effects of zolpidem on sleep EEG in patients with chronic primary insomnia.

STUDY OBJECTIVE: The purpose of this study was 1) to assess the effect of zolpidem or a placebo on sleep in two groups of insomniac patients with a diagnosis of moderate-to-severe chronic primary insomnia and 2) to determine the effect of zolpidem on sleep structure using spectral analysis. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Sleep laboratory of the Department of Pharmacology and Therapeutics at the Clinics Hospital. PARTICIPANTS: 12 female outpatients with chronic primary insomnia. INTERVENTIONS: Zolpidem was given at a daily dose of 10 mg for 15 nights. RESULTS: The hypnotic drug reduced sleep latency and waking time after sleep onset, and increased total sleep time and sleep efficiency. Values corresponding to visually scored slow wave sleep (stage 3 and 4) showed no significant changes. All-night spectral analysis of the EEG revealed that power density in NREM sleep was significantly increased in the low frequency band (0.25-1.0 Hz) in the zolpidem group during the first 2-h interval. CONCLUSIONS: In agreement with previous findings obtained in patients with chronic primary insomnia, zolpidem significantly improved sleep induction and maintenance. Moreover, zolpidem increased power density in the 0.25-1.0 Hz band during short-term and intermediate-term treatment. Nevertheless, other frequency bands in the delta range showed a relative decrease which was not statistically significant.

Adult↗

PubMed2000

C60 carboxyfullerene exerts a protective activity against oxidative stress-induced apoptosis in human peripheral blood mononuclear cells.

C60 carboxyfullerene is a novel buckminsterfullerene-derived compound that behaves as a free-radical scavenger. In the present report, we investigated whether this drug exerts a protective activity against oxidative stress-induced apoptosis. Human peripheral blood mononuclear cells (PBMCs) were challenged by 2-deoxy-d-ribose (dRib) or TNF-alpha plus cycloheximide as agents that trigger apoptosis by interfering with the redox status of cell and mitochondrial membrane potential. We found that carboxyfullerene was able to protect quiescent PBMCs from apoptosis caused either by 2-deoxy-d-ribose or TNF-alpha plus cycloheximide by a mechanism partially involving the mitochondrial membrane potential integrity, known to be associated with early stages of apoptosis. These results represent the first indication for a target activity of buckminsterfullerenes on cells of the immune system and their mitochondria.

Adult↗

PubMed2000

Characterization of an industrial biocatalyst: immobilized glutaryl-7-ACA acylase.

A batch of the immobilized industrial biocatalyst glutaryl-7-ACA acylase (GA), one of the two enzymes involved in the biotransformation of cephalosporin C (CefC) into 7-aminocephalosporanic acid (7-ACA), was characterized. K(m) value for glutaryl-7-ACA was 5 mM. Enzyme activity was found to be optimal at pH between 7 and 9.5 and to increase with temperature and in buffered solutions. To avoid product degradation, optimal reaction conditions were obtained working at 25 degrees C using a 50-mM phosphate buffer, pH 8.0. Immobilized GA showed good stability at pH value below 9 and at temperature up to 30 degrees C. The inactivation of immobilized GA in the presence of different amounts of H(2)O(2), a side product that might be present in the plant-scale industrial solutions of glutaryl-7-ACA, was also investigated, but the deactivation rates were negligible at H(2)O(2) concentration that might be reached under operative conditions. Finally, biocatalyst performance in the complete two-step enzymatic conversion process from CefC to 7-ACA was determined on a laboratory scale. Following the complete conversion of a 75 mM solution of CefC into glutaryl-7-ACA catalyzed by an immobilized D-amino acid oxidase (DAAO), immobilized GA was used for the transformation of this intermediate into the final product 7-ACA. This reaction was repeated for 42 cycles. An estimation of the residual activity of the biocatalyst showed that 50% inactivation of immobilized GA was reached after approximately 300 cycles, corresponding to an enzyme consumption of 0.4 kU per kg of isolated 7-ACA.

Amidohydrolases↗

PubMed2000

Second generation mimics of ganglioside GM1 as artificial receptors for cholera toxin: replacement of the sialic acid moiety.

In a program directed towards the design and synthesis of mimics of ganglioside GM1, the NeuAc recognition domain was replaced by simple hydroxy acids, and the affinity of the new ligands to the cholera toxin was determined by fluorescence spectroscopy. The (R)-lactic acid derivative 4 was found to display the highest affinity of the series (KD = 190 microM).

Cholera Toxin↗

PubMed2000

Plasma antioxidants and longevity: a study on healthy centenarians.

A large body of experimental research indicates that oxidative stress contributes to the processes related to aging and to the pathogenesis of several age-related diseases. Vitamins and antioxidant enzymes have a fundamental role in defending the organism from oxidative stress. To better understand the role of antioxidants in human aging, we measured plasma levels of vitamin C (ascorbic acid), uric acid, vitamin E (alpha-tocopherol), vitamin A (retinol), carotenoids, total thiol groups, and the activity of plasma superoxide dismutase (SOD) and glutathione peroxidase (GPX) as well as the activity of red blood cell (RBC) SOD in 32 healthy centenarians-17 elderly subjects aged 80-99 years, 34 elderly subjects aged 60-79 years, and 24 adults aged less than 60 years. Considering the "noncentenarians" only, we observed a consistent behavior in the antioxidant pattern, with a decrease of the nonenzymatic antioxidants and an increase of the enzymatic antioxidant activities relative to age. Remarkably, centenarians were characterized as having the highest levels of vitamins A and E, whereas the activities of both plasma and RBC SOD, which increase with age, decreased in centenarians. From these results, it is evident that healthy centenarians show a particular profile in which high levels of vitamin A and vitamin E seem to be important in guaranteeing their extreme longevity.

Aged↗

PubMed2000

Role of dorsal raphe nucleus serotonin 5-HT1A receptor in the regulation of REM sleep.

Cholinergic neurons in the laterodorsal (LDT) and the pedunculopontine (PPT) tegmental nuclei act to promote REM sleep (REMS). The predominantly glutamatergic neurons of the REMS-induction region of the medial pontine reticular formation are in turn activated by cholinergic cells, which results in the occurrence of tonic and phasic components of REMS. All these neurons are inhibited by serotonergic (5-HT), noradrenergic, and presumably histaminergic (H2 receptor) and dopaminergic (D2 and D3 receptor) cells. 5-Hydroxytryptamine-containing neurons in the dorsal raphe nucleus (DRN) virtually cease firing when an animal starts REMS, consequently decreasing the release of 5-HT during this state. The activation of GABA(A) receptors is apparently responsible for this phenomenon. Systemic administration of the selective 5-HT1A receptor agonist 8-OHDPAT induces dose-dependent effects; i.e. low doses increase slow wave sleep and reduce waking, whereas large doses increase waking and reduce slow wave sleep and REM sleep. Direct injection of 8-OHDPAT or flesinoxan, another 5-HT1A agonist into the DRN, or microdialysis perfusion of 8-OHDPAT into the DRN significantly increases REMS. On the other hand, infusion of 8-OHDPAT into the LDT selectively inhibits REMS, as does direct administration into the DRN of the 5-HT1A receptor antagonists pindolol or WAY 100635. Thus, presently available evidence indicates that selective activation of the somatodendritic 5-HT1A receptor in the DRN induces an increase of REMS. On the other hand, activation of the postsynaptic 5-HT1A receptor at the level of the PPT/LDT nuclei decreases REMS occurrence.

Electrophysiology↗

PubMed2000

Cytoskeleton alterations of erythrocytes from patients with Fanconi's anemia.

Fanconi's anemia (FA) is a very rare genetically heterogeneous disease which has been hypothesized to be defective in the detoxification of reactive oxygen species. In this work we report the results obtained by morphometric and biochemical analyses on the red blood cells (RBCs) from FA patients. With respect to RBCs from healthy donors the following changes have been detected: (i) a variety of ultrastructural alterations, mainly surface blebbing typical of acanthocytes and stomatocytes; (ii) a significant quantitative increase of these altered forms; (iii) modifications of spectrin cytoskeleton network; (iv) an altered redox balance, e.g. a decreased catalase activity and significant variations in the GSSG/GSH ratio. We hypothesize that remodeling of the redox state occurring in FA patients results in cytoskeleton-associated alterations of red blood cell integrity and function.

Adolescent↗

PubMed2000

Standardization of the physicochemical parameters to assess in vitro the beta-hematin inhibitory activity of antimalarial drugs.

Intraerythrocytic plasmodia form hemozoin as a detoxification product of hemoglobin-derived heme. An identical substance, beta-hematin (BH), can be obtained in vitro from hematin at acidic pH. Quinoline-antimalarials inhibit BH formation. Standardization of test conditions is essential for studying the interaction of compounds with this process and screening potential inhibitors. A spectrophotometric microassay of heme polymerization inhibitory activity (HPIA) (Basilico et al., Journal of Antimicrobial Chemotherapy 42, 55-60, 1998) previously reported was used to investigate the effect of pH and salt concentration on BH formation. The yield of BH formation decreased with pH. Moreover, under conditions used in the above HPIA assay (18 h, 37 degrees C, pH = 2.7), several salts including chloride and phosphate inhibited the process. Aminoquinoline drugs formulated as salts (chloroquine-phosphate, primaquine-diphosphate), but not chloroquine-base, also inhibited the reaction. Interference by salts was highest at low pH and decreased at higher pH (pH 4). Here, we describe different assay conditions that eliminate these problems (BHIA, beta-hematin inhibitory activity). By replacing hematin with hemin as the porphyrin and NaOH solution with DMSO as solvent, the formation of BH was independent of pH up to pH 5.1. No interference by salts was observed over the pH range 2.7-5.1. Dose-dependent inhibition of BH formation was obtained with chloroquine-base, chloroquine-phosphate, and chloroquine-sulfate at pH 5.1. Primaquine was not inhibitory. The final product, characterized by solubility in DMSO, consists of pure BH by FT-IR spectroscopy. The BHIA assay (hemin in DMSO, acetate buffer pH 5 +/- 0.1, 18 h at 37 degrees C) is designed to screen for those molecules forming pi-pi interactions with hematin and thus inhibiting beta-hematin formation.

Antimalarials↗

PubMed2000

Do men and women follow different trajectories to reach extreme longevity? Italian Multicenter Study on Centenarians (IMUSCE).

Gender accounts for important differences in the incidence and prevalence of a variety of age-related diseases. Considering people of far advanced age, demographic data document a clear-cut prevalence of females compared to males, suggesting that sex-specific mortality rates follow different trajectories during aging. In the present investigation, we report data from a nationwide study on Italian centenarians (a total of 1162 subjects), and from two studies on centenarians living in two distinct zones of Italy, i.e., the island of Sardinia (a total of 222 subjects) and the Mantova province (Northern Italy) (a total of 43 subjects). The female/male ratio was about 2:1 in Sardinia, 4:1 in the whole of Italy, and about 7:1 in the Mantova province. Thus, a complex interaction of environmental, historical and genetic factors, differently characterizing the various parts of Italy, likely plays an important role in determining the gender-specific probability of achieving longevity. Gender differences in the health status of centenarians are also reported, and an innovative score method to classify long-lived people in different health categories, according to clinical and functional parameters, is proposed. Our data indicate that not only is this selected group of people, as a whole, highly heterogeneous, but also that a marked gender difference exists, since male centenarians are less heterogeneous and more healthy than female centenarians. Immunological factors regarding the age-related increase in pro-inflammatory status, and the frequency of HLA ancestral haplotypes also show gender differences that likely contribute to the different strategies that men and women seem to follow to achieve longevity. Concerning the different impact of genetic factors on the probability of reaching the extreme limits of the human life-span, emerging evidence (regarding mtDNA haplogroups, Thyrosine Hydroxilase, and IL-6 genes) suggests that female longevity is less dependent on genetics than male longevity, and that female centenarians likely exploited a healthier life-style and more favorable environmental conditions, owing to gender-specific cultural and anthropological characteristics of the Italian society in the last 100 years.

Aged↗

PubMed2000

A cytofluorimetric study of T lymphocyte subsets in rat lymphoid tissues (thymus, lymph nodes) and peripheral blood: a continuous remodelling during the first year of life.

We previously demonstrated that the rat thymus undergoes a progressive remodelling long before the appearance of typical signs of involution [Quaglino, D., Capri, M., Bergamini, G., Euclidi, E., Zecca, L., Franceschi, C., Pasquali Ronchetti, I., 1998. Age-dependent remodelling of rat thymus. Morphological and cytofluorimetric analysis from birth up to one year of age. Eur. J. Cell. Biol. 76, 156-166]. To focus better on the complex remodelling that occurs in the rat immune system during the first year of life, we analysed the phenotype profile of thymocytes, and T lymphocytes from mesenteric lymph nodes and peripheral blood of the same animals by flow cytometry. Two experimental sets were performed simultaneously using the same animal strain, but starting and ending the study at different ages (15 days up to 300 days in the first experimental set, and 90 days up to 360 days of life in the second). In the rat these ages appear to be crucial not only for developmental, maturative and early involutional processes of the thymus, but also of the entire immune system. The main findings were the following: (1) in the thymus, CD8(-)CD4(-) cells increased, CD5(+)alphabeta TCR(-) and CD8(+)CD4(+) thymocytes decreased, while the most mature cell subset appeared well preserved with ageing; (2) in the lymph nodes, T helper and T cytotoxic lymphocytes decreased in the most aged animals. Memory/activated CD4(+)CD45RC(-) T cells decreased, while naive/resting CD4(+)CD45RC(+) cells increased in the youngest animals and decreased in the oldest. CD8(+)CD45RC(-) and CD8(+)CD45RC(+) lymphocytes showed a complex age-dependent trend, and (3) in peripheral blood, minor modifications were evident, such as an age-dependent increase in the alphabeta TCR(+)CD25(+) cell subset. Some of these changes were related to the developmental process, while others could likely be interpreted as early signs of immunosenescence. The role of these modifications in immune system is discussed within the framework of the remodelling hypothesis of immunosenescence. The age-dependent changes in these three lymphoid compartments, however, appear to be different and only partially overlapping, thus suggesting that the maturational, developmental and ageing processes have distinct characteristics in the central and peripheral lymphoid organs.

Age Factors↗