Publications by authors named "Mazzanti Gabriela"

60 Publications

Suspected adverse reactions to performance enhancing dietary supplements: Spontaneous reports from the Italian phytovigilance system.

Phytother Res 2021 Feb 10. Epub 2021 Feb 10.

Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, Rome, Italy.

Herbal tonic and adaptogens are often used to improve overall well-being. However, few clinical evidence supports their use and their safety is not known before marketing. In this context, the aim of our study was to analyze the spontaneous reports of suspected adverse reactions (ARs) to performance enhancing herbal dietary supplements collected by the Italian Phytovigilance System. Between March 2002 and September 2020, 110 spontaneous reports were collected, 58 of which related to products containing botanicals, alone or in association. Twenty-three serious reactions were reported, 21 of which required hospitalization, one was life-threatening and another caused disability. Dermatological and cardiovascular reactions were the most frequent. Hepatic ARs were the most serious (9 out of 10). A positive dechallenge was indicated in 69% of cases, while a positive rechallenge occurred in 15%. Concomitant use of other products was present in 18 reports (31%), while predisposing conditions were indicated in 17 (29%). Present data highlight safety concerns on herbal dietary supplements used as cognitive and physical performance enhancers, mainly due to their quality and use without expert supervision. Considering that postmarketing surveillance is not required for these products, spontaneous reports represent the only tool to point out risks related to food supplements.
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http://dx.doi.org/10.1002/ptr.7040DOI Listing
February 2021

Turmeric (Curcuma longa L.) food supplements and hepatotoxicity: an integrated evaluation approach.

Ann Ist Super Sanita 2020 Oct-Dec;56(4):462-469

Dipartimento Sicurezza Alimentare, Nutrizione e Sanità Pubblica Veterinaria, Istituto Superiore di Sanità, Rome, Italy.

Introduction: Turmeric is the common name for the rhizome of Curcuma longa L. In the recent years, food supplements containing turmeric have been marketed and widely used by an increasing number of consumers. Spontaneous reports of suspected adverse reactions to food supplements are collected within the Phytovigilance system.

Methods: An ad hoc multidisciplinary group investigated the suspected cases of hepatotoxicity reported to the Italian Phytovigilance system associated with the assumption of turmeric food supplements with the methodology specific to pharmacovigilance as well as for the evaluation of the quality and safety of food supplements.

Results: A cluster of 28 spontaneous reports of acute hepatitis, mostly with cholestasis, associated with turmeric products were sent to the Italian Phytovigilance system in the first six months of 2019. In all cases, except one, the causality assessment was at least possible. The suspected products were collected and analysed for the presence of drugs, heavy metals, aflatoxins, pesticides, synthetic dyes and pyrrolizidine alkaloids.

Conclusion: On the basis of the results of all the activities performed by multidisciplinary group, regulatory intervention was taken. This study highlights the importance of developing an integrated evaluation approach for the evaluation of the adverse effects associated with the use of food supplements.
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http://dx.doi.org/10.4415/ANN_20_04_08DOI Listing
December 2020

Chemopreventive Potential of Caryophyllane Sesquiterpenes: An Overview of Preliminary Evidence.

Cancers (Basel) 2020 Oct 18;12(10). Epub 2020 Oct 18.

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

Chemoprevention is referred to as a strategy to inhibit, suppress, or reverse tumor development and progression in healthy people along with high-risk subjects and oncologic patients through using pharmacological or natural substances. Numerous phytochemicals have been widely described in the literature to possess chemopreventive properties, although their clinical usefulness remains to be defined. Among them, caryophyllane sesquiterpenes are natural compounds widely occurring in nature kingdoms, especially in plants, fungi, and marine environments. Several structures, characterized by a common caryophyllane skeleton with further rearrangements, have been identified, but those isolated from plant essential oils, including β-caryophyllene, β-caryophyllene oxide, α-humulene, and isocaryophyllene, have attracted the greatest pharmacological attention. Emerging evidence has outlined a complex polypharmacological profile of caryophyllane sesquiterpenes characterized by blocking, suppressing, chemosensitizing, and cytoprotective properties, which suggests a possible usefulness of these natural substances in cancer chemoprevention for both preventive and adjuvant purposes. In the present review, the scientific knowledge about the chemopreventive properties of caryophyllane sesquiterpenes and the mechanisms involved have been collected and discussed; moreover, possible structure-activity relationships have been highlighted. Although further high-quality studies are required, the promising preclinical findings and the safe pharmacological profile encourage further studies to define a clinical usefulness of caryophyllane sesquiterpenes in primary, secondary, or tertiary chemoprevention.
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http://dx.doi.org/10.3390/cancers12103034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7603190PMC
October 2020

Assessment of adverse reactions to α-lipoic acid containing dietary supplements through spontaneous reporting systems.

Clin Nutr 2021 Mar 29;40(3):1176-1185. Epub 2020 Jul 29.

Pharmacology Unit, Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.

Background & Aims: Alpha-lipoic acid (ALA)-containing dietary supplements are widely used in clinical practice, although their safety assessment is under-investigated. We characterize the safety profile of ALA-containing products by analysing spontaneous reports of suspected adverse reactions (ARs).

Methods: Suspected ARs to ALA-containing products were extracted from the Italian Phytovigilance System (IPS), and scrutinized in terms of seriousness and causality (through WHO UMC system), with a specific focus on important (IMEs) and designated medical events (DMEs). To characterize the reporting profile from an international perspective, the WHO-VigiBase was also queried.

Results: From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 ARs to ALA-containing products were collected. Women were involved in 68.1% of cases. Skin (44.9%) and gastrointestinal disorders (10.8%) were the most frequently represented ARs. Causality assessment resulted as definite (15), probable (35), possible (24), unlikely (5), and unclassifiable (37). In 70% of cases, events occurred within 30 days of ALA use. Forty-five reports were serious (38.8%), being insulin autoimmune syndrome the most frequently reported (N = 10). IMEs were recorded in 20 cases, including four DMEs (3 angioedema and one anaphylactic shock). Similar distribution emerged from the 5641 reports in the WHO-VigiBase.

Conclusions: The remarkable reporting of unpredictable skin, immune and hepatic ARs, coupled with seriousness, strong causality and early onset, calls for a) careful risk-benefit assessment of ALA-containing products by regulators; b) awareness and monitoring by clinicians and c) continuous vigilance of their safety profile through valuable spontaneous reporting systems such as IPS.
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http://dx.doi.org/10.1016/j.clnu.2020.07.028DOI Listing
March 2021

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by β-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention.

Cells 2020 04 2;9(4). Epub 2020 Apr 2.

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

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene β-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. β-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of β-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by β-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.
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http://dx.doi.org/10.3390/cells9040858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7226839PMC
April 2020

Potentiation of Low-Dose Doxorubicin Cytotoxicity by Affecting P-Glycoprotein through Caryophyllane Sesquiterpenes in HepG2 Cells: an in Vitro and in Silico Study.

Int J Mol Sci 2020 Jan 17;21(2). Epub 2020 Jan 17.

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

Doxorubicin represents a valuable choice for different cancers, although the severe side effects occurring at the high effective dose limits its clinical use. In the present study, potential strategies to potentiate low-dose doxorubicin efficacy, including a metronomic schedule, characterized by a short and repeated exposure to the anticancer drug, and the combination with the natural chemosensitizing sesquiterpenes -caryophyllene and -caryophyllene oxide, were assessed in human hepatoma HepG2 cells. The involvement of P-glycoprotein (P-gp) in the HepG2-chemosensitization to doxorubicin was evaluated. Also, the direct interaction of caryophyllene sesquiterpenes with P-gp was characterized by molecular docking and dynamic simulation studies. A metronomic schedule allowed us to enhance the low-dose doxorubicin cytotoxicity and the combination with caryophyllane sesquiterpenes further potentiated this effect. Also, an increased intracellular accumulation of doxorubicin and rhodamine 123 induced by caryophyllane sesquiterpenes was found, thus suggesting their interference with P-gp function. A lowered expression of P-gp induced by the combinations, with respect to doxorubicin alone, was observed too. Docking studies found that the binding site of caryophyllane sesquiterpene was next to the ATP binding domain of P-gp and that -caryophyllene possessed the stronger binding affinity and higher inhibition potential calculated by MM-PBSA. Present findings strengthen our hypothesis about the potential chemosensitizing power of caryophyllane sesquiterpenes and suggest that combining a chemosensitizer and a metronomic schedule can represent a suitable strategy to overcome drawbacks of doxorubicin chemotherapy while exploiting its powerful activity.
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http://dx.doi.org/10.3390/ijms21020633DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014471PMC
January 2020

Hypoglycemic, Antiglycation, and Cytoprotective Properties of a Phenol-Rich Extract From Waste Peel of L. var. Dente di Cavallo DC2.

Molecules 2019 Aug 27;24(17). Epub 2019 Aug 27.

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

Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which are antioxidant and antidiabetic. In the present study, an ethyl acetate extract, obtained by Soxhlet from the peel of Dente di Cavallo DC2 pomegranate (PGE) and characterized to contain 4% / of ellagic acid, has been evaluated for its hypoglycemic, antiglycation, and antioxidative cytoprotective properties, in order to provide possible evidence for future nutraceutical applications. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation, and metal chelating abilities were studied. Moreover, the possible antioxidant cytoprotective properties of PGE under hyperglycemic conditions were assayed. Phenolic profile of the extract was characterized by integrated chromatographic and spectrophotometric methods. PGE resulted able to strongly inhibit the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it counteracted the intracellular oxidative stress under hyperglycemic conditions, by reducing the levels of reactive oxygen species and total glutathione. Among the identified phenolics, rutin was the most abundant flavonoid (about 4 % /). Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.
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http://dx.doi.org/10.3390/molecules24173103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749322PMC
August 2019

Suspected adverse reactions associated with herbal products used for weight loss: spontaneous reports from the Italian Phytovigilance System.

Eur J Clin Pharmacol 2019 Nov 19;75(11):1599-1615. Epub 2019 Aug 19.

Centre for Drug Research and Evaluation, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.

Purpose: Overweight and obesity represent worldwide a rising health problem. In this context, dietary supplements and herbal preparations are often used as self-medication for weight loss. The aim of this study was to describe the safety profile of dietary supplements for weight control by analyzing spontaneous reports of suspected adverse reactions (ARs) received by the Italian Phytovigilance System, from July 2010 to October 2017.

Methods: The suspected ARs were collected using an ad hoc reporting form, registered in a database at the National Institute of Health and evaluated by a multidisciplinary group of experts. The causality assessment was performed using the WHO-UMC system or the CIOMS/RUCAM score. In case of serious adverse reactions, a feedback is provided to the reporter by e-mail.

Results: Sixty-six spontaneous reports were collected. ARs involved cardiovascular system (26%), liver (14%), central nervous system (12%), skin (9%), gastrointestinal system (17%), thyroid (8%), kidney (4%), and other organs/systems (10%). In 64% of cases, the reaction was serious. Dechallenge was positive in 46 cases; three cases of positive rechallenge were reported. After the causality assessment, the association between the product intake and the adverse reaction was judged as possible in the majority of the cases (n = 43; 65%).

Conclusions: The data collected confirmed the existence of safety concerns on herbal dietary supplements used for body weight control, mainly related to quality of products and their use as self-medication. In this scenario, spontaneous reports represent the only tools available to monitor safety of these products.
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http://dx.doi.org/10.1007/s00228-019-02746-6DOI Listing
November 2019

Chemosensitization of hepatocellular carcinoma cells to sorafenib by β-caryophyllene oxide-induced inhibition of ABC export pumps.

Arch Toxicol 2019 03 18;93(3):623-634. Epub 2019 Jan 18.

Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca, Spain.

Several ATP-binding cassette (ABC) proteins reduce intracellular concentrations of antitumor drugs and hence weaken the response of cancer cells to chemotherapy. Accordingly, the inhibition of these export pumps constitutes a promising strategy to chemosensitize highly chemoresistant tumors, such as hepatocellular carcinoma (HCC). Here, we have investigated the ability of β-caryophyllene oxide (CRYO), a naturally occurring sesquiterpene component of many essential oils, to inhibit, at non-toxic doses, ABC pumps and improve the response of HCC cells to sorafenib. First, we have obtained a clonal subline (Alexander/R) derived from human hepatoma cells with enhanced multidrug resistance (MDR) associated to up-regulation (mRNA and protein) of MRP1 and MRP2. Analysis of fluorescent substrates export (flow cytometry) revealed that CRYO did not affect the efflux of fluorescein (MRP3, MRP4 and MRP5) but inhibited that of rhodamine 123 (MDR1) and calcein (MRP1 and MRP2). This ability was higher for CRYO than for other sesquiterpenes assayed. CRYO also inhibited sorafenib efflux, increased its intracellular accumulation (HPLC-MS/MS) and enhanced its cytotoxic response (MTT). For comparison, the effect of known ABC pumps inhibitors was also determined. They induced strong (diclofenac on MRPs), modest (verapamil on MDR1) or null (fumitremorgin C on BCRP) effect on sorafenib efflux and cytotoxicity. In the mouse xenograft model, the response to sorafenib treatment of subcutaneous tumors generated by mouse hepatoma Hepa 1-6/R cells, with marked MDR phenotype, was significantly enhanced by CRYO co-administration. In conclusion, at non-toxic dose, CRYO is able to chemosensitizating liver cancer cells to sorafenib by favoring its intracellular accumulation.
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http://dx.doi.org/10.1007/s00204-019-02395-9DOI Listing
March 2019

SPC Liposomes as Possible Delivery Systems for Improving Bioavailability of the Natural Sesquiterpene β-Caryophyllene: Lamellarity and Drug-Loading as Key Features for a Rational Drug Delivery Design.

Pharmaceutics 2018 Dec 13;10(4). Epub 2018 Dec 13.

Department of Chemistry and Technology of Drugs, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

The natural sesquiterpene β-caryophyllene (CRY) has been highlighted to possess interesting pharmacological potentials, particularly due to its chemopreventive and analgesic properties. However, the poor solubility of this sesquiterpene in aqueous fluids can hinder its uptake into cells, resulting in inconstant responses of biological systems, thus limiting its application. Therefore, identifying a suitable pharmaceutical form for increasing CRY bioavailability represents an important requirement for exploiting its pharmacological potential. In the present study, the ability of soybean phosphatidylcholine (SPC) liposomes to improve bioavailability and absorption of CRY in cancer cells has been evaluated. Liposomal formulations of CRY, differing for lamellarity (i.e., unilamellar and multilamellar vesicles or ULV and MLV) and for the drug loading (i.e., 1:0.1, 1:0.3 and 1:0.5 mol/mol between SPC and CRY) were designed with the aim of maximizing CRY amount in the liposome bilayer, while avoiding its leakage during storage. The low-loaded formulations significantly potentiated the antiproliferative activity of CRY in both HepG2 and MDA-MB-468 cells, reaching a maximum IC lowering (from two to five folds) with 1:0.3 and 1:0.1 SPC/CRY MLV. Conversely, increasing liposome drug-loading reduced the ability for CRY release, likely due to a possible interaction between SPC and CRY that affects the membrane properties, as confirmed by physical measures.
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http://dx.doi.org/10.3390/pharmaceutics10040274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6321237PMC
December 2018

Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems.

Drug Saf 2018 08;41(8):745-752

Pharmacology Unit, Department of Medical and Surgical Sciences, Alma Mater Studiorum - University of Bologna, Via Irnerio 48, 40126, Bologna, BO, Italy.

Introduction: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events.

Methods: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs.

Results: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10).

Conclusions: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.
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http://dx.doi.org/10.1007/s40264-018-0661-3DOI Listing
August 2018

Caryophyllane sesquiterpenes inhibit DNA-damage by tobacco smoke in bacterial and mammalian cells.

Food Chem Toxicol 2018 Jan 14;111:393-404. Epub 2017 Nov 14.

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

In the present study, the ability of the natural sesquiterpene β-caryophyllene (CRY) and its metabolite β-caryophyllene oxide (CRYO) to inhibit the genotoxicity of a condensate of cigarette smoke (CSC) was evaluated both in bacterial and mammalian cells. Also, the inhibition of the CSC-mediated STAT3 phosphorylation and intracellular oxidative stress was evaluated as potential chemopreventive mechanism. Under our experimental conditions, both the sesquiterpenes exhibited antimutagenic properties, being CRY the most potent compound. The antimutagenicity was highlighted in all experimental protocols, being particularly strong in the co- and post-treatments. The test substances also reduced the micronuclei frequency induced by CSC, with a major effectiveness of CRY. CRY was also able to reduce the CSC-mediated increase of the Y705- pSTAT3 levels, in spite of a lacking effect of CRYO. Furthermore, the sesquiterpenes CRY and CRYO displayed a moderate antioxidant activity, with a 25 % and 40 % inhibition of the ROS-levels increased by CSC, respectively. On the basis of these results, CRY seems to be a multi-target chemopreventive agent, although the genoprotective and antioxidant effects of CRYO suggest that both compounds deserve to be deeply investigated for a possible application in the prevention and treatment of different smoke-related ailments.
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http://dx.doi.org/10.1016/j.fct.2017.11.018DOI Listing
January 2018

Phytochemical analysis and effects on ingestive behaviour of a Caralluma fimbriata extract.

Food Chem Toxicol 2017 Oct 13;108(Pt A):63-73. Epub 2017 Jul 13.

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

Caralluma fimbriata Wall. is currently used as a "natural slimming" food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms.
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http://dx.doi.org/10.1016/j.fct.2017.07.027DOI Listing
October 2017

Genotoxicity assessment of piperitenone oxide: An in vitro and in silico evaluation.

Food Chem Toxicol 2017 Aug 10;106(Pt A):506-513. Epub 2017 Jun 10.

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

Piperitenone oxide, a natural flavouring agent also known as rotundifolone, has been studied for the genotoxicity assessment by an integrated in vitro and in silico experimental approach, including the bacterial reverse mutation assay, the micronucleus test, the comet assay and the computational prediction by Toxtree and VEGA tools. Under our experimental conditions, the monoterpene showed to induce both point mutations (i.e. frameshift, base-substitution and/or oxidative damage) and DNA damage (i.e. clastogenic or aneuploidic damage, or single-strand breaks). Computational prediction for piperitenone oxide agreed with the toxicological data, and highlighted the presence of the epoxide function and the α,β-unsaturated carbonyl as possible structural alerts for DNA damage. However, improving the toxicological libraries for natural occurring compounds is required in order to favour the applicability of in silico models to the toxicological predictions. Further in vivo evaluations are strictly needed in order to evaluate the role of the bioavailability of the substance and the metabolic fate on its genotoxicity profile. To the best of our knowledge, these data represent the first evaluation of the genotoxicity for this flavour compound and suggest the need of further studies to assess the safety of piperitenone oxide as a flavouring agent.
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http://dx.doi.org/10.1016/j.fct.2017.06.021DOI Listing
August 2017

Chemosensitizing Properties of β-Caryophyllene and β-Caryophyllene Oxide in Combination with Doxorubicin in Human Cancer Cells.

Anticancer Res 2017 03;37(3):1191-1196

Institute of Pharmacy and Molecular Biotechnology - Heidelberg University, Heidelberg, Germany.

Background/aim: The natural sesquiterpenes β-caryophyllene (CRY) and β-caryophyllene oxide (CRYO) were evaluated for their potential chemosensitizing properties.

Materials And Methods: CRY and CRYO cytotoxicity was tested against the Caco-2, CCRF/CEM and CEM/ADR5000 human cancer cell lines. Furthermore, combination experiments were carried out in order to study the ability of the sesquiterpenes to increase doxorubicin cytotoxicity. The possible interference of CRY and CRYO with functionality of ATP-binding cassette (ABC)-transporters was also investigated by Rhodamine123 efflux assay.

Results: Despite a low cytotoxicity, both substances were able to enhance the cytotoxicity of doxorubicin in all cell lines, with CRYO being the most effective reversal agent. Both sesquiterpenes were also able to increase the Rho123 content into cells, likely due to inhibition of the efflux pumps.

Conclusion: Our results highlight a potential role of CRY and CRYO as new chemosensitizing agents for doxorubicin chemotherapy and to re-sensitize cancer-resistant cells.
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http://dx.doi.org/10.21873/anticanres.11433DOI Listing
March 2017

Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system.

Br J Clin Pharmacol 2017 04 19;83(4):894-908. Epub 2017 Jan 19.

Centre for Epidemiology, National Institute of Health, Viale Regina Elena 299, 00161, Rome, Italy.

Aims: Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs).

Methods: Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried.

Results: From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase.

Conclusions: The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.
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http://dx.doi.org/10.1111/bcp.13171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5346868PMC
April 2017

Mutagenicity of cigarette butt waste in the bacterial reverse mutation assay: The protective effects of β-caryophyllene and β-caryophyllene oxide.

Environ Toxicol 2016 Nov 2;31(11):1319-1328. Epub 2015 Mar 2.

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

Cigarette filters pose a serious litter and toxic waste disposal problem, because of their not biodegradability and to the leaching of toxins in the environment. Therefore, cigarette butts need to be manipulated as special waste, with potential risks to human health and environment. In the present study, the genotoxic potential of a methanol extract from commonly discharged cigarette butts (CBE) was evaluated in the bacterial reverse mutation assay on Salmonella typhimurium TA98 and TA100 and Escherichia coli WP2uvrA strains, both in the absence and presence of the S9 exogenous metabolic activator. Furthermore, the ability of the natural sesquiterpenes β-caryophyllene (CRY) and β-caryophyllene oxide (CRYO) to inhibit the mutagenicity of CBE was studied as a possible preventive strategy. In order to identify the potential antimutagenic mechanisms, three different protocols (pretreatment, cotreatment, and posttreatment) were applied. CBE showed to increase the number of revertant colonies in all the strains tested in presence of S9, so resulting mutagenic. In the antimutagenicity assay, both CRY and CRYO significantly reduced the revertant colonies induced by CBE, although with different potency and specificity. For both sesquiterpenes, the antimutagenicity was strong in all experimental conditions, except for the cotreatment of CRY with CBE in WP2uvrA, which produced a moderate inhibition. Both desmutagenic and bioantimutagenic mechanisms seem to be involved in the antimutagenicity of the test substances. Taking into account the potential genotoxicity of cigarette butts, CRY and CRYO appear as possible further candidates as environmental decontaminants against this hazardous waste. © 2015 Wiley Periodicals, Inc. Environ Toxicol 31: 1319-1328, 2016.
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http://dx.doi.org/10.1002/tox.22136DOI Listing
November 2016

Curcumin and Resveratrol in the Management of Cognitive Disorders: What is the Clinical Evidence?

Molecules 2016 Sep 17;21(9). Epub 2016 Sep 17.

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

A growing body of in vitro and in vivo evidences shows a possible role of polyphenols in counteracting neurodegeneration: curcumin and resveratrol are attractive substances in this regard. In fact, epidemiological studies highlight a neuroprotective effect of turmeric (rhizome of Curcuma longa L.), the main source of curcumin. Moreover, the consumption of red wine, the main source of resveratrol, has been related to a lower risk of developing dementia. In this review, we analyzed the published clinical trials investigating curcumin and resveratrol in the prevention or treatment of cognitive disorders. The ongoing studies were also described, in order to give an overview of the current search on this topic. The results of published trials (five for curcumin, six for resveratrol) are disappointing and do not allow to draw conclusions about the therapeutic or neuroprotective potential of curcumin and resveratrol. These compounds, being capable of interfering with several processes implicated in the early stages of dementia, could be useful in preventing or in slowing down the pathology. To this aim, an early diagnosis using peripheral biomarkers becomes necessary. Furthermore, the potential preventive activity of curcumin and resveratrol should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability and that are well standardized.
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http://dx.doi.org/10.3390/molecules21091243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6273006PMC
September 2016

α-Hexylcinnamaldehyde Synergistically Increases Doxorubicin Cytotoxicity Towards Human Cancer Cell Lines.

Anticancer Res 2016 Jul;36(7):3347-51

Institute of Pharmacy and Molecular Biotechnology, Ruprecht Karls University, Heidelberg, Germany.

Aim: α-Hexylcinnamaldehyde (HCA), a compound derived from cinnamaldehyde, was evaluated for its potential chemosensitizing properties.

Materials And Methods: The cytotoxicity of HCA was tested against Caco-2, CCRF/CEM and CEM/ADR5000 human cancer cells. Furthermore, its ability to increase doxorubicin cytotoxicity was evaluated in combination assays. Rhodamine123 efflux assay was carried out in order to highlight the possible interference of HCA with functionality of ATP-binding cassette (ABC)-transporters.

Results: In spite of a low cytotoxicity, HCA increased the antiproliferative effect of doxorubicin in all the cell lines tested, being particularly effective in CCRF/CEM. The compound also reduced the rhodamine123 efflux in Caco-2 and CEM/ADR5000 cells, suggesting a possible interference with ABC transporter functionality.

Conclusion: Considering that the greatest synergism between HCA and DOX was found against CCRF/CEM cells (lacking ABC pumps), it seems likely that non-specific mechanisms, including the alteration of membrane permeability, could be involved in the chemosensitizing effect of HCA.
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July 2016

Sisymbrium Officinale (L.) Scop. and its Polyphenolic Fractions Inhibit the Mutagenicity of Tert-Butylhydroperoxide in Escherichia Coli WP2uvrAR Strain.

Phytother Res 2016 May 18;30(5):829-34. Epub 2016 Feb 18.

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

One Sisymbrium officinale (L.) Scop. aqueous dry extract (SOE) and its polyphenolic fractions (Fb, Fc, Fd and Fe) were evaluated for their ability to inhibit the oxidative mutagenicity of tert-butylhydroperoxide in the Ames test. The possible involvement of desmutagenic and/or bioantimutagenic mechanisms was evaluated by applying a three-time based protocol (pre-treatment, co-treatment and post-treatment). Furthermore, some protective antioxidant mechanisms were investigated. The total polyphenol and flavonol amount was also determined, and the fingerprint was outlined by high-performance thin-layer chromatography and densitometry. SOE, Fb and Fe exhibited strong antimutagenicity against tert-butylhydroperoxide in all treatment protocols, this suggesting the involvement of both desmutagenic and bioantimutagenic mechanisms. These samples also showed antioxidant properties, including neutralization of the superoxide anion, lipid peroxidation inhibition and chelation and reduction of iron. Fb and Fe were rich in polyphenols and flavonols, so suggesting a possible role of these compounds in the antimutagenicity. Taking into account that oxidative stress is responsible for the damage of various environmental toxicants, particularly tobacco smoke, present results can support the traditional use of hedge mustard by smokers to restore the vocal cord function affected by the oxidative damage and suggest a possible application of SOE and its fractions as food supplements. Copyright © 2016 John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/ptr.5588DOI Listing
May 2016

Letter to the Editor regarding "RIFM fragrance ingredient safety assessment, linalyl acetate, CAS registry number 115-95-7" by Api et al., 2015.

Food Chem Toxicol 2016 11 12;97S:S237-S239. Epub 2015 Dec 12.

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

Present letter is aimed at clarifying some critical points highlighted by Api et al. as major limits for the reliability of our data on the genotoxicity of linalyl acetate. Particularly, we explained the choice of the study design and methodology applied for carrying out the Ames test and the micronucleus assay.
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http://dx.doi.org/10.1016/j.fct.2015.12.009DOI Listing
November 2016

Multidisciplinary Approach to Determine the Optimal Time and Period for Extracting the Essential Oil from Mentha suaveolens Ehrh.

Molecules 2015 May 26;20(6):9640-55. Epub 2015 May 26.

Rome Center for Molecular Design, Department of Drug Chemistry and Technology, "Sapienza" University, P.le Aldo Moro 5, 00185 Rome, Italy.

A comprehensive study on essential oils (EOs) extracted from some Mentha suaveolens L. samples, collected in the countryside of Tarquinia, is reported. In this study, the procedure for essential oil preparation, in terms of harvesting and extraction time, was analyzed in detail for the first time. The GC/MS analysis, carried out on 18 samples, revealed that piperitenone oxide (PO), the main essential oils' chemical constituent, is primarily responsible for the related antifungal activity. Nevertheless, EOs with lower PO content indicate that other chemicals, such as para-cymenene, may participate in exerting the EOs' antifungal effect. Furthermore, the bacterial reverse mutation assay highlighted lack of mutagenic effect in all tested samples. Analysis of the results indicated that for higher activity, the essential oils should be produced with 3 h maximum hydrodistillation, regardless of the harvesting time. Differently, the maximum essential oil yield can be obtained in August and the highest piperitenone oxide percentage is obtainable in July.
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http://dx.doi.org/10.3390/molecules20069640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272612PMC
May 2015

Hepatotoxicity of green tea: an update.

Arch Toxicol 2015 Aug 16;89(8):1175-91. Epub 2015 May 16.

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

Green tea (GT), obtained from the leaves of Camellia sinensis (L.) Kuntze (Fam. Theaceae), is largely used for its potential health benefits such as reduction in risk of cardiovascular diseases and weight loss. Nevertheless, it is suspected to induce liver damage. Present work reviews the hepatic adverse reactions associated with GT-based herbal supplements, published by the end of 2008 to March 2015. A systematic research was carried out on PubMed, MedlinePlus, Scopus and Google Scholar databases, without any language restriction. Moreover, some accessible databases on pharmacovigilance or phytovigilance were consulted. The causality assessment was performed using the CIOMS/RUCAM score. Nineteen cases of hepatotoxicity related to the consumption of herbal products containing GT were identified. The hepatic reactions involved mostly women (16/19); the kind of liver damage was generally classified as hepatocellular (16/19). The causality assessment between consumption of herbal preparation and hepatic reaction resulted as probable in eight cases and as possible in eleven cases. In seven cases, patients used preparations containing only GT, while twelve reactions involved patients who took multicomponent preparations (MC). The reactions induced by GT had a generally long latency (179.1 ± 58.95 days), and the outcome was always resolution, with recovery time of 64.6 ± 17.78 days. On the contrary, liver injury associated with MC had a shorter latency (44.7 ± 13.85 days) and was more serious in four cases that required liver transplantation and, when resolution occurred, the recovery time was longer (118.9 ± 38.79). MC preparations contained numerous other components, many of which are suspected to induce liver damage, so it is difficult to ascribe the toxicity to one specific component, e.g., GT. Present data confirm a certain safety concern with GT, even if the number of hepatic reactions reported is low considering the great extent of use of this supplement. The mechanism of GT hepatotoxicity remains unclear, but factors related to the patient are becoming predominant. A major safety concern exists when GT is associated with other ingredients that can interact between them and with GT, enhancing the risk of liver damage. Patients should be discouraged from using herbal or dietary supplements containing complex mixtures and should be encouraged to use herbal and dietary supplement possibly under supervision of healthcare professionals.
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http://dx.doi.org/10.1007/s00204-015-1521-xDOI Listing
August 2015

α-Hexylcinnamaldehyde inhibits the genotoxicity of environmental pollutants in the bacterial reverse mutation assay.

J Nat Prod 2014 Dec 10;77(12):2664-70. Epub 2014 Dec 10.

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

The antimutagenicity of α-hexylcinnamaldehyde (1), a semisynthetic and more stable derivative of cinnamaldehyde, was evaluated against common environmental pollutants in the bacterial reverse mutation assay. The pre-, co-, and post-treatment protocols were applied to assess the involvement of desmutagenic and/or bioantimutagenic mechanisms. Compound 1 (9-900 μM) produced a strong antimutagenicity (>40% inhibition) in the Salmonella typhimurium TA98 strain against the nitroarenes 2-nitrofluorene and 1-nitropyrene in almost all experimental conditions. A strong inhibition was also reached against the nitroarene 1,8-dinitropyrene and the arylamine 2-aminoanthracene in the cotreatment at the highest concentrations tested. In order to evaluate if an inhibition of bacterial nitroreductase (NR) and O-acetyltransferase (OAT) could be involved in the antimutagenicity of 1 against nitroarenes, the substance was further tested against 1-nitropyrene (activated by both NR and OAT) in TA98NR and TA98 1,8-DNP strains (lacking the NR and OAT enzymes, respectively). Although both desmutagenic and bioantimutagenic mechanisms appear mostly involved in the antimutagenicity of 1, based on data obtained in the TA98NR strain, applying the pretreatment protocol, compound 1 seems to act as an inhibitor of the OAT-mediated mutagen bioactivation. These results provide justification for further studies on 1 as a possible chemopreventive agent.
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http://dx.doi.org/10.1021/np500567dDOI Listing
December 2014

Antimutagenic and antioxidant activity of a protein fraction from aerial parts of Urtica dioica.

Pharm Biol 2015 Jun 4;53(6):935-8. Epub 2014 Dec 4.

Department of Physiology and Pharmacology "V. Erspamer", Sapienza University of Rome , Rome , Italy .

Context: Urtica dioica L. (Urticaceae), stinging nettle, has been employed as a folklore remedy for a wide spectrum of ailments, including urinary disorders, prostatic hyperplasia, and liver diseases. It has been also used traditionally for cancer treatment.

Object: To evaluate the potential chemopreventive properties of a protein fraction from the aerial part of Urtica dioica (namely UDHL30).

Materials And Methods: UDHL30 has been tested for the antimutagenic activity in bacteria (50-800 μg/plate; Ames test by the preincubation method) and for the cytotoxicity on human hepatoma HepG2 cells (0.06-2 mg/mL; 24 and 48 h incubation). Moreover, the antioxidant activity of UDHL30 (0.1-1200 μg/mL; ABTS and superoxide-radical scavenger assays) was evaluated as potential protective mechanisms.

Results: UDHL30 was not cytotoxic on HepG2 cells up to 2 mg/mL; conversely, it exhibited a strong antimutagenic activity against the mutagen 2-aminoanthracene (2AA) in all strains tested (maximum inhibition of 56, 78, and 61% in TA98, TA100, and WP2uvrA strains, respectively, at 800 μg/plate). In addition, a remarkable scavenging activity against ABTS radical and superoxide anion (IC50 values of 19.9 ± 1.0 μg/mL and 75.3 ± 0.9 μg/mL, respectively) was produced.

Discussion And Conclusions: UDHL30 possesses antimutagenic and radical scavenging properties. Being 2AA a pro-carcinogenic agent, we hypothesize that the antimutagenicity of UDHL30 can be due to the inhibition of CYP450-isoenzymes, involved in the mutagen bioactivation. The radical scavenger ability could contribute to 2AA-antimutagenicity. These data encourage further studies in order to better define the potential usefulness of UDHL30 in chemoprevention.
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http://dx.doi.org/10.3109/13880209.2014.950386DOI Listing
June 2015

1H NMR-based urinary metabolic profiling reveals changes in nicotinamide pathway intermediates due to postnatal stress model in rat.

J Proteome Res 2014 Dec 20;13(12):5848-59. Epub 2014 Oct 20.

Department of Chemistry, ‡Department of Physiology and Pharmacology "V. Erspamer, §Department of General and Specialized Surgery "P. Stefanini", and ∥Department of Anatomical, Histological, Forensic and Orthopedic Sciences, Sapienza University of Rome , P.le Aldo Moro 5, 00185 Rome, Italy.

The maternal separation protocol in rodents is a widely recognized model of early life stress allowing acute and chronic physiological consequences to be studied. An (1)H NMR-based metabolomic approach was applied to urines to evaluate the systemic metabolic consequences of maternal separation stress in female rats after the beginning of weaning and 4 weeks later when the rats were reaching adulthood. Furthermore, because maternal separation is considered as a model mimicking the inflammatory bowel syndrome, the lactulose/mannitol test was used to evaluate the influence of postnatal maternal separation on gut permeability and mucosal barrier function by (1)H NMR spectroscopy analysis of urine. The results showed no statistical differences in gut permeability due to maternal separation. The application of ANOVA simultaneous component analysis allowed the contributions of physiological adaptations to the animal's development to be separated from the metabolic consequences due to postnatal stress. Systemic metabolic differences in the maternally separated pups were mainly due to the tryptophan/NAD pathway intermediate levels and to the methyladenosine level. Urinary NMR-based metabolic profiling allowed us to disentangle the metabolic adaptive response of the rats to postnatal stress during the animal's growth, highlighting the metabolic changes induced by weaning, gut closure, and maturity.
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http://dx.doi.org/10.1021/pr500748rDOI Listing
December 2014

Genotoxicity assessment of some cosmetic and food additives.

Regul Toxicol Pharmacol 2014 Feb 14;68(1):16-22. Epub 2013 Nov 14.

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

α-Hexylcinnamaldehyde (HCA) and p-tert-butyl-alpha-methylhydrocinnamic aldehyde (BMHCA) are synthetic aldehydes, characterized by a typical floral scent, which makes them suitable to be used as fragrances in personal care (perfumes, creams, shampoos, etc.) and household products, and as flavouring additives in food and pharmaceutical industry. The aldehydic structure suggests the need for a safety assessment for these compounds. Here, HCA and BMHCA were evaluated for their potential genotoxic risk, both at gene level (frameshift or base-substitution mutations) by the bacterial reverse mutation assay (Ames test), and at chromosomal level (clastogenicity and aneuploidy) by the micronucleus test. In order to evaluate a primary and repairable DNA damage, the comet assay has been also included. In spite of their potential hazardous chemical structure, a lack of mutagenicity was observed for both compounds in all bacterial strains tested, also in presence of the exogenous metabolic activator, showing that no genotoxic derivatives were produced by CYP450-mediated biotransformations. Neither genotoxicity at chromosomal level (i.e. clastogenicity or aneuploidy) nor single-strand breaks were observed. These findings will be useful in further assessing the safety of HCA and BMHCA as either flavour or fragrance chemicals.
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http://dx.doi.org/10.1016/j.yrtph.2013.11.003DOI Listing
February 2014

Antimutagenic and antioxidant activities of some bioflavours from wine.

Food Chem Toxicol 2013 Oct 24;60:141-6. Epub 2013 Jul 24.

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

Monoterpenes limonene and its metabolic derivatives, α-terpineol and 1,8-cineol, commonly found as aroma wine components, were studied for their antimutagenicity by the bacterial reverse mutation assay on different strains. Substances were also tested for their antioxidant activity, i.e. radical scavenger, chelation, reduction, and lipid peroxidation inhibition. Limonene and its metabolites, α-terpineol and 1,8-cineol, resulted able to inhibit the chemically-induced mutagenesis, although with a different specificity. The antimutagenicity of limonene has been generally retained by its metabolites and sometimes increased. In particular, α-terpineol exhibited the strongest inhibition, moreover it showed to be a remarkable ferrous ions chelating agent. Limonene and 1,8-cineol were devoid of antioxidant activity. Present results are a starting point in evaluating the potential of α-terpineol as a chemopreventive agent and suggest potential functional dietary benefits of wine.
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http://dx.doi.org/10.1016/j.fct.2013.07.042DOI Listing
October 2013

Chelidonium majus L. does not potentiate the hepatic effect of acetaminophen.

Exp Toxicol Pathol 2013 Nov 29;65(7-8):1117-20. Epub 2013 May 29.

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

Aim: The present study assessed the ability of Chelidonium majus to potentiate the hepatic effect of a sub-toxic dose of acetaminophen, in rats.

Results: C. majus, when administered alone, did not alter the liver function parameters in male, whereas an increase in fibrinogen level was found in female rats. Moreover, it did not affect the hepatic histomorphology in both male and female rats. The sub-toxic dose of acetaminophen induced: a significant increase in activated partial thromboplastin time in both genders, a focal hepatocellular necrosis with minor lymphocytes infiltrate and a slight but significant increase in total bilirubin, AST, and ALT in male rats, and in prothrombin time in female rats. The co-administration of C. majus did not increase the effects induced by acetaminophen, in both genders.

Conclusions: C. majus does not modify the hepatic effects of acetaminophen in our in vivo experimental model.
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http://dx.doi.org/10.1016/j.etp.2013.05.002DOI Listing
November 2013