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Biomedical subjects

C Di Giulio

Publications and source records attributed to C Di Giulio.

At least 19 recordsLinked to original sources
PubMed2006

High levels of antioxidant enzymatic defence assure good protection against hypoxic stress in spontaneously diabetic rats.

Recent data from literature report that reactive oxygen species (ROS) seem to play a crucial role in the etiology of both types I and II diabetes. This may render diabetic individuals more prone to oxidative injury when challenged with hypoxic stress. It is in fact well known that many diabetic complications cause ischaemic episodes, with a consequent reduction in oxygen supply to various tissues and organs. To check this hypothesis, in this work we tested type I diabetic individuals' antioxidant capability towards a hypoxic-mediated oxidative challenge. In particular, spontaneously diabetic and age-matched non-diabetic biobreeding (BB) Wistar rats were submitted to chronic normobaric hypoxia, and the response of antioxidant enzymes, as well as redox-sensitive transcription factor NF-kappaB and p53, were monitored. Results show that diabetic subjects present a dramatic enhancement in the major antioxidant enzymes activities, thus supporting the notion of diabetes-related changes in cellular redox status. This allows diabetic individuals to counteract hypoxia-mediated oxidative challenge better than the non-diabetic counterpart. Also the behaviour of both the redox-sensitive nuclear transcription factor NF-kappaB and p53 protein in response to hypoxic stimulation seems to support the hypothesis of a better ROS scavenging efficiency in diabetics under hypoxic conditions. In conclusion, high levels of antioxidant enzymatic defences in diabetic BB rats reflect a positive adaptive response able to assure an efficient protection not only against chronic, diabetes-mediated reactive oxygen species (ROS) overproduction, but also versus further oxidative damage.

Animals↗
PubMed2005

Regional changes in the metabolite profile after long-term hypoxia-ischemia in brains of young and aged rats: a quantitative proton MRS study.

Quantitative proton magnetic resonance spectroscopy (MRS) was used to determine region-specific metabolic changes in young and aged animals subjected to a long-term hypoxic-ischemic injury. Focal ischemia, which was studied as an experimental stroke model, was induced in 3- and 24-month-old rats by unilateral common carotid artery occlusion associated with 24 h of hypoxia. Eight metabolites were quantified from extracts in three different brain regions (hippocampus, frontoparietal and occipital cortices) from both the ipsilateral and contralateral sides. Our findings showed significant differences in lactate and myo-inositol concentration values in the hippocampus of the aged rats as compared to the same area of the young adult group under normoxic conditions. After hypoxia-ischemia (HI), the most relevant changes in metabolite concentrations were found in the hippocampal region of both young and aged groups as compared to their age-matched controls. Of the three brain areas under investigation, the hippocampus proved to be particularly susceptible to the prolonged hypoxia-ischemia perturbation. The effects were more evident in the aged animals.

Age Factors↗
PubMed2005

Balance between hypertrophic and hypoxic stimulus in caspase-3 activation during rat heart development.

During heart development, cell hyperplasia and hypertrophy are the main mechanisms by which cardiac mass grows. Both these processes along with programmed cell death lead to complete growth and function. In addition, since the establishment of cardiac function depends on the relationship between oxygen supply and demand, we investigated some of the molecular mechanisms at the basis of rat myocardial cell response to hypoxic stress at different times of neonatal life. In particular, the role played by hypertrophic and survival factors like NF-kB and IAP-1 (Inhibiting Apoptosis Protein) and by death factors ASK-1 (Apoptosis Signal Regulating Kinase), JNK/SAPK (Jun-N-Terminal-Kinase/Stress-Activated Protein Kinase) pathways in regulating caspase-3 expression and activity has been evaluated by immunohistochemical and Western blotting analyses, respectively. Level of phosphorylation of IkBalpha and IAP-1 expression were substantial in 8-day-old hypoxic hearts, suggesting the persistence of NF-kB driven hypertrophic signal along with a rescue attempt against hypoxic stress. In contrast, ASK-1 mediated JNK/SAPK activation, regulating Bcl(2) levels, allows Bax homodimerization and caspase-3 activation in the same experimental conditions. Thus, a regulation carried out by NF-kB and JNK/SAPK pathways on caspase-3 activation at day 8 of neonatal life can be suggested as the main factor for the heart 'adaptive' response to hypoxia.

Animals↗
PubMed2003

Selected contribution: Carotid body as a model for aging studies: is there a link between oxygen and aging?

The carotid body (CB) is the site in the body that triggers awareness of changes in blood oxygen pressure. Aging is characterized by a decrease in oxygen supply to tissues, in reduction of tissue Po2, and in the activity of several enzymes and metabolic factors. The ventilatory response to hypoxia is attenuated with aging related to the age-dependent structure modifications including the basal reduction of oxygen requirements. The aged CB shows an increase in extracellular matrix, a reduction in number and volume of type I cells, and a reduction in volume of mitochondria that was consistent with and similar to that during chronic hypoxia; this phenomenon seems to operate also during aging as shown by the reduced volume of mitochondria in the aged CB. During chronic hypoxia, CB hypertrophy is less evident in aged CB than in young CB. Therefore, hypoxia and aging seem to share some type of link at different cell sites. CB represents an experimental model adequate for studying aging processes because of its high blood flow and metabolism, and thus it serves as a means to understanding the oxygen modulation of the aging process.

Aging↗
PubMed2003

Sustained hypoxia promotes hyperactive response of carotid body in the cat.

Carotid body chemosensory activities were measured before and after 0.2, 5,6 and 7 h of sustained isocapnic (PaCO(2) approximately equal to 30 Torr) hypoxia (PaO(2) approximately equal to 43 Torr) in the cats (n=7). The activity increased from 5.4 impsec(-1) at 0.2 h to about 13 impsec(-1) at 7 h. This increase in chemosensory activities were due to both an augmented sensitivity and to a long-term facilitation and not due to arterial [H(+)] changes.

Animals↗
PubMed2003

Atrial natriuretic peptide stimulates cat carotid body chemoreceptors in vivo.

It is known that atrial natriuretic peptide (ANP) is released from cardiac myocyte and other stores during hypoxia and is involved in pulmonary-cardiovascular reflexes and in natriuresis and diuresis. Since the carotid body initiates hypoxic chemoreflexes, we hypothesized that ANP could potentiate the hypoxic stimulation of the carotid body chemoreceptor in vivo. We studied the effect of close intra-arterial injection of ANP on carotid chemoreceptor activity in anesthetized male cats which were paralyzed and artificially ventilated. Graded doses of ANP (0-10 nmoles) were administered by intra-arterial injections and they produced an excitatory response. Single dose of ANP (6.5 nmoles) at four steady-state levels of arterial PO(2), at constant PCO(2), produced increases of chemoreceptor activity. This increase of chemoreceptor activity with ANP in the presence of CO(2)-HCO(3)(-) in vitro could make a difference from those without CO(2)-HCO(3)(-) in vivo.

Adaptation, Physiological↗
PubMed2003

Oxygen supply modulates MCP-1 release in monocytes from young and aged rats: decrease of MCP-1 transcription and translation is age-related.

Hyper or hypoxia may affect the immune system's chemokine production. Monocyte chemotactic protein-1 (MCP-1), an important chemotactic cytokine can be activated by active oxygen species. Groups of rats were exposed to hypoxic and hyperoxic environmental conditions for 60 h and MCP-1 was determined in their peripheral blood mononuclear cells by Elisa and Reverse Transcriptase Polymerase Chain Reaction (RT-PCR). In this study we evaluated if the ability of monocytes to produce MCP-1 under basal conditions or after stimulation with lipopolysaccharide (LPS) or phytohaemagglutinin (PHA) was differently affected by exposure to hyper or hypoxic conditions in young and aged rats. MCP-1 expression and production in monocyte/macrophages from rats at normoxic conditions was reduced in aged subjects. However, spontaneous, LPS or PHA-induced MCP-1 production was up-regulated by exposure to hyperoxic conditions in both young (62 +/- 8, 99 +/- 7, 102 +/- 8 pg/ml, respectively) and aged rats (79 +/- 4, 112 +/- 9, 117 +/- 10 pg/ ml, respectively). We conclude that hyperoxia is an important regulator of MCP-1 release and support the hypothesis that increased % of O2 may serve to initiate MCP-1 production which then serves to recruit and regulate the distribution of mononuclear cells to the sites of inflammation.

Aging↗
PubMed2002

Antibodies to bovine beta-casein in diabetes and other autoimmune diseases.

Cow's milk is thought to be an environmental trigger for autoimmune response in Type 1 diabetes. In the present study, our aim was to investigate the antibody response to bovine beta-casein in different immune- and non-immune-mediated diseases and to establish whether such an antibody response is specific to Type 1 diabetes. We measured antibodies to bovine beta-casein using an enzyme-linked immunosorbent assay in a total of 519 sera from subjects as follows: 71 patients with Type 1 diabetes, 33 patients with coeliac disease, 100 patients with latent autoimmune diabetes in adults (LADA), 50 patients with autoimmune thyroid disease (ATD), 50 patients with Type 2 diabetes, 24 patients with multiple sclerosis (MS), and 3 different groups of controls (n = 191). Significantly increased levels of antibodies to beta-casein were found in patients with Type 1 diabetes, coeliac disease and in LADA compared to age-matched controls (p = 0.01, p = 0.02 and p = 0.01, respectively). No differences were observed in beta-casein antibody titres between patients with other disease conditions (MS, and ATD) and age-matched controls. The highest antibody response to beta-casein in Type 1 diabetic patients and in patients with coeliac disease could reflect the gut mucosal immune disorders common to Type 1 diabetes and coeliac disease. Furthermore, the elevated beta-casein antibody levels found in LADA patients suggest that the antibody response to this protein may be relevant in autoimmune diabetes.

Adolescent↗
PubMed2001

Role of 5-HT(2C) receptors in the control of central dopamine function.

Substantial evidence suggests that the functional status of the mesocorticolimbic dopamine (DA) system originating in the ventral tegmental area is under a phasic and tonic inhibitory control by the 5-HT system that acts by stimulating 5-HT(2C) receptor subtypes. Indeed, electrophysiological and biochemical data demonstrate that 5-HT(2C) receptor agonists decrease, whereas 5-HT(2C) receptor antagonists enhance, mesocorticolimbic DA function. However, 5-HT(2C) receptors do not appear to play a relevant role in the control of the nigrostriatal DA system originating in the substantia nigra pars compacta. In this article, the role of 5-HT(2C) receptors in the control of brain DA function will be reviewed, and the search for new therapies for neuropsychiatric disorders, such as depression, schizophrenia and drug addiction, based on these findings will be discussed.

Animals↗
PubMed2001

Ultrastructural modifications and phosphatidylinositol-3-kinase expression and activity in myocardial tissue deriving from rats in different experimental conditions.

Oxygen supply is essential in the maintenance of the physiological cell metabolism. In fact, both lower and higher O2 concentrations induce modifications of the enzymatic activity of the cell which determine, in turn, morphological changes at nuclear and cytoplasmic level. Among the molecules involved in the maintenance of the cellular homeostasis, the signal transduction pathway PI-3-kinase/AKT-1 should be included. Here we suggest a relationship between the modulation of this pathway and the morphological modifications occurring "in vivo" in myocardial tissue upon hypoxic and hyperoxic stress. In particular, down regulation of this pathway, which when activated is known to deliver an anti-apoptotic signal, is concomitant to the maintenance of the apoptotic events occurring in these cells in response to oxidative stresses.

Animals↗
PubMed2001

Endothelial nitric oxide synthase (eNOS) expression and localization in healthy and diabetic rat hearts.

Several studies suggest that nitric oxide (NO) production is reduced in diabetes and that the decrease of NO may be related to the pathogenesis of diabetic endothelial damage. NO synthase (NOS) catalyses the conversion of L-arginine to L-citrulline in the presence of oxygen and NADPH-diaphorase (NADPH-d). In this study, we evaluated the expression of endothelial NOS (eNOS) enzyme and its co-enzyme in diabetic rat hearts. Male Wistar rats (n = 20, 4 mo old) and 20 male Bio Breeding Wistar (BB/W) rats of the same age were used; the Wistar rats represent the control non-diabetic rats while the BB/W rats represent the diabetic group. After the hearts were excised, the NADPH-d co-enzyme was visualized by a histochemical method and the endothelial isoform of NOS was localized by immunohistochemistry. In addition, eNOS gene expression was estimated by rt-PCR, and eNOS protein level was detected by Western blot analysis. The eNOS visualization, which involved immunoprecipitation, and the NADPH-d visualization, which involved histochemical staining, were both diminished in endothelial cells of the vascular wall of diabetic hearts, compared to non-diabetic hearts. The eNOS protein level, evaluated by Western blotting, was evident as an intense band in cardiac homogenates of non-diabetic and diabetic rats. The expression of mRNA for eNOS did not differ significantly between the two groups. These findings indicate that, in this rat heart model, diabetes does not influence the overall eNOS protein level or its mRNA level. However, there a diminution in the deposition of eNOS in cardiac endothelial cells of diabetic rats, versus non-diabetic controls, suggesting a relation between eNOS and the loss of vasodilatory response that is observed in diabetes.

Animals↗
PubMed2000

Endothelial NOS expression and ischemia-reperfusion in isolated working rat heart from hypoxic and hyperoxic conditions.

Induction of endothelial nitric oxide synthase (eNOS) contributes to the mechanism of heart protection against ischemia-reperfusion damage. We analyzed the effects of hypoxia and hyperoxia on eNOS expression in isolated working rat hearts after ischemia-reperfusion damage. Adult male Wistar rats were submitted to chronic hypoxia (2 weeks) and hyperoxia (72 h). The hearts were submitted to 15 min of ischemia and reperfused for 60 min, then we evaluated hemodynamic parameters and creatine phosphokinase (CPK) release. eNOS expression was estimated by RT-PCR; enzyme localization was evaluated by immunohistochemistry and the eNOS protein levels were detected by Western blot. All hemodynamic parameters in hypoxic conditions were better with respect to other groups. The CPK release was lower in hypoxic (P<0.01) than in normoxic and hyperoxic conditions. The eNOS deposition was significantly higher in the hypoxic group versus the normoxic or hyperoxic groups. The eNOS protein and mRNA levels were increased by hypoxia versus both other groups. Chronic hypoxic exposure may decrease injury and increase eNOS protein and mRNA levels in heart subjected to ischemia-reperfusion.

Animals↗
PubMed2000

Biochemical and ultrastructural alterations in rat after hyperoxic treatment: effect of taurine and hypotaurine.

The cell ultrastructure and some detoxifying enzyme activities were studied in skeletal muscles of young rats kept for 84 h under normobaric hyperoxia (95% O2) or normoxia as control. Rat were injected i.p.. Every 12 h either with 1 ml saline, 1 ml saline+30 mg hypotaurine or 1 ml saline+30 mg taurine. Ultrastructural observation revealed an highly protective effect on tissue damages due to hyperoxia in taurine-treated rats and, at less extent, in hypotaurine-treated ones. Enzymatic assays suggest a different mechanism of the two molecules in their protective action.

Animals↗
PubMed1999

Bioequivalence of levothyroxine tablets administered to a target population in steady state.

Two parallel trials were carried out with levothyroxine sodium salt in 50 and 100 microg strengths, respectively, giving 100 microg day-1(50x2 microg day-1 or 100x1 microg day-1) in both trials in a repeated dose regimen. Twenty patients suffering from primary hypothyroidism under treatment with 100 microg day-1 of thyroxine sodium salt were enrolled in each trial. They were clinically and chemically euthyroid. Each trial lasted 114 days, with 57 days being devoted to the first treatment (test or reference) and 57 days to the other (reference or test), according to a two-period, two-sequence, two-formulation design in a steady state without wash-out. The test formulation was prepared with a technological improvement and is being produced to replace that at present on the market. Serum concentrations of free and total levothyroxine, and free and total levotriiodothyronine were assayed repeatedly during the treatment and in timed samples after the last dose of each formulation, using radioimmunoassays. Cmax and AUCss,tau were considered to be target parameters for bioequivalence which was assessed through 90% confidence intervals in the 0.80-1.25 range, as required by EU and US FDA operating guidelines. The results have shown that of these hormones, the free and total parent compound thyroxine is that which most clearly showed a peak after dosing, whereas its metabolite, free and total triiodothyronine, fluctuated around pre-dose concentrations. Bioequivalence was fully assessed with Cmax and AUCss,tau, with all four hormones tested and at both strengths administered. The two test formulations in 50 and 100 microg are thus bioequivalent with the two reference preparations. Tolerability was very good in all cases.

Adult↗
PubMed1998

Further characterization of stimulus interaction of cat carotid chemoreceptors.

The hypothesis that the maximal response to pCO2 of carotid body chemoreceptors would be the same regardless of pO2, if the receptor molecule behaves like a hemoglobin molecule, was investigated using single or a few fiber carotid body chemoreceptors in cats in vivo which were anesthetized and artificially ventilated. In one series, graded levels of CO2 inhalation in steady-state at p(a)O2 = 354 +/- 19 Torr showed a linear response from 1 to 20.1 +/- 2.3 imp/s for p(a)CO2 increase from 32 to 178 +/- 18 Torr, and at p(a)O2 of 48 +/- 3.8 Torr, from 3.8 to 18.6 +/- 1.7 imp/s for p(a)CO2 increase from 21 to 109 +/- 11 Torr, levelling off thereafter. In another series of multi-fiber preparation, close intra-arterial injection of blood plus saline containing pCO2 of about 270 Torr gave peak responses of 44 +/- 9, 42 +/- 6 and 42 +/- 7 imp/s at p(a)O2 of 40 +/- 4, 82 +/- 6 and 388 +/- 18 Torr, respectively. Thus, the chemosensory responses to p(a)CO2 reached the same level of maximal activity regardless of p(a)O2. Taken together, the maximal responses in both steady-state and transient-state to p(a)CO2 appeared to be the same at hypoxic and hyperoxic p(a)O2. This stimulus-response relationship of the receptor molecule is analogous to O2-CO2 interaction with hemoglobin molecule with a Bohr effect, reaching a saturation point at a finite pO2.

Acidosis↗