Publications by authors named "Anna Maria Giudetti"

29 Publications

  • Page 1 of 1

Urinary Metabolic Biomarkers in Cancer Patients: An Overview.

Methods Mol Biol 2021 ;2292:203-212

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.

The pathogenesis of cancer involves multiple molecular alterations at the level of genome, epigenome, and stromal environment, resulting in several deregulated signal transduction pathways. Metabolites are not only end products of gene and protein expression but also a consequence of the mutual relationship between the genome and the internal environment. Considering that metabolites serve as a comprehensive chemical fingerprint of cell metabolism, metabolomics is emerging as the method able to discover metabolite biomarkers that can be developed for early cancer detection, prognosis, and response to treatment. Urine represents a noninvasive source, available and rich in metabolites, useful for cancer diagnosis, prognosis, and treatment monitoring. In this chapter, we reported the main published evidences on urinary metabolic biomarkers in the studied cancers related to hepatopancreatic and urinary tract with the aim at discussing their promising role in clinical practice.
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http://dx.doi.org/10.1007/978-1-0716-1354-2_18DOI Listing
April 2021

An altered lipid metabolism characterizes Charcot-Marie-Tooth type 2B peripheral neuropathy.

Biochim Biophys Acta Mol Cell Biol Lipids 2020 12 21;1865(12):158805. Epub 2020 Aug 21.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni n. 165, 73100 Lecce, Italy. Electronic address:

Charcot-Marie Tooth type 2B (CMT2B) is a rare inherited peripheral neuropathy caused by five missense mutations in the RAB7A gene, which encodes a small GTPase of the RAB family. Currently, no cure is available for this disease. In this study, we approached the disease by comparing the lipid metabolism of CMT2B-derived fibroblasts to that of healthy controls. We found that CMT2B cells showed increased monounsaturated fatty acid level and increased expression of key enzymes of monounsaturated and polyunsaturated fatty acid synthesis. Moreover, in CMT2B cells a higher expression of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS), key enzymes of de novo fatty acid synthesis, with a concomitantly increased [1-C]acetate incorporation into fatty acids, was observed. The expression of diacylglycerol acyltransferase 2, a rate-limiting enzyme in triacylglycerol synthesis, as well as triacylglycerol levels were increased in CMT2B compared to control cells. In addition, as RAB7A controls lipid droplet breakdown and lipid droplet dynamics have been linked to diseases, we analyzed these organelles and showed that in CMT2B cells there is a strong accumulation of lipid droplets compared to control cells, thus reinforcing our data on abnormal lipid metabolism in CMT2B. Furthermore, we demonstrated that ACC and FAS expression levels changed upon RAB7 silencing or overexpression in HeLa cells, thus suggesting that metabolic modifications observed in CMT2B-derived fibroblasts can be, at least in part, related to RAB7 mutations.
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http://dx.doi.org/10.1016/j.bbalip.2020.158805DOI Listing
December 2020

Brief daily access to cafeteria-style diet impairs hepatic metabolism even in the absence of excessive body weight gain in rats.

FASEB J 2020 07 28;34(7):9358-9371. Epub 2020 May 28.

School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino, Italy.

Numerous nutritional approaches aimed at reducing body weight have been developed as a strategy to reduce obesity. Most of these interventions rely on reducing caloric intake or limiting calories access to a few hours per day. In this work, we analyzed the effects of the extended (24 hours/day) or restricted (1 hour/day) access to a cafeteria-style (CAF) diet, on rat body weight and hepatic lipid metabolism, with respect to control rats (CTR) fed with a standard chow diet. The body weight gain of restricted-fed rats was not different from CTR, despite the slightly higher total caloric intake, but resulted significantly lower than extended-fed rats, which showed a CAF diet-induced obesity and a dramatically higher total caloric intake. However, both CAF-fed groups of rats showed, compared to CTR, unhealthy serum and hepatic parameters such as higher serum glucose level, lower HDL values, and increased hepatic triacylglycerol and cholesterol amount. The hepatic expression and activity of key enzymes of fatty acid synthesis, acetyl-CoA carboxylase (ACC), and fatty acid synthase (FAS), was similarly reduced in both CAF-fed groups of rats with respect to CTR. Anyway, while in extended-fed rats this reduction was associated to a long-term mechanism involving sterol regulatory element-binding protein-1 (SREBP-1), in restricted-fed animals a short-term mechanism based on PKA and AMPK activation occurred in the liver. Furthermore, hepatic fatty acid oxidation (FAO) and oxidative stress resulted significantly increased in extended, but not in restricted-fed rats, as compared to CTR. Overall, these results demonstrate that although limiting the total caloric intake might successfully fight obesity development, the nutritional content of the diet is the major determinant for the health status.
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http://dx.doi.org/10.1096/fj.201902757RDOI Listing
July 2020

Oleoylethanolamide decreases frustration stress-induced binge-like eating in female rats: a novel potential treatment for binge eating disorder.

Neuropsychopharmacology 2020 10 30;45(11):1931-1941. Epub 2020 Apr 30.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185, Rome, Italy.

Binge eating disorder (BED) is the most frequent eating disorder, for which current pharmacotherapies show poor response rates and safety concerns, thus highlighting the need for novel treatment options. The lipid-derived messenger oleoylethanolamide (OEA) acts as a satiety signal inhibiting food intake through the involvement of central noradrenergic and oxytocinergic neurons. We investigated the anti-binge effects of OEA in a rat model of binge-like eating, in which, after cycles of intermittent food restrictions/refeeding and palatable food consumptions, female rats show a binge-like intake of palatable food, following a 15-min exposure to their sight and smell ("frustration stress"). Systemically administered OEA dose-dependently (2.5, 5, and 10 mg kg) prevented binge-like eating. This behavioral effect was associated with a decreased activation (measured by mapping the expression of c-fos, an early gene widely used as a marker of cellular activation) of brain areas responding to stress (such as the nucleus accumbens and amygdala) and to a stimulation of areas involved in the control of food intake, such as the VTA and the PVN. These effects were paralleled, also, to the modulation of monoamine transmission in key brain areas involved in both homeostatic and hedonic control of eating. In particular, a decreased dopaminergic response to stress was observed by measuring dopamine extracellular concentrations in microdialysates from the nucleus accumbens shell, whereas an increased serotonergic and noradrenergic tone was detected in tissue homogenates of selected brain areas. Finally, a decrease in corticotropin-releasing factor (CRF) mRNA levels was induced by OEA in the central amygdala, while an increase in oxytocin mRNA levels was induced in the PVN. The restoration of a normal oxytocin receptor density in the striatum paralleled the oxytocinergic stimulation produced by OEA. In conclusion, we provide evidence suggesting that OEA might represent a novel potential pharmacological target for the treatment of binge-like eating behavior.
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http://dx.doi.org/10.1038/s41386-020-0686-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609309PMC
October 2020

H-NMR Based Serum Metabolomics Highlights Different Specific Biomarkers between Early and Advanced Hepatocellular Carcinoma Stages.

Cancers (Basel) 2020 Jan 18;12(1). Epub 2020 Jan 18.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100 Lecce, Italy.

The application of non-targeted serum metabolomics profiling represents a noninvasive tool to identify new clinical biomarkers and to provide early diagnostic differentiation, and insight into the pathological mechanisms underlying hepatocellular carcinoma (HCC) progression. In this study, we used proton Nuclear Magnetic Resonance (H-NMR) Spectroscopy and multivariate data analysis to profile the serum metabolome of 64 HCC patients, in early (n = 28) and advanced (n = 36) disease stages. We found that H-NMR metabolomics profiling could discriminate early from advanced HCC patients with a cross-validated accuracy close to 100%. Orthogonal partial least squares discriminant analysis (OPLS-DA) showed significant changes in serum glucose, lactate, lipids and some amino acids, such as alanine, glutamine, 1-methylhistidine, lysine and valine levels between advanced and early HCC patients. Moreover, in early HCC patients, Kaplan-Meier analysis highlighted the serum tyrosine level as a predictor for overall survival (OS). Overall, our analysis identified a set of metabolites with possible clinical and biological implication in HCC pathophysiology.
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http://dx.doi.org/10.3390/cancers12010241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016798PMC
January 2020

NMR-Based Metabolomic Approach Tracks Potential Serum Biomarkers of Disease Progression in Patients with Type 2 Diabetes Mellitus.

J Clin Med 2019 May 21;8(5). Epub 2019 May 21.

Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni, 73100 Lecce, Italy.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia associated with alterations in carbohydrate, lipid, and protein metabolism. The prognosis of T2DM patients is highly dependent on the development of complications, and therefore the identification of biomarkers of T2DM progression, with minimally invasive techniques, is a huge need. In the present study, we applied a H-Nuclear Magnetic Resonance (H-NMR)-based metabolomic approach coupled with multivariate data analysis to identify serum metabolite profiles associated with T2DM development and progression. To perform this, we compared the serum metabolome of non-diabetic subjects, treatment-naïve non-complicated T2DM patients, and T2DM patients with complications in insulin monotherapy. Our analysis revealed a significant reduction of alanine, glutamine, glutamate, leucine, lysine, methionine, tyrosine, and phenylalanine in T2DM patients with respect to non-diabetic subjects. Moreover, isoleucine, leucine, lysine, tyrosine, and valine levels distinguished complicated patients from patients without complications. Overall, the metabolic pathway analysis suggested that branched-chain amino acid (BCAA) metabolism is significantly compromised in T2DM patients with complications, while perturbation in the metabolism of gluconeogenic amino acids other than BCAAs characterizes both early and advanced T2DM stages. In conclusion, we identified a metabolic serum signature associated with T2DM stages. These data could be integrated with clinical characteristics to build a composite T2DM/complications risk score to be validated in a prospective cohort.
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http://dx.doi.org/10.3390/jcm8050720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571571PMC
May 2019

3,5-diiodo-L-thyronine increases de novo lipogenesis in liver from hypothyroid rats by SREBP-1 and ChREBP-mediated transcriptional mechanisms.

IUBMB Life 2019 07 1;71(7):863-872. Epub 2019 Feb 1.

Department of Biological and Environmental Sciences and Technologies, University of Salento, 73100, Lecce, Italy.

Hepatic de novo lipogenesis (DNL), the process by which carbohydrates are converted into lipids, is strictly controlled by nutritional and hormonal status. 3,5-Diiodo-L-thyronine (T2), a product of the 3,5,3'-triiodo-L-thyronine (T3) peripheral metabolism, has been shown to mimic some T3 effects on lipid metabolism by a short-term mechanism independent of protein synthesis. Here, we report that T2, administered for 1 week to hypothyroid rats, increases total fatty acid synthesis from acetate in isolated hepatocytes. Studies carried out on liver subcellular fractions demonstrated that T2 not only increases the activity and the expression of acetyl-CoA carboxylase and fatty acid synthase but also of other proteins linked to DNL such as the mitochondrial citrate carrier and the cytosolic ATP citrate lyase. Parallelly, T2 stimulates the activities of enzymes supplying cytosolic NADPH needed for the reductive steps of DNL. With respect to both euthyroid and hypothyroid rats, T2 administration decreases the hepatic mRNA level of SREBP-1, a transcription factor which represents a master regulator of DNL. However, when compared to hypothyroid rats T2 significantly increases, without bringing to the euthyroid value, the content of both mature (nSREBP-1), and precursor (pSREBP-1) forms of the SREBP-1 protein as well as their ratio. Moreover, T2 administration strongly augmented the nuclear content of ChREBP, another crucial transcription factor involved in the regulation of lipogenic genes. Based on these results, we can conclude that in the liver of hypothyroid rats the transcriptional activation by T2 of DNL genes could depend, at least in part, on SREBP-1- and ChREBP-dependent mechanisms. © 2019 IUBMB Life, 2019.
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http://dx.doi.org/10.1002/iub.2014DOI Listing
July 2019

A specific lipid metabolic profile is associated with the epithelial mesenchymal transition program.

Biochim Biophys Acta Mol Cell Biol Lipids 2019 03 19;1864(3):344-357. Epub 2018 Dec 19.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy; Laboratory of Clinical Proteomic, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy. Electronic address:

Several studies have identified a specific metabolic program that is associated with the process of epithelial-mesenchymal transition (EMT). Whereas much is known about the association between glucose metabolism and EMT, the contribution of lipid metabolism is not still completely understood. Here, we studied epithelial and mesenchymal breast cancer cells by proteomic and lipidomic approaches and identified significant differences that characterised these models concerning specific metabolic enzymes and metabolites including fatty acids and phospholipids. Higher levels of monounsaturated fatty acids together with increased expression of enzymes of de novo fatty acid synthesis is the distinct signature of epithelial with respect to mesenchymal cells that, on the contrary, show reduced lipogenesis, higher polyunsaturated fatty acids level and increased expression of genes involved in the triacylglycerol (TAG) synthesis and lipid droplets formation. In the mesenchymal model, the diacylglycerol acyltransferase (DGAT)-1 appears to be the major enzyme involved in TAG synthesis and inhibition of DGAT1, but not DGAT2, drastically reduces the incorporation of labeled palmitate into TAG. Moreover, knockdown of β-catenin demonstrated that this metabolic phenotype in under the control of a network of transcriptional factors and that β-catenin has a specific role in the regulation of lipid metabolism in mesenchymal cells.
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http://dx.doi.org/10.1016/j.bbalip.2018.12.011DOI Listing
March 2019

Aberrant Metabolism in Hepatocellular Carcinoma Provides Diagnostic and Therapeutic Opportunities.

Oxid Med Cell Longev 2018 4;2018:7512159. Epub 2018 Nov 4.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.

Hepatocellular carcinoma (HCC) accounts for over 80% of liver cancer cases and is highly malignant, recurrent, drug-resistant, and often diagnosed in the advanced stage. It is clear that early diagnosis and a better understanding of molecular mechanisms contributing to HCC progression is clinically urgent. Metabolic alterations clearly characterize HCC tumors. Numerous clinical parameters currently used to assess liver functions reflect changes in both enzyme activity and metabolites. Indeed, differences in glucose and acetate utilization are used as a valid clinical tool for stratifying patients with HCC. Moreover, increased serum lactate can distinguish HCC from normal subjects, and serum lactate dehydrogenase is used as a prognostic indicator for HCC patients under therapy. Currently, the emerging field of metabolomics that allows metabolite analysis in biological fluids is a powerful method for discovering new biomarkers. Several metabolic targets have been identified by metabolomics approaches, and these could be used as biomarkers in HCC. Moreover, the integration of different omics approaches could provide useful information on the metabolic pathways at the systems level. In this review, we provided an overview of the metabolic characteristics of HCC considering also the reciprocal influences between the metabolism of cancer cells and their microenvironment. Moreover, we also highlighted the interaction between hepatic metabolite production and their serum revelations through metabolomics researches.
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http://dx.doi.org/10.1155/2018/7512159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247426PMC
January 2019

Modulation of the Oxidative Stress and Lipid Peroxidation by Endocannabinoids and Their Lipid Analogues.

Antioxidants (Basel) 2018 Jul 18;7(7). Epub 2018 Jul 18.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy.

Growing evidence supports the pivotal role played by oxidative stress in tissue injury development, thus resulting in several pathologies including cardiovascular, renal, neuropsychiatric, and neurodegenerative disorders, all characterized by an altered oxidative status. Reactive oxygen and nitrogen species and lipid peroxidation-derived reactive aldehydes including acrolein, malondialdehyde, and 4-hydroxy-2-nonenal, among others, are the main responsible for cellular and tissue damages occurring in redox-dependent processes. In this scenario, a link between the endocannabinoid system (ECS) and redox homeostasis impairment appears to be crucial. Anandamide and 2-arachidonoylglycerol, the best characterized endocannabinoids, are able to modulate the activity of several antioxidant enzymes through targeting the cannabinoid receptors type 1 and 2 as well as additional receptors such as the transient receptor potential vanilloid 1, the peroxisome proliferator-activated receptor alpha, and the orphan G protein-coupled receptors 18 and 55. Moreover, the endocannabinoids lipid analogues -acylethanolamines showed to protect cell damage and death from reactive aldehydes-induced oxidative stress by restoring the intracellular oxidants-antioxidants balance. In this review, we will provide a better understanding of the main mechanisms triggered by the cross-talk between the oxidative stress and the ECS, focusing also on the enzymatic and non-enzymatic antioxidants as scavengers of reactive aldehydes and their toxic bioactive adducts.
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http://dx.doi.org/10.3390/antiox7070093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6070960PMC
July 2018

Oxidative Stress in Aging Brain: Nutritional and Pharmacological Interventions for Neurodegenerative Disorders.

Oxid Med Cell Longev 2018;2018:3416028. Epub 2018 Feb 11.

Department of Clinical and Experimental Medicine, University of Foggia, 71100 Foggia, Italy.

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http://dx.doi.org/10.1155/2018/3416028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896401PMC
December 2018

Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease.

J Alzheimers Dis 2017 ;59(2):615-631

Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.

A disruption to circadian rhythmicity and the sleep/wake cycle constitutes a major feature of Alzheimer's disease (AD). The maintenance of circadian rhythmicity is regulated by endogenous clock genes and a number of external Zeitgebers, including light. This study investigated the light induced changes in the expression of clock genes in a triple transgenic model of AD (3×Tg-AD) and their wild type littermates (Non-Tg). Changes in gene expression were evaluated in four brain areas¾suprachiasmatic nucleus (SCN), hippocampus, frontal cortex and brainstem¾of 6- and 18-month-old Non-Tg and 3×Tg-AD mice after 12 h exposure to light or darkness. Light exposure exerted significant effects on clock gene expression in the SCN, the site of the major circadian pacemaker. These patterns of expression were disrupted in 3×Tg-AD and in 18-month-old compared with 6-month-old Non-Tg mice. In other brain areas, age rather than genotype affected gene expression; the effect of genotype was observed on hippocampal Sirt1 expression, while it modified the expression of genes regulating the negative feedback loop as well as Rorα, Csnk1ɛ and Sirt1 in the brainstem. In conclusion, during the early development of AD, there is a disruption to the normal expression of genes regulating circadian function after exposure to light, particularly in the SCN but also in extra-hypothalamic brain areas supporting circadian regulation, suggesting a severe impairment of functioning of the clock gene pathway. Even though this study did not demonstrate a direct association between these alterations in clock gene expression among brain areas with the cognitive impairments and chrono-disruption that characterize the early onset of AD, our novel results encourage further investigation aimed at testing this hypothesis.
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http://dx.doi.org/10.3233/JAD-160942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5523844PMC
April 2018

Increased intake of energy-dense diet and negative energy balance in a mouse model of chronic psychosocial defeat.

Eur J Nutr 2018 Jun 17;57(4):1485-1498. Epub 2017 Mar 17.

Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, P.le A. Moro, 5, 00185, Roma, Italy.

Purpose: Chronic exposure to stress may represent a risk factor for developing metabolic and eating disorders, mostly driven by the overconsumption of easily accessible energy-dense palatable food, although the mechanisms involved remain still unclear. In this study, we used an ethologically oriented murine model of chronic stress caused by chronic psychosocial defeat (CPD) to investigate the effects of unrestricted access to a palatable high fat diet (HFD) on food intake, body weight, energy homeostasis, and expression of different brain neuropeptides. Our aim was to shed light on the mechanisms responsible for body weight and body composition changes due to chronic social stress.

Methods: In our model of subordinate (defeated), mice (CPD) cohabitated in constant sensory contact with dominants, being forced to interact on daily basis, and were offered ad libitum access either to an HFD or to a control diet (CD). Control mice (of the same strain as CPD mice) were housed in pairs and left unstressed in their home cage (UN). In all these mice, we evaluated body weight, different adipose depots, energy metabolism, caloric intake, and neuropeptide expression.

Results: CPD mice increased the intake of HFD and reduced body weight in the presence of enhanced lipid oxidation. Resting energy expenditure and interscapular brown adipose tissue (iBAT) were increased in CPD mice, whereas epididymal adipose tissue increased only in HFD-fed unstressed mice. Propiomelanocortin mRNA levels in hypothalamic arcuate nucleus increased only in HFD-fed unstressed mice. Oxytocin mRNA levels in the paraventricular nucleus and neuropeptide Y mRNA levels within the arcuate were increased only in CD-fed CPD mice. In the arcuate, CART was increased in HFD-fed UN mice and in CD-fed CPD mice, while HFD intake suppressed CART increase in defeated animals. In the basolateral amygdala, CART expression was increased only in CPD animals on HFD.

Conclusions: CPD appears to uncouple the intake of HFD from energy homeostasis causing higher HFD intake, larger iBAT accumulation, increased energy expenditure and lipid oxidation, and lower body weight. Overall, the present study confirms the notion that the chronic activation of the stress response can be associated with metabolic disorders, altered energy homeostasis, and changes of orexigenic and anorexigenic signaling. These changes might be relevant to better understand the etiology of stress-induced obesity and eating disorders and might represent a valid therapeutic approach for the development of new therapies in this field.
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http://dx.doi.org/10.1007/s00394-017-1434-yDOI Listing
June 2018

Fats for thoughts: An update on brain fatty acid metabolism.

Int J Biochem Cell Biol 2017 03 5;84:40-45. Epub 2017 Jan 5.

Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni, 73100 Lecce, Italy. Electronic address:

Brain fatty acid (FA) metabolism deserves a close attention not only for its energetic aspects but also because FAs and their metabolites/derivatives are able to influence many neural functions, contributing to brain pathologies or representing potential targets for pharmacological and/or nutritional interventions. Glucose is the preferred energy substrate for the brain, whereas the role of FAs is more marginal. In conditions of decreased glucose supply, ketone bodies, mainly formed by FA oxidation, are the alternative main energy source. Ketogenic diets or medium-chain fatty acid supplementations were shown to produce therapeutic effects in several brain pathologies. Moreover, the positive effects exerted on brain functions by short-chain FAs and the consideration that they can be produced by intestinal flora metabolism contributed to the better understanding of the link between "gut-health" and "brain-health". Finally, attention was paid also to the regulatory role of essential polyunsaturated FAs and their derivatives on brain homeostasis.
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http://dx.doi.org/10.1016/j.biocel.2016.12.015DOI Listing
March 2017

Linking lipid peroxidation and neuropsychiatric disorders: focus on 4-hydroxy-2-nonenal.

Free Radic Biol Med 2017 10 4;111:281-293. Epub 2017 Jan 4.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome, Piazzale A. Moro 5, 00185 Roma, Italy.

4-hydroxy-2-nonenal (HNE) is considered to be a strong marker of oxidative stress; the interaction between HNE and cellular proteins leads to the formation of HNE-protein adducts able to alter cellular homeostasis and cause the development of a pathological state. By virtue of its high lipid concentration, oxygen utilization, and the presence of metal ions participating to redox reactions, the brain is highly susceptible to the formation of free radicals and HNE-related compounds. A variety of neuropsychiatric disorders have been associated with elevations of HNE concentration. For example, increased levels of HNE were found in the cortex of bipolar and schizophrenic patients, while HNE plasma concentrations resulted high in patients with major depression. On the same line, high brain concentrations of HNE were found associated with Huntington's inclusions. The incidence of high HNE levels is relevant also in the brain and cerebrospinal fluid of patients suffering from Parkinson's disease. Intriguingly, in this case the increase of HNE was associated with an accumulation of iron in the substantia nigra, a brain region highly affected by the pathology. In the present review we recapitulate the findings supporting the role of HNE in the pathogenesis of different neuropsychiatric disorders to highlight the pathogenic mechanisms ascribed to HNE accumulation. The aim of this review is to offer novel perspectives both for the understanding of etiopathogenetic mechanisms that remain still unclear and for the identification of new useful biological markers. We conclude suggesting that targeting HNE-driven cellular processes may represent a new more efficacious therapeutical intervention.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.12.046DOI Listing
October 2017

The Role of Brain Cholesterol and its Oxidized Products in Alzheimer's Disease.

Curr Alzheimer Res 2016 ;13(2):198-205

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome Address: Piazzale Aldo Moro, 5 - 00185 Rome, Italy.

The human brain is the most cholesterol-rich organ harboring 25% of the total cholesterol pool of the whole body. Cholesterol present in the central nervous system (CNS) comes, almost entirely, from the endogenous synthesis, being circulating cholesterol unable to cross the blood-brain barrier (BBB). Astrocytes seem to be more active than neurons in this process. Neurons mostly depend on cholesterol delivery from nearby cells for axonal regeneration, neurite extension and synaptogenesis. Within the brain, cholesterol is transported by HDL-like lipoproteins associated to apoE which represents the main apolipoprotein in the CNS. Although CNS cholesterol content is largely independent of dietary intake or hepatic synthesis, a relationship between plasma cholesterol level and neurodegenerative disorders, such as Alzheimer's disease (AD), has often been reported. To this regard, alterations of cholesterol metabolism were suggested to be implicated in the etiology of AD and amyloid production in the brain. Therefore a special attention was dedicated to the study of the main factors controlling cholesterol metabolism in the brain. Brain cholesterol levels are tightly controlled: its excessive amount can be reduced through the conversion into the oxidized form of 24-S-hydroxycholesetrol (24-OH-C), which can reach the blood stream. In fact, the BBB is permeable to 24-OH-C as well as to 27-OH-C, another oxidized form of cholesterol mainly synthesized by non- neural cells. In this review, we summarize the main mechanisms regulating cholesterol homeostasis and review the recent advances on the role played by cholesterol and cholesterol oxidized products in AD. Moreover, we delineate possible pharmacological strategies to control AD progression by affecting cholesterol homeostasis.
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http://dx.doi.org/10.2174/1567205012666150921103426DOI Listing
October 2016

Bioenergetics profile of CD4(+) T cells in relapsing remitting multiple sclerosis subjects.

J Biotechnol 2015 May 19;202:31-9. Epub 2015 Feb 19.

Department of Biological and Environmental Sciences and Technologies, University of Salento, via Monteroni, Lecce, Italy. Electronic address:

Multiple sclerosis (MS) is a chronic inflammatory autoimmune demyelinating disease of the central nervous system. There are four clinical forms of MS, the most common of which is characterized by a relapsing remitting course (RRMS). The etiology of MS is unknown, but many studies suggested that genetic, environmental and infectious agents may contribute to the development of this disease. In experimental autoimmune encephalomyelitis (EAE), the animal model for MS, it has been shown that CD4(+) T cells play a key role in MS pathogenesis. In fact, these cells are able to cross the blood-brain barrier and cause axonal damage with neuronal death. T cell activation critically depends on mitochondrial ATP synthesis and reactive oxygen species (ROS) production. Interestingly, lots of studies linked the oxidative damage arising from mitochondrial changes to neurodegenerative disorders, such as MS. Based on these evidences, this work focused on the metabolic reprogramming of CD4(+) T cells in MS subjects, being this cell population directly implicated in pathogenesis of disease, paying attention to mitochondrial function and response to oxidative stress. Such aspects, once clarified, may open new opportunities for a therapeutic metabolic modulation of MS disorder.
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http://dx.doi.org/10.1016/j.jbiotec.2015.02.015DOI Listing
May 2015

Proteomics analysis of E-cadherin knockdown in epithelial breast cancer cells.

J Biotechnol 2015 May 4;202:3-11. Epub 2014 Nov 4.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Monteroni, Lecce, Italy; Laboratory of Clinical Proteomic, "Giovanni Paolo II" Hospital, ASL-Lecce, Italy. Electronic address:

E-cadherin is the core protein of the epithelial adherens junction. Through its cytoplasmic domain, E-cadherin interacts with several signaling proteins; among them, α- and β-catenins mediate the link of E-cadherin to the actin cytoskeleton. Loss of E-cadherin expression is a crucial step of epithelial-mesenchymal transition (EMT) and is involved in cancer invasion and metastatization. In human tumors, down-regulation of E-cadherin is frequently associated with poor prognosis. Despite the critical role of E-cadherin in cancer progression, little is known about proteome alterations linked with its down-regulation. To address this point, we investigated proteomics, biophysical and functional changes of epithelial breast cancer cell lines upon shRNA-mediated stable knockdown of E-cadherin expression (shEcad). shEcad cells showed a distinct proteomic signature including altered expression of enzymes and proteins involved in cytoskeletal dynamic and migration. Moreover, these results suggest that, besides their role in mechanical adhesion, loss of E-cadherin expression may contribute to cancer progression by modifying a complex network of pathways that tightly regulate fundamental processes as oxidative stress, immune evasion and cell metabolism. Altogether, these results extend our knowledge on the cellular modifications associated with E-cadherin down-regulation in breast cancer cells.
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http://dx.doi.org/10.1016/j.jbiotec.2014.10.034DOI Listing
May 2015

Silybin exerts antioxidant effects and induces mitochondrial biogenesis in liver of rat with secondary biliary cirrhosis.

Free Radic Biol Med 2014 Aug 9;73:117-26. Epub 2014 May 9.

Centro CURE, Institute of Internal Medicine, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy. Electronic address:

The accumulation of toxic hydrophobic bile acids in hepatocytes, observed during chronic cholestasis, induces substantial modification in the redox state and in mitochondrial functions. Recent reports have suggested a significant role of impaired lipid metabolism in the progression of chronic cholestasis. In this work we report that changes observed in the expression of the lipogenic enzymes acetyl-CoA carboxylase and fatty acid synthase were associated with a decrease in the activity of citrate carrier (CIC), a protein of the inner mitochondrial membrane closely related to hepatic lipogenesis. We also verified that the impairment of citrate transport was dependent on modification of the phospholipid composition of the mitochondrial membrane and on cardiolipin oxidation. Silybin, an extract of silymarin with antioxidant and anti-inflammatory properties, prevented mitochondrial reactive oxygen species (ROS) production, cardiolipin oxidation, and CIC failure in cirrhotic livers but did not affect the expression of lipogenic enzymes. Moreover, supplementation of silybin was also associated with mitochondrial biogenesis. In conclusion, we demonstrate that chronic cholestasis induces cardiolipin oxidation that in turn impairs mitochondrial function and further promotes ROS production. The capacity of silybin to limit mitochondrial failure is part of its hepatoprotective property.
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http://dx.doi.org/10.1016/j.freeradbiomed.2014.05.002DOI Listing
August 2014

Down-regulation of LPCAT expression increases platelet-activating factor level in cirrhotic rat liver: potential antiinflammatory effect of silybin.

Biochim Biophys Acta 2013 Dec 12;1832(12):2019-26. Epub 2013 Jul 12.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.

Cholestasis is one of the major causes of liver diseases. A chronic accumulation of toxic bile acids in the liver, which occurs in this condition, can induce fibrosis and cirrhosis. Inflammation is a fundamental component of acute and chronic cholestatic liver injury. Platelet-activating factor (PAF) is a proinflammatory lipid which may be generated by two independent pathways called the de novo and remodeling pathway being the last responsible for the synthesis of PAF during inflammation. In recent years a key role in PAF remodeling has been attributed to lysophosphatidylcholine acyltransferase (LPCAT) enzymes. Although the knowledge on their characteristic is growing, the exact mechanism of LPCAT in pathological conditions remains still unknown. Here, we reported that the level of lyso-PAF and PAF significantly increased in the liver of cirrhotic vs. control rats together with a significant decrease in both mRNA abundance and protein level of both LPCAT1 and LPCAT2. Acyltransferase activities of both LPCAT1 and LPCAT2 were parallel decreased in the liver of cirrhotic animals. Interestingly, treatment with silybin strongly decreased the level of both pro-inflammatory lipids and restored the activity and expression of both LPCAT1 and LPCAT2 of cirrhotic liver. Silybin effect was specific for LPCAT1 and LPCAT2 since it did not affect LPCAT3 mRNA abundance of cirrhotic liver.
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http://dx.doi.org/10.1016/j.bbadis.2013.07.005DOI Listing
December 2013

Low level of hydrogen peroxide induces lipid synthesis in BRL-3A cells through a CAP-independent SREBP-1a activation.

Int J Biochem Cell Biol 2013 Jul 10;45(7):1419-26. Epub 2013 Apr 10.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.

Although H2O2 is traditionally known to have cytotoxic effects, recent studies argue about its regulatory role on lipid metabolism. However, the mechanism underlying the induction of lipid biosynthesis by oxidative stress still remains unknown. To shed light on this aspect we investigated the H2O2-induced lipogenesis in rat liver BRL-3A cells. We found that a short-term exposition of cells to 35μM H2O2 didn't cause any significant sign of cell damage measured by following diene formation and lactate dehydrogenase release from cells. However, in this stressful condition, a significant increase of [1-(14)C]acetate incorporation into fatty acids and cholesterol, associated to an increase in the activity and expression of key enzymes of fatty acid and cholesterol synthesis, were measured. mRNA and protein contents of the transcription factors SREBP-1 and SREBP-2, involved in the activation of lipid synthesis, increased as well. The analysis of molecular mechanism of SREBP-1 activation revealed, in treated compared to control cells, a higher SREBP-1a mRNA translation involving an internal ribosome entry side (IRES), present in the leader region of its mRNA. Longer exposition to the pro-oxidant induced a progressive loss of cell viability together with an increase of cell triacylglycerol content.
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http://dx.doi.org/10.1016/j.biocel.2013.04.004DOI Listing
July 2013

Many faces of mitochondrial uncoupling during age: damage or defense?

J Gerontol A Biol Sci Med Sci 2013 Aug 4;68(8):892-902. Epub 2013 Jan 4.

Dipartimento di Scienze Mediche e Chirurgiche, Università di Foggia 71122, Foggia, Italy.

An increased mitochondrial proton leak occurs in aging, but the origin of such modification remains unclear. This study defined the cause of mitochondrial uncoupling in mitotic (liver) and postmitotic (heart) rat tissues during aging and its effects on energy homeostasis and free radical production. Proton leak in old heart mitochondria was dependent on uncoupling proteins' upregulation, whereas it was caused by alterations in the mitochondrial membrane composition in old liver. ATP homeostasis was impaired in both tissues from old animals and was associated to disrupted F0F1-ATPase activity. H2O2 production rate and 4-hydroxy-2-nonenalprotein adducts were higher in old liver mitochondria compared with young liver mitochondria, but they were similar in heart mitochondria from both groups. Moreover, key mitochondrial biogenesis regulators were upregulated in old liver but downregulated in old heart. In conclusion, uncoupling proteins mediate proton leak and avoid oxidative damage in heart, acting as a protective mechanism. This does not occur in liver, where ATP depletion and oxidative stress may stimulate mitochondrial biogenesis and eliminate damaged cells.
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http://dx.doi.org/10.1093/gerona/gls332DOI Listing
August 2013

Beneficial effects of n-3 PUFA on chronic airway inflammatory diseases.

Prostaglandins Other Lipid Mediat 2012 Dec 11;99(3-4):57-67. Epub 2012 Oct 11.

Laboratory of Biochemistry and Molecular Biology, Department of Biological and Environmental Sciences and Technologies, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy.

Chronic airway inflammation is a common symptom of several diseases such as asthma, chronic obstructive pulmonary disease (COPD), and cystic fibrosis. Excessive or inappropriate immune system activity and/or failure to resolve an acute inflammation spontaneously can induce functional changes in the walls and parenchyma of the airways. Continuous recruitment of inflammatory cells to the site of inflammation and the production of protein (i.e., cytokines, chemokines, enzymes, etc.) and lipid (eicosanoids) pro-inflammatory mediators contribute directly or indirectly to changes in airway structure and function. Pro-inflammatory eicosanoids are mainly formed by the metabolism of arachidonic acid, an n-6 polyunsaturated fatty acid esterified at the s-n2 position of membrane phospholipids. Unlike n-6 polyunsaturated fatty acids (PUFA), n-3 PUFA decrease inflammation. The anti-inflammatory effect of n-3 PUFA derives from their ability to compete with arachidonic acid in the production of eicosanoids, thereby decreasing the production of pro-inflammatory cytokines and reducing immune cell functions. Moreover, n-3 PUFA can give rise to a series of pro-resolving mediators with anti-inflammatory actions, such as resolvins and protectins. While most studies have reported n-3 PUFA to have beneficial effects on chronic airway diseases, some have questioned the anti-inflammatory effects of n-3 PUFA in inflammatory airway diseases. This paper summarizes the main mechanisms by which n-3 PUFA exert anti-inflammatory and pro-resolving effects, focusing on their use in airway disorders with an inflammatory component.
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http://dx.doi.org/10.1016/j.prostaglandins.2012.09.006DOI Listing
December 2012

A krill oil supplemented diet suppresses hepatic steatosis in high-fat fed rats.

PLoS One 2012 7;7(6):e38797. Epub 2012 Jun 7.

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce, Italy.

Krill oil (KO) is a dietary source of n-3 polyunsaturated fatty acids, mainly represented by eicosapentaenoic acid and docosahexaenoic acid bound to phospholipids. The supplementation of a high-fat diet with 2.5% KO efficiently prevented triglyceride and cholesterol accumulation in liver of treated rats. This effect was accompanied by a parallel reduction of the plasma levels of triglycerides and glucose and by the prevention of a plasma insulin increase. The investigation of the molecular mechanisms of KO action in high-fat fed animals revealed a strong decrease in the activities of the mitochondrial citrate carrier and of the cytosolic acetyl-CoA carboxylase and fatty acid synthetase, which are both involved in hepatic de novo lipogenesis. In these animals a significant increase in the activity of carnitine palmitoyl-transferase I and in the levels of carnitine was also observed, suggesting a concomitant stimulation of hepatic fatty acid oxidation. The KO supplemented animals also retained an efficient mitochondrial oxidative phosphorylation, most probably as a consequence of a KO-induced arrest of the uncoupling effects of a high-fat diet. Lastly, the KO supplementation prevented an increase in body weight, as well as oxidative damage of lipids and proteins, which is often found in high-fat fed animals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038797PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3369862PMC
December 2012

Mitochondrial oxidative stress and respiratory chain dysfunction account for liver toxicity during amiodarone but not dronedarone administration.

Free Radic Biol Med 2011 Dec 17;51(12):2234-42. Epub 2011 Sep 17.

CURE Center for Liver Disease Research and Treatment, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, 71122 Foggia, Italy.

The role played by oxidative stress in amiodarone-induced mitochondrial toxicity is debated. Dronedarone shows pharmacological properties similar to those of amiodarone but several differences in terms of toxicity. In this study, we analyzed the effects of the two drugs on liver mitochondrial function by administering an equivalent human dose to a rat model. Amiodarone increased mitochondrial H(2)O(2) synthesis, which in turn induced cardiolipin peroxidation. Moreover, amiodarone inhibited Complex I activity and uncoupled oxidative phosphorylation, leading to a reduction in the hepatic ATP content. We also observed a modification of membrane phospholipid composition after amiodarone administration. N-acetylcysteine completely prevented such effects. Although dronedarone shares with amiodarone the capacity to induce uncoupling of oxidative phosphorylation, it did not show any of the oxidative effects and did not impair mitochondrial bioenergetics. Our data provide important insights into the mechanism of mitochondrial toxicity induced by amiodarone. These results may greatly influence the clinical application and toxicity management of these two antiarrhythmic drugs.
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http://dx.doi.org/10.1016/j.freeradbiomed.2011.09.004DOI Listing
December 2011

A silybin-phospholipid complex prevents mitochondrial dysfunction in a rodent model of nonalcoholic steatohepatitis.

J Pharmacol Exp Ther 2010 Mar 11;332(3):922-32. Epub 2009 Dec 11.

Centre for the Study of Liver Diseases, Institute of Internal Medicine, Department of Medical and Occupational Sciences, University of Foggia, Foggia, Italy.

Mitochondrial dysfunction and oxidative stress are determinant events in the pathogenesis of nonalcoholic steatohepatitis. Silybin has shown antioxidant, anti-inflammatory, and antifibrotic effects in chronic liver disease. We aimed to study the effect of the silybin-phospholipid complex (SILIPHOS) on liver redox balance and mitochondrial function in a dietary model of nonalcoholic steatohepatitis. To accomplish this, glutathione oxidation, mitochondrial oxygen uptake, proton leak, ATP homeostasis, and H(2)O(2) production rate were evaluated in isolated liver mitochondria from rats fed a methionine- and choline-deficient (MCD) diet and the MCD diet plus SILIPHOS for 7 and 14 weeks. Oxidative proteins, hydroxynonenal (HNE)- and malondialdehyde (MDA)-protein adducts, and mitochondrial membrane lipid composition were also measured. Treatment with SILIPHOS limited glutathione depletion and mitochondrial H(2)O(2) production. Moreover, SILIPHOS preserved mitochondrial bioenergetics and prevented mitochondrial proton leak and ATP reduction. Finally, SILIPHOS limited the formation of HNE- and MDA-protein adducts. In conclusion, SILIPHOS is effective in preventing severe oxidative stress and preserving hepatic mitochondrial bioenergetics in nonalcoholic steatohepatitis induced by the MCD diet. The modifications of mitochondrial membrane fatty acid composition induced by the MCD diet are partially prevented by SILIPHOS, conferring anti-inflammatory and antifibrotic effects. The increased vulnerability of lipid membranes to oxidative damage is limited by SILIPHOS through preserved mitochondrial function.
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http://dx.doi.org/10.1124/jpet.109.161612DOI Listing
March 2010

Different dietary fatty acids have dissimilar effects on activity and gene expression of mitochondrial tricarboxylate carrier in rat liver.

FEBS Lett 2004 Dec;578(3):280-4

Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Laboratorio di Biochimica, Università di Lecce, Via Prov. le Lecce-Monteroni, I-73100 Lecce, Italy.

The tricarboxylate carrier (TCC), an integral protein of the mitochondrial inner membrane, transports mitochondrial acetyl-CoA into the cytosol, where lipogenesis occurs. We investigated in rat liver mitochondria the effect of diets enriched with saturated fatty acids (beef tallow, BT), monounsaturated fatty acids (olive oil, OO) or n-3 polyunsaturated fatty acids (fish oil, FO), respectively, on the activity and expression of TCC. TCC activity decreased, in parallel with TCC mRNA abundance, only upon FO-feeding. The TCC transcription rate, mRNA turnover and RNA processing indicated that FO administration regulates TCC gene at transcriptional and post-transcriptional steps, whereas BT- and OO-feeding do not seem to affect either TCC activity or gene expression.
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http://dx.doi.org/10.1016/j.febslet.2004.11.014DOI Listing
December 2004

Differential effects of coconut oil- and fish oil-enriched diets on tricarboxylate carrier in rat liver mitochondria.

J Lipid Res 2003 Nov 16;44(11):2135-41. Epub 2003 Aug 16.

Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Laboratorio di Biochimica, Università di Lecce, Via Prov.le Lecce-Monteroni, I-73100 Lecce, Italy.

The mitochondrial tricarboxylate carrier (TCC) plays an important role in lipogenesis being TCC-responsible for the efflux from the mitochondria to the cytosol of acetyl-CoA, the primer for fatty acid synthesis. In this study, we investigated the effects of two high-fat diets with different fatty acid composition on the hepatic TCC activity. Rats were fed for 3 weeks on a basal diet supplemented with 15% of either coconut oil (CO), abundant in medium-chain saturated fatty acids, or fish oil (FO), rich in n-3 polyunsaturated fatty acids. Mitochondrial fatty acid composition was differently influenced by the dietary treatments, while no appreciable change in phospholipid composition and cholesterol level was observed. Compared with CO, the TCC activity was markedly decreased in liver mitochondria from FO-fed rats; kinetic analysis of the carrier revealed a decrease of the Vmax, with no change of the Km. No difference in the Arrhenius plot between the two groups was observed. Interestingly, the carrier protein level and the corresponding mRNA abundance decreased following FO treatment. These data indicate that FO administration markedly decreased the TCC activity as compared with CO. This effect is most likely due to a reduced gene expression of the carrier protein.
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http://dx.doi.org/10.1194/jlr.M300237-JLR200DOI Listing
November 2003

Starvation-induced posttranscriptional control of rat liver mitochondrial citrate carrier expression.

Biochem Biophys Res Commun 2002 Dec;299(3):418-23

Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Laboratorio di Biochimica, Università di Lecce, Via Prov. Lecce-Monteroni, Lecce, Italy.

Starvation has been associated with a reduced citrate carrier (CTP) activity in rat liver mitochondria. In the present study the molecular mechanism responsible for this reduction was investigated. Northern blot analysis performed with hepatic total RNA showed a decrease of about 40% in the CTP mRNA abundance in starved rats, when compared to fed animals. Nuclear run-on assay did not reveal any appreciable difference in the rate of CTP mRNA synthesis between the two groups of animals, while the apparent half-life of CTP mRNA in hepatocytes from fed and starved rats was 11 and 6h, respectively. Therefore, these results suggest that in starved rats the regulation of hepatic CTP expression occurs at posttranscriptional level. Moreover, the reduced CTP activity in starved animals gradually increased by refeeding. The carrier activity reached fed rat values 6-9h following refeeding. Interestingly, the accumulation of CTP mRNA raised in parallel with the transport activity.
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http://dx.doi.org/10.1016/s0006-291x(02)02666-9DOI Listing
December 2002