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M Calvani

Publications and source records attributed to M Calvani.

At least 19 recordsLinked to original sources
PubMed2006

Urinary excretion of L-carnitine and its short-chain acetyl-L-carnitine in patients undergoing carboplatin treatment.

PURPOSE: To evaluate the effect of the anti-cancer drug carboplatin on plasma concentrations and urinary excretion of L-carnitine (LC) and its main ester, acetyl-L-carnitine (ALC), in cancer patients. METHODS: Plasma and urine concentrations of LC and ALC from 11 patients on carboplatin therapy (1 h intravenous infusion; AUC dose 4.8 +/- 1.1 mg/ml min) in combination with docetaxel, paclitaxel or vinorelbine, were determined by high-performance liquid chromatography with fluorimetric detection. RESULTS: Before carboplatin therapy, the mean +/- SD plasma concentrations of LC and ALC were 47.8 +/- 10.9 and 7.04 +/- 1.04 nmoles/ml, respectively, and remained constant throughout the entire study period. In contrast, urinary excretion of LC and ALC, increased significantly during the chemotherapy from 115 +/- 105 to 480 +/- 348 micromoles/day (P < 0.01) and from 41 +/- 41 to 89 +/- 52 micromoles/day (P < 0.05) for LC and ALC, respectively, subsequently reverting to normal 6 days after the end of chemotherapy. Similarly, the renal clearance of LC and ALC increased substantially during chemotherapy from 1.67 +/- 1.43 to 9.05 +/- 9.52 ml/min (P < 0.05) and from 4.02 +/- 4.51 to 7.97 +/- 5.05 ml/min (P = not significant) for LC and ALC, respectively, reverting to normal 6 days after the end of chemotherapy. Plasma concentrations and urinary excretion of glucose, phosphate and urea nitrogen and creatinine clearance, however, were not affected by carboplatin therapy, indicating no impaired kidney function. CONCLUSION: Treatment with carboplatin was associated with a marked urinary loss of LC and ALC, most likely due to inhibition of carnitine reabsorption in the kidney.

Acetylcarnitine↗
PubMed2006

Acetyl-L-carnitine affects nonassociative learning processes in the leech Hirudo medicinalis.

Acetyl-L-carnitine is a natural molecule widely distributed in vertebrate and invertebrate nervous system. It is known to have significant effects on neuronal activity playing a role as neuroprotective and anti-nociceptive agent, as well as neuromodulatory factor. About its capability of affecting learning processes the available data are controversial. In the present study, we utilized the simplified model system of the leech Hirudo medicinalis to analyze the effects of acetyl-L-carnitine, assessing whether and how it might affect elementary forms of nonassociative learning processes. In leeches with the head ganglion disconnected from the first segmental ganglion, repetitive application of weak electrical shocks onto the caudal portion of the body wall induces habituation of swim induction whereas brush strokes on the dorsal skin produces sensitization or dishabituation when the nociceptive stimulus is delivered on previously habituated animals. Herein, the effects of different concentrations of acetyl-L-carnitine (2 mM - 0.05 mM) have been tested at different times on both sensitization and dishabituation. The results show that a single treatment of acetyl-L-carnitine blocked the onset of sensitization in a dose- and time-dependent manner. In fact, the most effective concentration able to block this process was 2 mM, which induced its major effects 11 days after the treatment, whereas 0.05 mM was unable to affect the sensitization process at all considered time points. On the contrary, acetyl-L-carnitine did not completely abolish dishabituation at the tested concentrations and at every time point. Finally, acetyl-L-carnitine also impaired the habituation of swim induction, but only 11 days after treatment.

Acetylcarnitine↗
PubMed2006

Acetyl-L-carnitine feeding to unloaded rats triggers in soleus muscle the coordinated expression of genes involved in mitochondrial biogenesis.

The expressional profile of mitochondrial transcripts and of genes involved in the mitochondrial biogenesis pathway induced by ALCAR daily supplementation in soleus muscle of control and unloaded 3-month-old rats has been analyzed. It has been found that ALCAR treatment is able to upregulate the expression level of mitochondrial transcripts (COX I, ATP6, ND6, 16 S rRNA) in both control and unloaded animals. Interestingly, ALCAR feeding to unloaded rats resulted in the increase of transcript level for master factors involved in mitochondrial biogenesis (PGC-1alpha, NRF-1, TFAM). It also prevented the unloading-induced downregulation of mRNA levels for kinases able to transduce metabolic (AMPK) and neuronal stimuli (CaMKIIbeta) into mitochondrial biogenesis. No significant effect on the expressional level of such genes was found in control ALCAR-treated rats. In addition, ALCAR feeding was able to prevent the loss of mitochondrial protein content due to unloading condition. Correlation analysis revealed a strong coordination in the expression of genes involved in mitochondrial biogenesis only in ALCAR-treated suspended animals, supporting a differentiated effect of ALCAR treatment in relation to the loading state of the soleus muscle. In conclusions, we demonstrated the ability of ALCAR supplementation to promote only in soleus muscle of hindlimb suspended rats an orchestrated expression of genes involved in mitochondrial biogenesis, which might counteract the unloading-induced metabolic changes, preventing the loss of mitochondrial proteins.

Acetylcarnitine↗
PubMed2006

Behavioral and electrophysiological changes induced by acetyl-L-carnitine in aged freely-moving rats.

In chronically-implanted, drug-free, behaving aged Fischer rats, intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.) acetyl-L-carnitine (ALCAR) injections powerfully enhanced motor behavior and head movements aimed at attention and exploratory activity. This effect was dose-dependent and associated with the abolition or substantial reduction of the incidence and duration of the spontaneous EEG generalized hypersynchronous patterns termed High Voltage Spindle (HVS), with an increase in EEG monitored theta activity. The results suggest that ALCAR may stimulate the motivational system and disrupt the hypersynchronous processes by inhibiting the GABAergic thalamic reticular neurons and/or activating the brain stem cholinergic reticular system (pedunculo pontine tegmental, PPT and laterodorsal tegmental, LDT nuclei).

Acetylcarnitine↗
PubMed2006

[Egg allergy].

Egg is one of the most important allergen in childhood feeding. The pathogenic mechanism in egg allergy is immediate, type I, IgE-mediated hypersensitivity, although other mechanisms are possible. The aim of this review is to point out that diagnosis of egg protein allergy is mainly clinical and double-blind placebo-controlled food challenge is nowadays the gold standard. Although reference values for prick test and sIgE have been proposed, which can foretell symptoms in groups of egg sensitive children, these values are not so accurate for a single diagnosis, since they mainly refer to children with atopic dermatitis, and to specific ranges of age. Children with atopic dermatitis can show allergy at the first egg ingestion, as for cow milk allergy, because the sensitization may happen in utero or through breast milk. The only available therapy in case of egg allergy is the complete removal of hen egg from the child's diet, yet considering cross-reaction with other birds' eggs, while cross- reaction with poultry and/or other birds' meat has been signalled only in 5% of cases. From this review it is clear how egg allergic children can be vaccinated against measles-mumps rubella.

Child↗
PubMed2005

Metabolic profiling by 13C-NMR spectroscopy: [1,2-13C2]glucose reveals a heterogeneous metabolism in human leukemia T cells.

Metabolic profiling is defined as the simultaneous assessment of substrate fluxes within and among the different pathways of metabolite synthesis and energy production under various physiological conditions. The use of stable-isotope tracers and the analysis of the distribution of labeled carbons in various intermediates, by both mass spectrometry and NMR spectroscopy, allow the role of several metabolic processes in cell growth and death to be defined. In the present paper we describe the metabolic profiling of Jurkat cells by isotopomer analysis using (13)C-NMR spectroscopy and [1,2-(13)C(2)]glucose as the stable-isotope tracer. The isotopomer analysis of the lactate, alanine, glutamate, proline, serine, glycine, malate and ribose-5-phosphate moiety of nucleotides has allowed original integrated information regarding the pentose phosphate pathway, TCA cycle, and amino acid metabolism in proliferating human leukemia T cells to be obtained. In particular, the contribution of the glucose-6-phosphate dehydrogenase and transketolase activities to phosphoribosyl-pyrophosphate synthesis was evaluated directly by the determination of isotopomers of the [1'-(13)C], [4',5'-(13)C(2)]ribosyl moiety of nucleotides. Furthermore, the relative contribution of the glycolysis and pentose cycle to lactate production was estimated via analysis of lactate isotopomers. Interestingly, pyruvate carboxylase and pyruvate dehydrogenase flux ratios measured by glutamate isotopomers and the production of isotopomers of several metabolites showed that the metabolic processes described could not take place simultaneously in the same macrocompartments (cells). Results revealed a heterogeneous metabolism in an asynchronous cell population that may be interpreted on the basis of different metabolic phenotypes of subpopulations in relation to different cell cycle phases.

Carbon Isotopes↗
PubMed2005

Could the low level of expression of the gene encoding skeletal muscle mitofusin-2 account for the metabolic inflexibility of obesity?

AIMS/HYPOTHESIS: In obesity the cellular capacity to switch from using lipid to carbohydrate and vice versa as the energy substrate, known as 'metabolic flexibility', is impaired. Mitofusin 2 (MFN2), a mitochondrial membrane protein, seems to contribute to the maintenance and operation of the mitochondrial network, and its expression is reduced in obesity. The aim of this study was to verify whether MFN2 might be implicated in the metabolic inflexibility of obesity. MATERIALS AND METHODS: Insulin sensitivity was measured in six morbidly obese women before and 2 years after malabsorptive bariatric surgery (BMI 53.3+/-10.5 vs 30.3+/-4.0 kg/m2). Skeletal muscle MFN2, SLC2A4 (formerly known as GLUT4), COX3 (encoding cytochrome c oxidase subunit III) and CS (encoding citrate synthase) mRNA levels were measured by real-time PCR. RESULTS: Following bilio-pancreatic surgery, significant increases in MFN2 mRNA (from 0.4+/-0.2 to 1.7+/-1.1 arbitrary units [AU], p=0.019) and SLC2A4 mRNA (0.38+/-0.12 to 0.76+/-0.24 AU, p=0.04) were observed, while increases in COX3 mRNA (from 14.2+/-6.4 to 20.2+/-12.5 AU) and CS mRNA (from 0.4+/-0.1 to 0.7+/-0.3 AU) failed to reach statistical significance. Insulin-mediated whole-body glucose uptake significantly (p<0.0001) increased from 21.2+/-4.1 to 52.8+/-5.9 micromol kg fat-free mass(-1) min(-1) and glucose oxidation rose from 11.1+/-2.1 to 37.7+/-4.7 micromol kg fat-free mass(-1) min(-1) (p<0.0001). Levels of MFN2 mRNA were strongly correlated with the absolute values for the glucose oxidation rate, both during fasting (glucose oxidation =3.55 MFN2 mRNA + 3.93; R2=0.92, p<0.0001) and during the clamp (glucose oxidation=18.8 MFN2 mRNA+34.7; R2=0.80, p<0.0001). The percentage changes in MFN2 mRNA were positively correlated with the percentage change in glucose oxidation during the clamp (glucose oxidation percent (%) change=0.3 MFN2 mRNA percent (%) change+153.2; R2=0.61, p<0.001). CONCLUSIONS/INTERPRETATION: We propose that the significant increase in MFN2 mRNA levels may explain the increase in glucose oxidation observed in morbid obesity following bariatric surgery.

Adult↗
PubMed2005

tBid induces alterations of mitochondrial fatty acid oxidation flux by malonyl-CoA-independent inhibition of carnitine palmitoyltransferase-1.

Recent studies suggest a close relationship between cell metabolism and apoptosis. We have evaluated changes in lipid metabolism on permeabilized hepatocytes treated with truncated Bid (tBid) in the presence of caspase inhibitors and exogenous cytochrome c. The measurement of beta-oxidation flux by labeled palmitate demonstrates that tBid inhibits beta-oxidation, thereby resulting in the accumulation of palmitoyl-coenzyme A (CoA) and depletion of acetyl-carnitine and acylcarnitines, which is pathognomonic for inhibition of carnitine palmitoyltransferase-1 (CPT-1). We also show that tBid decreases CPT-1 activity by a mechanism independent of both malonyl-CoA, the key inhibitory molecule of CPT-1, and Bak and/or Bax, but dependent on cardiolipin decrease. Overexpression of Bcl-2, which is able to interact with CPT-1, counteracts the effects exerted by tBid on beta-oxidation. The unexpected role of tBid in the regulation of lipid beta-oxidation suggests a model in which tBid-induced metabolic decline leads to the accumulation of toxic lipid metabolites such as palmitoyl-CoA, which might become participants in the apoptotic pathway.

BH3 Interacting Domain Death Agonist Protein↗
PubMed2005

Differential expression of multiple transglutaminases in human colon: impaired keratinocyte transglutaminase expression in ulcerative colitis.

BACKGROUND AND AIMS: Ulcerative colitis (UC) is characterised by refractory inflammatory ulceration and damage to the colon. The mechanisms underlying impaired healing have yet to be defined. As transglutaminase expression resulting in matrix protein cross linking is associated with increased wound healing in a rat model of colitis, we hypothesised that different types of transglutaminase might also play a role in UC. PATIENTS AND METHODS: Endoscopic and histological indices were studied in 26 patients with UC (10 active and 16 inactive) and in 20 normal controls undergoing colonoscopy. Transglutaminase activity was evaluated in plasma (factor XIIIa) by a radioenzymatic method. Factor XIIIa, tissue and keratinocyte transglutaminase protein content, and mRNA expression in the colon were evaluated by western blot analysis and semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Colonic location of transglutaminases and their reaction products, the epsilon-(gamma-glutamyl)lysine bonds, was evaluated by immunohistochemistry using specific monoclonal antibodies. RESULTS: Transglutaminase activity was significantly lower in the plasma of patients with active UC (4.2 (2.4) mU/ml; p<0.05 v controls) than in those with inactive UC and controls (10.6 (2.2) and 12.1 (1.7) mU/ml). As shown by western blot, protein levels of tissue transglutaminase and factor XIIIa were unchanged in active UC compared with inactive disease and controls, while the keratinocyte form was reduced in active UC. Tissue transglutaminase and factor XIIIa immunostaining was strongly present in damaged areas colocalising with isopeptide bonds. In contrast, the keratinocyte form was almost absent in active UC and localised in the upper part of the crypts in normal subjects. RT-PCR showed upregulation of tissue transglutaminase mRNA in active UC (320% compared with controls) while keratinocyte transglutaminase gene expression was downregulated in active UC. CONCLUSIONS: The results of the present study support the concept that, in the damaged colon, transglutaminases are needed in response to chronic injury and underline the key role of these enzymes in mucosal healing.

Adult↗
PubMed2004

Acetyl-L-carnitine induces a sustained potentiation of the afterhyperpolarization.

Acetyl-L-carnitine is known to improve many aspects of the neural activity even if its exact role in neurotransmission is still unknown. This study investigates the effects of acetyl-L-carnitine in T segmental sensory neurons of the leech Hirudo medicinalis. These neurons are involved in some forms of neural plasticity associated with learning processes. Their physiological firing is accompanied by a large afterhyperpolarization that is mainly due to the Na+/K+ ATPase activity and partially to a Ca2+ -dependent K+ current. A clear-cut hyperpolarization and a significant increase of the afterhyperpolarization have been recorded in T neurons of leeches injected with 2 mM acetyl-L-carnitine some days before. Acute treatments of 50 microM acetyl-L-carnitine induced similar effects in T cells of naive animals. In the presence of apamin, a pharmacological blocker of Ca2+ -dependent K+ channel, acetyl-L-carnitine still enhanced the residual afterhyperpolarization, suggesting an effect of the drug on the Na+/K+ATPase. Acetyl-L-carnitine also increased the hyperpolarization induced by intracellular injection of Na+ ions. Therefore, acetyl-L-carnitine seems to be able to exert a positive sustained effect on the Na+/K+ ATPase activity in leech T sensory neurons. Moreover, in these cells, widely arborized, the afterhyperpolarization seems to play an important role in determining the action potential transmission at neuritic bifurcations. A computational model of a T cell has been previously developed considering detailed data for geometry and the modulation of the pump current. Herein, we showed that to a larger afterhyperpolarization, due to the acetyl-L-carnitine-induced effects, corresponds a decrement in the number of action potentials reaching synaptic terminals.

Acetylcarnitine↗
PubMed2004

Infectious and uterus related complications during pregnancy and development of atopic and nonatopic asthma in children.

BACKGROUND: It has been suggested that environmental factors early in life, particularly related to hygiene and infections, seem to be involved in the increase of asthma and allergic disease observed recently in developed countries. The possible effect of these factors also in utero have yet to be completely clarified. The aim of this study was to investigate the association between infective and uterus related complications during pregnancy, as well as related drug factors, with atopic and nonatopic asthma in children. METHODS: This was a case-controlled study enrolling 338 children with asthma and 467 controls, who had never suffered from wheeze or asthma. Fever episodes, flu episodes, threatened abortions and related drug factors were retrospectively assessed by parental report via a standardized questionnaire. Atopy was determined by skin-prick tests to 10 prevalent allergens at the time of examination. RESULTS: Flu episodes during pregnancy were significantly associated with development of asthma in children [adjusted odds ratio (aOR) 1.91; 95% confidence interval (95% CI) 1.1-3.2], mainly with nonatopic asthma. Fever episodes showed similar results (aOR 2.16; 95% CI 1.2-3.9), but were associated with both atopic and nonatopic asthma. The effect seems mainly due to flu and fever episodes contracted in the third trimester. Exposure to isoxsuprine was significantly associated with asthma (aOR 1.54; 95% CI 1.08-2.19) while threatened abortions were more frequent in the asthma group than in controls, although the difference was statistically significant only when such events occurred in the second trimester (aOR 2.06; 95% CI 1.07-3.94). Both threatened abortions and exposure to isoxsuprine were associated only with nonatopic asthma. CONCLUSIONS: This study confirms that prenatal infective complications may contribute to the development of asthma in children and show a possible role for a new risk factor for asthma, that is exposure to isoxsuprine. Therefore, larger prospective studies, capable of separating atopic and nonatopic asthma, would serve to confirm these results and to explain the possible mechanism through which these factors may act.

Adult↗
PubMed2004

Single-cell quantitative RT-PCR analysis of Cpt1b and Cpt2 gene expression in mouse antral oocytes and in preimplantation embryos.

Fatty acids represent an important energy source for preimplantation embryos. Fatty acids oxidation is correlated with the embryo oxygen consumption which remains relatively constant up to the 8-cell stage, but suddenly increases between the 8-cell and morula stages. The degradation of fatty acids occurs in mitochondria and is catalyzed by several carnitine acyl transferases, including two carnitine palmitoyl transferases, CPT-I and CPT-II. We have carried out a study to determine the relative number of transcripts of Cpt1b and Cpt2 genes encoding for m-CPT-I and CPT-II enzymes, during mouse preimplantation development. Here we show that Cpt1b transcripts are first and temporally detected at the 2-cell stage and reappear at the morula and blastocyst stage. Cpt2 transcripts decrease following fertilization to undetectable levels and are present again later at the morula stage. These results show that transcription of both Cpt1b and Cpt2 is triggered at the morula stage, concomitantly with known increasing profiles of oxygen uptake and fatty acids oxidation. Based on the number of Cpt2 transcripts detected, we could discriminate the presence of two groups of embryos with high and low number of transcripts, from the zygote throughout preimplantation development. To further investigate if the establishment of these two groups of embryos occurs prior to fertilization, we have analyzed the relative number of transcripts of both genes in antral and ovulated MII oocytes. As for preimplantation embryos, MII oocytes show two groups of Cpt2 expression. Antral oocytes, classified according to their chromatin configuration in SN (surrounded nucleolus, in which the nucleolus is surrounded by a rim of Hoechst-positive chromatin) and NSN (not surrounded nucleolus, in which this rim is absent), show three groups with different numbers of Cpt2 transcripts. All NSN oocytes have a number of Cpt2 transcripts doubled compared to that of the group of MII oocytes with high expression. Instead, SN oocytes could be singled out into two groups with high and low numbers of Cpt2 transcripts, similar to those found in MII oocytes. The results of this study point out a correlation between the timing of fatty acids oxidation during preimplantation development and the expression of two genes encoding two enzymes involved in the oxidative pathway. Furthermore, although the biological meaning for the presence of two groups of oocytes/embryos with different levels of Cpt2 transcripts remains unclear, the data obtained suggest a possible correlation between the levels of Cpt2 expression and embryo developmental competence.

Animals↗
PubMed2004

Metabotropic receptors as targets for drugs of potential use in the treatment of neuropathic pain.

Glutamate is the major neurotransmitter in the mammalian central nervous system and plays a pivotal role in both acute and chronic pain. The actions of glutamate are mediated by two receptor families: ionotropic glutamate receptors (iGluRs), and metabotropic glutamate receptors (mGluRs). Activation of glutamate receptor can elicit both hyperalgesic and analgesic effects. Eight mGluRs subtypes (mGluR1-mGluR8) have been identified and classified into three groups. Among these, group I mGluRs (mGlu1 and -5) have been implicated in the processes of central sensitization and persistent nociception, whereas activation of group II mGluRs (mGlu2/3) is effective against neuropathic or inflammatory pain. In this review we focus on the role of mGlu2/3 in the modulation of persistent pain, and on their potential use as drug targets in pain management.

Acetylcarnitine↗
PubMed2003

The carnitine system and body composition.

Carnitine is a trimethylamine molecule that plays a unique role in cell energy metabolism. Mitochondrial betaoxidation of long-chain fatty acids, the major process by which fatty acids are oxidized, is ubiquitously dependent on carnitine. Control of mitochondrial beta-oxidation through carnitine adapts to differing requirements in different tissues. The physiological role of carnitine and its system in body composition is understood from insights into skeletal muscle metabolism, which converge into the metabolic heterogeneity of muscle fibers, and contractile properties that are correlated with phenotypes of resistance to fatigue. In skeletal muscle, the importance of the function of the carnitine system in the control and regulation of fuel partitioning not only relates to the metabolism of fatty acids and the capacity for fatty acid utilization, but also to systemic fat balance and insulin resistance. The carnitine system is shown to be determinant in insulin regulation of fat and glucose metabolic rate in skeletal muscle, this being critical in determining body composition and relevant raised levels of risk factors for cardiovascular disease, obesity, hypertension, and type 2 diabetes.

Animals↗
PubMed2003

Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine.

Recent studies suggest that NO and its reactive derivative peroxynitrite are implicated in the pathogenesis of multiple sclerosis (MS). Patients dying with MS demonstrate increased astrocytic inducible nitric oxide synthase activity, as well as increased levels of iNOS mRNA. Peroxynitrite is a strong oxidant capable of damaging target tissues, particularly the brain, which is known to be endowed with poor antioxidant buffering capacity. Inducible nitric oxide synthase is upregulated in the central nervous system (CNS) of animals with experimental allergic encephalomyelitis (EAE) and in patients with MS. We have recently demonstrated in patients with active MS a significant increase of NOS activity associated with increased nitration of proteins in the cerebrospinal fluid (CSF). Acetylcarnitine is proposed as a therapeutic agent for several neurodegenerative disorders. Accordingly, in the present study, MS patients were treated for 6 months with acetylcarnitine and compared with untreated MS subjects or with patients noninflammatory neurological conditions, taken as controls. Western blot analysis showed in MS patients increased nitrosative stress associated with a significant decrease of reduced glutathione (GSH). Increased levels of oxidized glutathione (GSSG) and nitrosothiols were also observed. Interestingly, treatment of MS patients with acetylcarnitine resulted in decreased CSF levels of NO reactive metabolites and protein nitration, as well as increased content of GSH and GSH/GSSG ratio. Our data sustain the hypothesis that nitrosative stress is a major consequence of NO produced in MS-affected CNS and implicate a possible important role for acetylcarnitine in protecting brain against nitrosative stress, which may underlie the pathogenesis of MS.

Acetylcarnitine↗