Publications by authors named "Elisabetta Casalino"

16 Publications

  • Page 1 of 1

Bioisosteric Modification of To042: Synthesis and Evaluation of Promising Use-Dependent Inhibitors of Voltage-Gated Sodium Channels.

ChemMedChem 2021 Sep 14. Epub 2021 Sep 14.

Department of Pharmacy - Pharmaceutical Sciences, University of Bari Aldo Moro, via E. Orabona 4, 70125, Bari, Italy.

Three analogues of To042, a tocainide-related lead compound recently reported for the treatment of myotonia, were synthesized and evaluated in vitro as skeletal muscle sodium channel blockers possibly endowed with enhanced use-dependent behavior. Patch-clamp experiments on hNav1.4 expressed in HEK293 cells showed that N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine, the aryloxyalkyl bioisostere of To042, exerted a higher use-dependent block than To042 thus being able to preferentially block the channels in over-excited membranes while preserving healthy tissue function. It also showed the lowest active transport across BBB according to the results of P-glycoprotein (P-gp) interacting activity evaluation and the highest cytoprotective effect on HeLa cells. Quantum mechanical calculations and dockings gave insights on the most probable conformation of the aryloxyalkyl bioisostere of To042 in solution and the target residues involved in the binding, respectively. Both approaches indicated the conformations that might be adopted in both the unbound and bound state of the ligand. Overall, N-[(naphthalen-1-yl)methyl]-4-[(2,6-dimethyl)phenoxy]butan-2-amine exhibits an interesting toxico-pharmacological profile and deserves further investigation.
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http://dx.doi.org/10.1002/cmdc.202100496DOI Listing
September 2021

A Multi-Biomarker Approach in European Sea Bass Exposed to Dynamic Temperature Changes under Dietary Supplementation with Essential Oil.

Animals (Basel) 2021 Apr 1;11(4). Epub 2021 Apr 1.

Department of Veterinary Medicine, University of Bari Aldo Moro, Casamassima km 3, 70010 Valenzano, Italy.

A feeding trial for 150 days was carried out to evaluate the cross-effects between oregano essential oil (EO) dietary supplementation and dynamic temperature change in sea bass. Under exposure to rising temperature (13-25 °C), fish were fed with a control diet (CD) and two experimental diets supplemented with 100 (D100) and 200 ppm (D200) of EO. Feed inclusion of EO promoted the activity of antioxidant enzymes in sea bass exposed to increasing temperature. Consistently with the temperature rise, TBARS concentrations increased in CD and D200 groups, whereas were almost stable in D100. Trend of blood glucose in fish fed on CD was likely affected by glycogenolysis and gluconeogenesis. Similarly, the depletion of triglycerides and cholesterol in fish fed on CD likely supported the energy cost of gluconeogenesis. On the other hand, the reduction of glucose, triglycerides, and cholesterol in D100 and D200 was mainly attributable to the hypoglycemic and hypolipidemic effects of EO. The higher levels of serum protein observed in D100 and D200 groups were also associated to a reduced thermal stress compared to CD. EO dietary supplementation may be a promising strategy to alleviate the negative effects of temperature shift on sea bass physiological and oxidative state.
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http://dx.doi.org/10.3390/ani11040982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8066705PMC
April 2021

Comparison of Mineral, Metabolic, and Oxidative Profile of Saanen Goat during Lactation with Different Mediterranean Breed Clusters under the Same Environmental Conditions.

Animals (Basel) 2020 Mar 4;10(3). Epub 2020 Mar 4.

Department of Veterinary Medicine, University of Bari Aldo Moro, Casamassima km 3, 70010 Valenzano, Italy.

This study aimed to describe metabolic, oxidative, and mineral blood profiles of Saanen does through lactation compared with Mediterranean breed clusters (Maltese and Rossa Mediterranea, and Jonica, Garganica, and Girgentana). Milk and blood samples of 57 dairy goats (9-10 goats per breed) were collected from the 2nd to the 30th week of lactation every 2-3 weeks. Saanen showed greater milk yield and somatic cell score, and lower fat and protein percentage through lactation ( < 0.05) than the Mediterranean breed clusters. Blood analysis revealed that stage of lactation had a greater impact than breed cluster, except for uric acid, alkaline phosphatase, and aspartate aminotransferase. Plasmatic non-esterified fatty acids indicated a greater negative energy balance in Saanen than the other breed clusters during early and medium lactation stages ( < 0.05). Serum Cl, Mg, and Ca increased in all the breed clusters from early to the following stages of lactation ( < 0.05). No significant prooxidant/antioxidant imbalances were detected in any of the three clusters during the entire lactation. In conclusion, Mediterranean breeds tended to recover earlier from negative energy balance than Saanen, but effects of breed or stage of lactation on long-term oxidative stress indicators were not evident.
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http://dx.doi.org/10.3390/ani10030432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175111PMC
March 2020

Survey of biochemical and oxidative profile in donkey foals suckled with one natural and one semi-artificial technique.

PLoS One 2018 6;13(6):e0198774. Epub 2018 Jun 6.

Department of Veterinary Medicine, University "A. Moro" of Bari, Valenzano, Bari, Italy.

Dairy donkey milking procedures require separating foals from their dams for a few hours a day. Artificial suckling in this species is a good technique for improving milk production and foal welfare. The aim of the work is to compare the effect of two different diets on donkey foals when separated from jennies for milking procedures with and without a milk replacer. Forty newborn Martina Franca donkey foals were subdivided into two experimental groups. Both groups were separated from their respective dams from 8.00to 20.00to allow the jennies to be milked. During the separation, all the foals had access ad libitum to water, hay and feed. During the separation period, one group had the availability of a mechanical milk replacer dispenser, so foals were partially artificially suckled (AS), while the other group had no milk replacer available, and so were totally naturally suckled (NS). The AS group had milk replacer availability until 120±7d of life. Both groups were naturally weaned at 168±7d. Blood samples were collected weekly starting from birth until two wks after weaning (i.e. at 182d), from all the foals included in the trial. Almost all the analytes were influenced by suckling technique and age of foals. Alanine-aminotransferase, aspartate-aminotransferase, alkaline phosphatase, NEFA, lipid hydroperoxides, serum proteins showed the greatest differences between the two experimental groups. Separating foals from their dams for 12hdaily for 24 weeks does not lead to pathological subclinical and metabolic conditions, thus confirming the high rusticity and resistance of the donkey.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0198774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5991377PMC
January 2019

Dietary Phenolic Compounds: Biochemistry, Metabolism and Significance in Animal and Human Health.

Curr Drug Metab 2017 ;18(10):905-913

Department of Emergency and Organ Transplantation (DETO), Section of Veterinary Science and Animal Production, University of Study of Bari 'Aldo Moro', Valenzano 70010 BA. Italy.

Background: Polyphenols are plant secondary metabolites present in the human and animal diet, and numerous studies have demonstrated the beneficial effects of polyphenol-rich ingredients.

Methods: To date, the research for natural antioxidants as alternative to synthetic products is of great interest among scientists. The present review emphasizes the importance of knowing the content and the quality of phenolic compounds present in natural ingredients.

Results: The aim of the present review is also a critical analysis of achievements related to polyphenols action in livestock production with a particular emphasis on their antioxidant-related properties both in vitro and in vivo. Moreover, this paper includes information related to the relationships between dietary consumption of polyphenols and risk of disease occurrence in both animal and human.

Conclusion: From the current scientific understanding, polyphenolic compounds offer significant expectation for health promotion.
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http://dx.doi.org/10.2174/1389200218666170925124004DOI Listing
September 2018

Enhancement of the antiviral activity against caprine herpesvirus type 1 of Acyclovir in association with Mizoribine.

Res Vet Sci 2017 Apr 16;111:120-123. Epub 2017 Feb 16.

Department of Veterinary Medicine, University of Bari, Valenzano, Bari, Italy. Electronic address:

Caprine herpesvirus 1 (CpHV-1) infection in goats is responsible for genital lesions resembling the lesions induced by herpesvirus 2 in humans (HHV-2). The immunosuppressive drug Mizoribine (MIZ) is able to increase the antiviral activity of Acyclovir (ACV) against herpesvirus infections, raising interesting perspectives on new combined therapeutic strategies. In this study the anti-CpHV-1 activity in vitro of ACV alone or in combination with MIZ was evaluated. ACV (100μg/ml) displayed an antiviral effect on CpHV-1 replication. This inhibitory effect was higher when ACV (100μg/ml) was used in association with MIZ (20μg/ml). Other combinations of ACV and MIZ in various concentrations were not as effective as ACV 100μg/ml/MIZ 20μg/ml. These findings suggest that the association of ACV and MIZ is potentially useful for treatment of genital infection by herpesviruses.
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http://dx.doi.org/10.1016/j.rvsc.2017.02.012DOI Listing
April 2017

An extra-virgin olive oil rich in polyphenolic compounds has antioxidant effects in meat-type broiler chickens.

Environ Sci Pollut Res Int 2016 Apr 26;23(7):6197-204. Epub 2015 Nov 26.

Department of Veterinary Medicine, University of Bari 'Aldo Moro', Valenzano, 70010, Bari, Italy.

The aim of this study was to extend the knowledge on the antioxidant effect of extra-virgin olive oil (EVOO) in the liver of broiler chickens not subjected to any form of insult. A total of 120 male broiler chickens (Hubbard strain) were divided into three groups and fed ad libitum with three isoenergetic diets from hatching until slaughter age (49 days) on a completely randomized design. The dietary treatments consisted of 2.5% added oil or fat from three sources as follows: diet containing sunflower oil (SFO); diet containing lard (LRD), and diet containing extra-virgin olive oil (EVOO). The activity of the main antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GS-Px) and glutathione S-transferase (GST), and lipid peroxidation as thiobarbituric acid-reactive substances (TBARS) content, was measured in the liver of chickens. The susceptibility to undergo lipid peroxidation was assessed by exposing liver homogenate to 30 °C or to an ascorbate/iron mixture as pro-oxidant system. Dietary oil or fat type improved significantly (P < 0.05) the body weight and gain as well as feed efficiency in birds fed EVOO compared to those fed with the other treatments. Supplementing EVOO in the diet significantly (P < 0.05) reduced lipid peroxidation by increasing antioxidant defense system. These findings, besides adding more results on the antioxidant effect of extra-virgin olive oil on liver of other experimental model other than rats and humans, could be significant for animal welfare, with consequent benefits for both producers and consumers.
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http://dx.doi.org/10.1007/s11356-015-5852-1DOI Listing
April 2016

Genotoxic damage of benzo[a]pyrene in cultured sea bream (Sparus aurata L.) hepatocytes: harmful effects of chronic exposure.

Mar Environ Res 2014 Sep 18;100:74-85. Epub 2014 Apr 18.

Unit of Pharmacology and Toxicology, Department of Veterinary Medicine, University of Bari "Aldo Moro", Italy.

The large majority of studies on the genotoxic hazard of PAHs polluted water widely applied the ENA assay as versatile tool in large number of wild and farmed aquatic species. Nuclear abnormalities are commonly considered to be a direct consequence of genotoxic lesions in DNA macromolecule, and such evaluation might be helpful in identifying the genotoxic damage induced by the most harmful PAHs such as B[a]P. Regarding at the fish species subjected to aquaculture, most of the toxicological data come from wild fish and mainly focus on freshwater fish, but very little is known for other marine major aquacultured species. The gilthead sea bream (Sparus aurata L.) is the most economically important sparid species cultured along the Mediterranean costs, and it has been proved a very sensitive species to acute B[a]P exposure. However, further investigation is needed on several other types of genotoxic assessments, especially for chronic effects. This work was totally based on an in vitro model for chronic toxicity, using long-term S. aurata hepatocytes in primary culture, continuously exposed to low levels of BaP, over a prolonged period of time, to provide evidences for latent toxicity response. We aimed to investigate the kind of nuclear damage in gilthead sea bream hepatocytes continuously exposed to B[a]P sublethal doses. Cells were exposed to several B[a]P concentrations (10 μg/mL, 1 μg/mL, 1 ng/mL, 1 pg/mL) for two exposure times (24 and 72 h), and then tested both for apoptosis induction and for nuclear abnormalities by immunofluorescence analysis. The presence of severe nuclear damage, revealed cells progressing towards abnormal genotypes, due to a series of aberrant mitosis followed by unequal distribution of chromosomal content. The nuclear atypia (NA) more frequently observed were: a) micronuclei (MN); b) nuclear buds or blebs (NBUDs); c) notched nuclei; d) lobed nuclei; e) nuclei with nucleoplasmic bridge (NPBs); f) nuclei squashed, with a residual nuclear membrane; g) open nuclei, with membrane tape unrolled; and h) apoptotic bodies. Our results showed at medium-low doses a sustained genotoxic response, whose potency increased with the exposure time, becoming apparent as apoptosis induction, both by cell surface and nuclear changes. At the lowest doses, the longer was B[a]P exposure, greater was the involvement on masses of replicating cells, establishing the connection between the escape from apoptosis and the selection of tumoral cell evolution. In view of these results, there is no evidence of a threshold dose below which B[a]P was found not to be genotoxic in sea bream cultured hepatocytes.
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http://dx.doi.org/10.1016/j.marenvres.2014.04.003DOI Listing
September 2014

Antioxidant role of hydroxytyrosol on oxidative stress in cadmium-intoxicated rats: different effect in spleen and testes.

Drug Chem Toxicol 2014 Oct 20;37(4):420-6. Epub 2014 Jan 20.

Department of Veterinary Medicine, University of Bari "Aldo Moro" , Str. Prov. per Casamassima km 3 , Valenzano, Italy .

Hydroxytyrosol (2-(3,4dihydroxyphenyl)ethanol, (DPE), a phenolic compound present in olive oil, is known to have antioxidant properties. The aim of this study was to investigate the effect of DPE on oxidative stress induced by cadmium injections (CdCl2 2.5 mg/kg body weight) in spleen and testes of adult male rats. Oxidative stress was evaluated by measuring lipid peroxidation by thiobarbituric acid reactive substances (TBARS) as well as superoxide dismutase (SOD) and catalase (CAT) activities in cytosol and mitochondria. We found that in spleen no TBARS formation was detected following CdCl2 injections; however, DPE induces decrease in TBARS level in treated and untreated rats. On the contrary, we observed that DPE showed no effect on cadmium-induced lipid peroxidation in testes. Cytosolic activities of SOD and CAT decreased significantly only in spleen, where DPE restores the values to the control levels. Noteworthy, mitochondrial activities of SOD and CAT were strongly reduced by cadmium treatment both in spleen and testes, and DPE was not be able to restore their activity. Overall, the results from this study indicated that the DPE has different antioxidant efficiency in spleen and testis of cadmium intoxicated rats.
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http://dx.doi.org/10.3109/01480545.2013.878950DOI Listing
October 2014

Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases.

Toxicol Sci 2013 Sep 28;135(1):218-28. Epub 2013 Jun 28.

Department of Biosciences, Biotechnology and Biopharmaceutics, University of Bari, 70126 Bari, Italy.

Manganese (Mn) is an environmental contaminant and its overexposure contributes to the pathophysiological processes of numerous disorders of the central nervous system in humans with mechanisms of action not completely understood. Activation of astrocytes and the subsequent release of neurotoxic factors have been implicated to contribute to neurodegeneration. Here, we assessed the molecular basis of the effects of Mn on modulation of matrix metalloproteinases-2 (MMP-2) and -9 (MMP-9) in rat astrocyte cultures. Primary cultures of rat astrocytes were exposed to different doses of MnCl2. Culture supernatants and cell lysates were used for the detection of MMP-2 and MMP-9 levels and mRNA expression, respectively. The exposure of astrocytes to MnCl2 induced the levels and expression of MMP-9 in a dose-dependent manner. The addition of resveratrol (RSV) inhibited both levels and expression of MMP-9 in astrocytes, whereas N-acetylcysteine (NAC) and quercetin (QRC) were ineffective in inhibiting MMP-9. As a possible mechanism of Mn-induced MMP-9, we determined intracellular redox state in Mn-treated astrocytes by assessing superoxide dismutase (SOD) activity and intracellular reactive oxygen species (ROS) and found a significant increase of ROS and a decrease of SOD activity. RSV, NAC, and QRC restored the redox state. The study of the mitogen-activated protein kinase signaling pathway demonstrated that MMP-9 transcription is mainly regulated by extracellular-regulated protein kinases (ERK). Pretreatment with RSV significantly reduced ERK activation suggesting that its ability to counteract MMP-9 overexpression is due not only to a general redox balance phenomenon but also to the modulation of ERK signaling pathway.
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http://dx.doi.org/10.1093/toxsci/kft146DOI Listing
September 2013

Effects of dietary yeast Saccaromyces cerevisiae on the antioxidant system in the liver of juvenile sea bass Dicentrarchus labrax.

Fish Physiol Biochem 2012 Oct 8;38(5):1497-505. Epub 2012 Apr 8.

Division of Aquaculture, Department of Public Health and Animal Science, University of Bari, Str. Prov. per Casamassima km 3, 70010, Valenzano, Italy.

The main goal of this work was to determine the effect of dietary live yeast Saccharomyces cerevisiae on the oxidative status of sea bass Dicentrarchus labrax juveniles. Fishes were fed on three diets: the GM group were fed a diet containing lyophilized yeast grown on grape must, the CS group were fed a diet containing lyophilized yeast grown on cornstarch, and the control group were fed a diet without yeast. The activity of the main antioxidative enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase, glutathione S-transferase (GST), and glutathione (GSH) content, as well as lipid peroxidation, was measured in the liver of sea bass juveniles 90 days after hatching. Supplementation of the diet with S. cerevisiae significantly reduced the SOD and CAT activity, increased the GST activity, decreased the GSH content, and had no effect on lipid peroxidation. The results support the already reported radical-scavenging properties of yeast and usefulness of its employment as antiperoxidative agent in fish.
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http://dx.doi.org/10.1007/s10695-012-9640-2DOI Listing
October 2012

The Nrf2 transcription factor contributes to the induction of alpha-class GST isoenzymes in liver of acute cadmium or manganese intoxicated rats: comparison with the toxic effect on NAD(P)H:quinone reductase.

Toxicology 2007 Jul 13;237(1-3):24-34. Epub 2007 May 13.

Unit of Veterinary Biochemistry, Department of Pharmaco-Biology, University of Bari, Str. Prov. per Casamassima Km 3, 70010 Valenzano, Bari, Italy.

In rat liver, in addition to their intrinsic transferase activity, alpha-class GSTs have Se-independent glutathione peroxidase activity toward fatty acid hydroperoxides, cumene hydroperoxide and phospholipids hydroperoxides but not toward H(2)O(2.) We have previously shown that hepatic GST activity by these isoenzymes is significantly increased 24h after cadmium or manganese administration (Casalino et al., 2004). Here it is reported that Se-independent glutathione peroxidase activity by alpha-class GSTs is also stimulated in the liver of intoxicated rats. The stimulation is associated with a higher level of alpha-class GST proteins, whose induction is blocked by actinomycin D co-administration. The observed Se-independent glutathione peroxidase activity is due to alpha-class GST isoenzymes, as indicated by the studies with diethyldithiocarbamate which, at any concentration, equally inhibits both GST and Se-independent glutathione peroxidase and is an uncompetitive inhibitor of both enzymes. As for liver Se-GSPx, it is not at all affected under these toxic conditions. For comparison, we have evaluated the status of another important antioxidant enzyme, NAD(P)H:quinone reductase, 24h after cadmium or manganese administration. NQO1 too results strongly stimulated in the liver of the intoxicated rats. In these animals, a higher expression of Nrf2 protein is observed, actively translocated from the cytoplasm to the nucleus. The results with the transcription inhibitor, actinomycin D, and the effects on Nrf2 protein are the first clear indication that acute manganese intoxication, similarly to that of cadmium and other heavy metals, increases both the hepatic level of Nrf2 and its transfer from the cytoplasm to the nucleus where it actively regulates the induction of phase II enzymes.
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http://dx.doi.org/10.1016/j.tox.2007.04.020DOI Listing
July 2007

Acute cadmium intoxication induces alpha-class glutathione S-transferase protein synthesis and enzyme activity in rat liver.

Toxicology 2006 Jan 16;217(2-3):240-5. Epub 2005 Nov 16.

Department of Pharmaco-Biology, Laboratory of Veterinary Biochemistry, University of Bari, Str. Prv. per Casamassima, km 3, 70100 Valenzano, Bari, Italy.

Acute cadmium intoxication affects glutathione S-transferase (GST) in rat liver. It has been found that 24h after i.p. cadmium administration to rats, at a dose of 2.5 mg CdCl(2)kg(-1) body weight, the activity of this enzyme in liver cytosol increased by 40%. A less stimulatory effect persisted till 48 h and thereafter the enzyme activity normalized. Since, GST isoenzymes belong to different classes in mammalian tissues, we used quantitative immunoassays to verify which family of GST isoenzymes is influenced by this intoxication. Only alpha-class glutathione S-transferase (alpha-GST) proteins were detected in rat liver cytosol and their level increased by about 25%, 24h after cadmium treatment. No pi-GST isoforms were found in liver cytosol from either normal or cadmium-treated rats. Co-administration of actinomycin D with cadmium normalized both the protein level and the activity of alpha-GST, suggesting that some effect occurs on enzyme transcription of these isoenzymes by this metal. On the other hand, it seems unlikely that the stimulatory effect is due to the high level of peroxides caused by lipid peroxidation, since Vitamin E administration strongly reduced the TBARS level, but did not cause any GST activity decrease.
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http://dx.doi.org/10.1016/j.tox.2005.09.020DOI Listing
January 2006

Rat liver glutathione S-transferase activity stimulation following acute cadmium or manganese intoxication.

Toxicology 2004 Jul;200(1):29-38

Sezione di Chimica e Biochimica Veterinaria del Dipartimento Farmaco-Biologico, Università degli Studi di Bari, Str. Prov. per Casamassima, Km 3, 70010 Valenzano, Bari, Italy.

The effect of cadmium or manganese administration on rat liver glutathione S-transferase (GST) has been investigated. The activity of this enzyme in liver cytosol, where almost all the cellular activity is present, had increased by more than 36% 24 h after a single i.p. injection of CdCl(2) (2.5 mg kg(-1) b.w.) or MnCl(2) (2.0 mg kg(-1) b.w.). After shorter and longer time intervals, a lower enzyme activity stimulation was observed in both cases. When liver cytosol was incubated for 10 min with 75 microM CdCl(2) or 40 microM MnCl(2), no effect was observed on enzyme activity. The increase in GST following cadmium or manganese administration was blocked by prior administration of actinomycin D, indicative of a possible transcription-dependent response. The liver soluble GST from both control and metal-treated rats was not at all affected by Vitamin E, in the range of 20-300 microM. By contrast, hematin was seen to be a competitive inhibitor of this liver enzyme from both types of rats by using CDNB as substrate and the K(i) value was equal to 0.22 microM. The possibility that under the conditions used class alpha GST isoenzymes are affected by cadmium or manganese is discussed.
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http://dx.doi.org/10.1016/j.tox.2004.03.004DOI Listing
July 2004

Antioxidant effect of hydroxytyrosol (DPE) and Mn2+ in liver of cadmium-intoxicated rats.

Comp Biochem Physiol C Toxicol Pharmacol 2002 Dec;133(4):625-32

Department of Pharmaco-Biology, University of Bari, Str Prov Per Casamassima, Km 3, 70010 Valenzano,(Ba), Italy.

Liver TBARS formation in cadmium-intoxicated rats was completely reduced by administering a low amount of MnCl(2) (2 mg/kg b.w.) 1 h before intoxication. A similar antioxidant effect was first shown by hydroxytyrosol (2-(3,4-dihydroxyphenyl)ethanol, (DPE), a phenolic compound present in olive oil, given twice to rats (9 mg/kg b.w.) after cadmium administration. The antioxidant properties shown in vivo by both Mn(2+) and DPE were also active in vitro when rat liver microsomes were subjected to lipid peroxidation by cadmium or other prooxidant systems. The increase in liver glutathione concentrations occurring in cadmium-intoxicated rats, was also found, for the first time, 24 h after MnCl(2) administration. Unlike cadmium intoxication, which caused a higher formation of both glutathione and TBARS, Mn(2+) induced glutathione synthesis without any TBARS formation. The same situation was also observed when cadmium plus Mn(2+) or cadmium plus DPE was given to rats. Our data show that: (a). both DPE and low Mn(2+) concentrations may have an antioxidant effect in the livers of cadmium-intoxicated rats and (b). Mn(2+), like cadmium, induces liver glutathione synthesis and this effect is probably independent of TBARS formation.
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http://dx.doi.org/10.1016/s1532-0456(02)00180-1DOI Listing
December 2002

Molecular inhibitory mechanisms of antioxidant enzymes in rat liver and kidney by cadmium.

Toxicology 2002 Sep;179(1-2):37-50

Department of Pharmaco-Biology, Laboratory of Veterinary Biochemistry, University of Bari, Str. Prov. per Casamassima, Km 3, 70010 Valenzano, Bari, Italy.

Catalase, Mn-superoxide dismutase (MnSOD) and Cu,Zn-superoxide dismutase (CuZnSOD) activities were studied in rat liver and kidney 6-48 h after CdCl(2) intraperitoneal administration or 10-30 days daily oral CdCl(2) intake in drinking water. This approach provided some indications as to the sensitivity of each enzyme to cadmium toxicity. These experiments showed that the formation of thiobarbituric acid reactive substance (TBARS) did not strictly depend on how well the antioxidant enzyme worked. From in vitro experiments it appeared that TBARS removal by vitamin E did not restore the three enzyme activities at all. As for cadmium's inhibitory mechanism on catalase activity, our data, obtained in the pH range 6.0-8.0, are a preliminary indication that the negative effect of this metal is probably due to imidazole residue binding of His-74 which is essential in the decomposition of hydrogen peroxide. Cadmium inhibition of liver mitochondrial MnSOD activity was completely removed by Mn(2+) ions, suggesting that the reducing effect on this enzyme is probably due to the substitution of cadmium for manganese. We also observed the antioxidant capacity of Mn(2+) ions, since they were able to normalize the increased TBARS levels occurring when liver mitochondria were exposed to cadmium. The reduced activity of CuZnSOD does not seem to be due to the replacement of Zn by Cd, nor to the peroxides formed. As this enzyme activity was almost completely recovered after 48 h, we hypothesize that the momentary inhibition is imputable to a cadmium/enzyme interaction. This causes some perturbation in the enzyme topography which is critical for its catalytic activity. The pathological implications linked to antioxidant enzyme disorders induced by cadmium toxicity are discussed.
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http://dx.doi.org/10.1016/s0300-483x(02)00245-7DOI Listing
September 2002
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