Publications by authors named "Di Sotto Antonella"

46 Publications

Phytochemical Analysis and Biological Activities of the Ethanolic Extract of Vahl Flowering Aerial Parts Collected in Central Italy.

Biomolecules 2021 Mar 3;11(3). Epub 2021 Mar 3.

Dipartimento di Chimica, Università di Roma "La Sapienza", Piazzale Aldo Moro 5, 00185 Rome, Italy.

In this paper, the first phytochemical analysis of the ethanolic extract of Vahl flowering aerial parts collected in Italy and its biological activities were reported. Eleven compounds were identified i.e., α-linolenic acid (), tri-linoleoyl--glycerol (), pheophorbide ethyl ester (), pilloin (), sinensetin (), yuanhuanin (), rutamontine (), syringin (), -coumaric acid (), -anisic acid () and caffeic acid (). To the best of our knowledge, compounds (-, and ) were isolated from for the first time during this work, whereas sinensetin () represents a newly identified component of the entire Thymelaeaceae family. The extract was found to possess radical scavenging against both DPPH and 2,2'-azino-(3-thylbenzothiazoline-6-sulfonic acid (ABTS) radicals, with at least a 40-fold higher potency against the latter. Moreover, chelating abilities against both ferrous and ferric ions have been highlighted, thus suggesting a possible indirect antioxidant power of the extract. Although the precise bioactive compounds remain to be discovered, the polyphenolic constituents, including phenolic acids, tannins and flavonoids, seem to contribute to the antioxidant power of the phytocomplex. In addition, the extract produced cytotoxic effects in MDA-MB-231 and U87-MG cancer cell lines, especially at the concentration of 625 μg/mL and after 48-72 h. Further studies are required to clarify the contribution of the identified compounds in the bioactivities of the extract and to support possible future applications.
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http://dx.doi.org/10.3390/biom11030379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001904PMC
March 2021

β-Hexachlorocyclohexane: A Small Molecule with a Big Impact on Human Cellular Biochemistry.

Biomedicines 2020 Nov 16;8(11). Epub 2020 Nov 16.

Department of Biochemical Science "A. Rossi Fanelli", Faculty of Pharmacy and Medicine, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

Organochlorine pesticides (OCPs) belong to a heterogeneous class of organic compounds blacklisted by the Stockholm Convention in 2009 due to their harmful impact on human health. Among OCPs, β-hexachlorocyclohexane (β-HCH) is one of the most widespread and, at the same time, poorly studied environmental contaminant. Due to its physicochemical properties, β-HCH is the most hazardous of all HCH isomers; therefore, clarifying the mechanisms underlying its molecular action could provide further elements to draw the biochemical profile of this OCP. For this purpose, LNCaP and HepG2 cell lines were used as models and were subjected to immunoblot, immunofluorescence, and RT-qPCR analysis to follow the expression and mRNA levels, together with the distribution, of key biomolecules involved in the intracellular responses to β-HCH. In parallel, variations in redox homeostasis and cellular bioenergetic profile were monitored to have a complete overview of β-HCH effects. Obtained results strongly support the hypothesis that β-HCH could be an endocrine disrupting chemical as well as an activator of AhR signaling, promoting the establishment of an oxidative stress condition and a cellular metabolic shift toward aerobic glycolysis. In this altered context, β-HCH can also induce DNA damage through H2AX phosphorylation, demonstrating its multifaceted mechanisms of action.
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http://dx.doi.org/10.3390/biomedicines8110505DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7698094PMC
November 2020

Correlation between the Antimicrobial Activity and Metabolic Profiles of Cell Free Supernatants and Membrane Vesicles Produced by DSM 17938.

Microorganisms 2020 Oct 24;8(11). Epub 2020 Oct 24.

Department of Pharmacy, "G. d'Annunzio" University of Chieti-Pescara, 66100 Chieti, Italy.

The aim of the work is to assess the antimicrobial activities of Cell Free Supernatants (CFS) and Membrane Vesicles (MVs), produced by DSM 17938, versus Gram-positive and Gram-negative bacteria and investigate their metabolic profiles. The Minimum Inhibitory Concentration was determined through the broth microdilution method and cell proliferation assay and the Minimum Bactericidal Concentration was determined by Colony Forming Units counts. The characteristics of the antimicrobial compounds were evaluated by pH adjustments, proteinase treatment, and size fractionation of the CFS. The cytotoxicity of CFS was tested on two human cell lines. A detailed snapshot of the . metabolism was attained through an untargeted metabolic profiling by means of high resolution Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (FT-ICR MS) coupled with Electrospray Ionization Source (ESI). The results showed (i) a greater efficacy of CFS and its fractions towards Gram-negative compared to Gram-positive bacteria; (ii) an antimicrobial effect related to pH-dependent compounds but not to MVs; (iii) a molecular weight < 3 KDa as well as an a non-proteinaceous nature of the antimicrobial compounds; and (iv) more than 200 and 500 putative metabolites annotated in MVs and supernatants, covering several classes of metabolites, including amino acids, lipids, fatty and organic acids, polyalcohols, nucleotides, and vitamins. Some putative compounds were proposed not only as characteristic of specific fractions, but also possibly involved in antimicrobial activity.
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http://dx.doi.org/10.3390/microorganisms8111653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692313PMC
October 2020

Chemico-Biological Characterization of Torpedino Di Fondi Tomato Fruits: A Comparison with San Marzano Cultivar at Two Ripeness Stages.

Antioxidants (Basel) 2020 Oct 21;9(10). Epub 2020 Oct 21.

Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le Aldo Moro 5, 00185 Rome, Italy.

Torpedino di Fondi (TF) is a hybrid tomato landrace developed in Sicily and recently introduced in the south Lazio area along with the classical San Marzano (SM) cultivar. The present study aimed at characterizing TF tomatoes at both pink and red ripening stages, and at comparing them with traditional SM tomatoes. A multidisciplinary approach consisting of morphological, chemical (FT-ICR MS, NMR, HPLC, and spectrophotometric methods), and biological (antioxidant and antifungal in vitro activity) analyses was applied. Morphological analysis confirmed the mini-San Marzano nature and the peculiar crunchy and solid consistency of TF fruits. Pink TF tomatoes displayed the highest content of hydrophilic antioxidants, like total polyphenols (0.192 mg/g), tannins (0.013 mg/g), flavonoids (0.204 mg/g), and chlorophylls a (0.344 mg/g) and b (0.161 mg/g), whereas red TF fruits were characterized by the highest levels of fructose (3000 mg/100 g), glucose (2000 mg/100 g), tryptophan (2.7 mg/100 g), phenylalanine (13 mg/100 g), alanine (25 mg/100 g), and total tri-unsaturated fatty acids (13% mol). Red SM fruits revealed the greatest content of lipophilic antioxidants, with 1234 mg/g of total carotenoids. In agreement with phenolics content, TF cultivar showed the greatest antioxidant activity. Lastly, red TF inhibited species (, and ) growth.
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http://dx.doi.org/10.3390/antiox9101027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590105PMC
October 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

Plant-Derived Nutraceuticals and Immune System Modulation: An Evidence-Based Overview.

Vaccines (Basel) 2020 Aug 22;8(3). Epub 2020 Aug 22.

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

Immunomodulators are agents able to affect the immune system, by boosting the immune defences to improve the body reaction against infectious or exogenous injuries, or suppressing the abnormal immune response occurring in immune disorders. Moreover, immunoadjuvants can support immune system acting on nonimmune targets, thus improving the immune response. The modulation of inflammatory pathways and microbiome can also contribute to control the immune function. Some plant-based nutraceuticals have been studied as possible immunomodulating agents due to their multiple and pleiotropic effects. Being usually more tolerable than pharmacological treatments, their adjuvant contribution is approached as a desirable nutraceutical strategy. In the present review, the up to date knowledge about the immunomodulating properties of polysaccharides, fatty acids and labdane diterpenes have been analyzed, in order to give scientific basic and clinical evidence to support their practical use. Since promising evidence in preclinical studies, limited and sometimes confusing results have been highlighted in clinical trials, likely due to low methodological quality and lacking standardization. More investigations of high quality and specificity are required to describe in depth the usefulness of these plant-derived nutraceuticals in the immune system modulation, for health promoting and disease preventing purposes.
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http://dx.doi.org/10.3390/vaccines8030468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563161PMC
August 2020

Antiarthritic Effects of a Root Extract from DC: Novel Insights into the Molecular Mechanisms and Possible Bioactive Phytochemicals.

Nutrients 2020 Aug 23;12(9). Epub 2020 Aug 23.

Department of Biochemical Sciences, Sapienza University of Roma, P.le Aldo Moro 5, 00185 Roma, Italy.

(Burch.) DC. ex Meisn. is a traditional remedy for osteoarticular diseases, including osteoarthritis (OA), although the bioactive constituents and mechanisms involved are yet to be clarified. In the present study, an aqueous root extract (HPE; containing 1.2% harpagoside) was characterized for its effects on synoviocytes from OA patients and phytochemical composition in polyphenols, and volatile compounds were detected. HPE powder was dissolved in different solvents, including deionized water (HPE), DMSO (HPE), 100% / ethanol (HPE), and 50% / ethanol (HPE). The highest polyphenol levels were found in HPE and HPE, whereas different volatile compounds, mainly β-caryophyllene and eugenol, were detected in all the extracts except for HPE. HPE and HPE were able to enhance CB2 receptor expression and to downregulate PI-PLC β2 in synovial membranes; moreover, all the extracts inhibited FAAH activity. The present results highlight for the first time a multitarget modulation of the endocannabinoid system by HPE, likely ascribable to its hydrosoluble compounds, along with the presence of volatile compounds in root. Although hydrosoluble compounds seem to be mainly responsible for endocannabinoid modulation by HPE, a possible contribution of volatile compounds can be suggested, strengthening the hypothesis that the entire phytocomplex can contribute to the healing properties.
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http://dx.doi.org/10.3390/nu12092545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7551290PMC
August 2020

L. Inflorescences from Monoecious Cultivars Grown in Central Italy: An Untargeted Chemical Characterization from Early Flowering to Ripening.

Molecules 2020 Apr 20;25(8). Epub 2020 Apr 20.

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

The chemical composition of the inflorescences from four L. monoecious cultivars (Ferimon, Uso-31, Felina 32 and Fedora 17), recently introduced in the Lazio Region, was monitored over the season from June to September giving indications on their sensorial, pharmaceutical/nutraceutical proprieties. Both untargeted (NMR) and targeted (GC/MS, UHPLC, HPLC-PDA/FD and spectrophotometry) analyses were carried out to identify and quantify compounds of different classes (sugars, organic acids, amino acids, cannabinoids, terpenoids, phenols, tannins, flavonoids and biogenic amines). All cultivars in each harvesting period showed a THC content below the Italian legal limit, although in general THC content increased over the season. Citric acid, malic acid and glucose showed the highest content in the late flowering period, whereas the content of proline drastically decreased after June in all cultivars. Neophytadiene, nerolidol and chlorogenic acid were quantified only in Felina 32 cultivar, characterized also by a very high content of flavonoids, whereas alloaromadendrene and -cinnamic acid were detected only in Uso-31 cultivar. Naringenin and naringin were present only in Fedora 17 and Ferimon cultivars, respectively. Moreover, Ferimon had the highest concentration of biogenic amines, especially in July and August. Cadaverine was present in all cultivars but only in September. These results suggest that the chemical composition of L. inflorescences depends on the cultivar and on the harvesting period. Producers can use this information as a guide to obtain inflorescences with peculiar chemical characteristics according to the specific use.
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http://dx.doi.org/10.3390/molecules25081908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221798PMC
April 2020

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

Phytochemical and biological characterization of Italian "sedano bianco di Sperlonga" Protected Geographical Indication celery ecotype: A multimethodological approach.

Food Chem 2020 Mar 16;309:125649. Epub 2019 Oct 16.

Istituto per i Sistemi Biologici, Laboratorio di Risonanza Magnetica "Annalaura Segre", CNR, 00015 Monterotondo (Rome), Italy. Electronic address:

Celery is a widely used vegetable known for its peculiar sensorial and nutritional properties. Here, the white celery (Apium graveolens L.) "sedano bianco di Sperlonga" PGI ecotype was investigated to obtain the metabolic profile of its edible parts (blade leaves and petioles) also related to quality, freshness and biological properties. A multi-methodological approach, including NMR, MS, HPLC-PDA, GC-MS and spectrophotometric analyses, was proposed to analyse celery extracts. Sugars, polyalcohols, amino acids, organic acids, phenols, sterols, fatty acids, phthalides, chlorophylls, tannins and flavonoids were detected in different concentrations in blade leaf and petiole extracts, indicating celery parts as nutraceutical sources. The presence of some phenols in celery extracts was here reported for the first time. Low contents of biogenic amines and mycotoxins confirmed celery quality and freshness. Regarding the biological properties, ethanolic celery extracts inhibited the oxidative-mediated DNA damage induced by tert-butylhydroperoxide and scavenged DPPH and ABTS radicals.
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http://dx.doi.org/10.1016/j.foodchem.2019.125649DOI Listing
March 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

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

Chromatographic Analyses, In Vitro Biological Activities, and Cytotoxicity of Cannabis sativa L. Essential Oil: A Multidisciplinary Study.

Molecules 2018 Dec 10;23(12). Epub 2018 Dec 10.

Department of Pharmacy, University "G. d'Annunzio" of Chieti-Pescara, 66100 Chieti, Italy.

Due to renewed interest in the cultivation and production of Italian L., we proposed a multi-methodological approach to explore chemically and biologically both the essential oil and the aromatic water of this plant. We reported the chemical composition in terms of cannabinoid content, volatile component, phenolic and flavonoid pattern, and color characteristics. Then, we demonstrated the ethnopharmacological relevance of this plant cultivated in Italy as a source of antioxidant compounds toward a large panel of enzymes (pancreatic lipase, α-amylase, α-glucosidase, and cholinesterases) and selected clinically relevant, multidrug-sensible, and multidrug-resistant microbial strains (, , , and spp.), evaluating the cytotoxic effects against normal and malignant cell lines. Preliminary in vivo cytotoxicity was also performed on larvae. The results corroborate the use of this natural product as a rich source of important biologically active molecules with particular emphasis on the role exerted by naringenin, one of the most important secondary metabolites.
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http://dx.doi.org/10.3390/molecules23123266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6320915PMC
December 2018

Antiviral and Antioxidant Activity of a Hydroalcoholic Extract from L.

Oxid Med Cell Longev 2018 24;2018:5919237. Epub 2018 Jul 24.

Department of Public Health and Infectious Diseases, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.

A hydroalcoholic extract from female inflorescences of L. (HOP extract) was evaluated for its anti-influenza activity. The ability of the extract to interfere with different phases of viral replication was assessed, as well as its effect on the intracellular redox state, being unbalanced versus the oxidative state in infected cells. The radical scavenging power, inhibition of lipoperoxidation, and ferric reducing activity were assayed as antioxidant mechanisms. A phytochemical characterization of the extract was also performed. We found that HOP extract significantly inhibited replication of various viral strains, at different time from infection. Viral replication was partly inhibited when virus was incubated with extract before infection, suggesting a direct effect on the virions. Since HOP extract was able to restore the reducing conditions of infected cells, by increasing glutathione content, its antiviral activity might be also due to an interference with redox-sensitive pathways required for viral replication. Accordingly, the extract exerted radical scavenging and reducing effects and inhibited lipoperoxidation and the tBOOH-induced cytotoxicity. At phytochemical analysis, different phenolics were identified, which altogether might contribute to HOP antiviral effect. In conclusion, our results highlighted anti-influenza and antioxidant properties of HOP extract, which encourage further studies to evaluate its possible application.
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http://dx.doi.org/10.1155/2018/5919237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081516PMC
October 2018

A Polyphenol Rich Extract from L. DR2 Peel Exhibits Antioxidant Properties and Anti-Herpes Simplex Virus Type 1 Activity In Vitro.

Molecules 2018 Aug 17;23(8). Epub 2018 Aug 17.

Department of Public Health and Infectious Diseases, Istituto Pasteur Italia-Fondazione Cenci-Bolognetti, Sapienza University, P.le Aldo Moro 5, 00185 Rome, Italy.

DR2B and DR2C extracts, obtained by ethanolic maceration of peel from commercially and physiologically ripe aubergine berries, were studied for the antioxidative cytoprotective properties and anti-HSV-1 activity, in line with the evidence that several antioxidants can impair viral replication by maintaining reducing conditions in host cells. The antioxidative cytoprotective effects against tBOOH-induced damage were assessed in Caco2 cells, while antiviral activity was studied in Vero cells; polyphenolic fingerprints were characterized by integrated phytochemical methods. Results highlighted different compositions of the extracts, with chlorogenic acid and delphinidin-3-rutinoside as the major constituents; other peculiar phytochemicals were also identified. Both samples reduced reactive oxygen species (ROS) production and exhibited scavenging and chelating properties. DR2C partly counteracted the tBOOH-induced cytotoxicity, with a remarkable lowering of lactate metabolism under both normoxia and hypoxia; interestingly, it increased intracellular GSH levels. Furthermore, DR2C inhibited the HSV-1 replication when added for 24 h after viral adsorption, as also confirmed by the reduction of many viral proteins' expression. Since DR2C was able to reduce NOX4 expression during HSV-1 infection, its antiviral activity may be correlated to its antioxidant properties. Although further studies are needed to better characterize DR2C activity, the results suggest this extract as a promising new anti-HSV-1 agent.
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http://dx.doi.org/10.3390/molecules23082066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222547PMC
August 2018

A multi-methodological approach in the study of Italian PDO "Cornetto di Pontecorvo" red sweet pepper.

Food Chem 2018 Jul 10;255:120-131. Epub 2018 Feb 10.

Dipartimento di Fisiologia e Farmacologia "V. Ersparmer", Sapienza Università di Roma, P.le Aldo Moro 5, 00185 Rome, Italy.

A multi-methodological approach was applied to study red sweet peppers (Capsicum annuum L.) ecotype "Cornetto di Pontecorvo" grown in a greenhouse or in open field. This approach includes morphological analysis, chemical composition determination, and biological activity evaluation of different extracts from pepper fruits. Untargeted analyses, namely NMR spectroscopy and mass spectrometry, allowed the comprehensive pepper metabolite profile of pepper pulp, peel and seeds hydroalcoholic and organic extracts to be determined, showing the presence of sugars, organic acids, amino acids and other secondary metabolites. Targeted analyses, such as HPLC-PDA, HPLC-TLC and spectrophotometric analyses allowed polyphenols, tannins, flavonoids and pigments content to be determined. Samples quality and freshness were verified by the low content of biogenic amines and mycotoxins, as determined using HPLC-FLD and HPLC-MS, respectively. Preliminary biological results demonstrated the ability of the organic extracts to inhibit α-amylase, a key enzyme in the control of glucose metabolism.
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http://dx.doi.org/10.1016/j.foodchem.2018.02.050DOI Listing
July 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

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

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

New insights in oxybutynin chemical stability: Identification in transdermal patches of a new impurity arising from oxybutynin N-oxide rearrangement.

Eur J Pharm Sci 2016 Mar 18;84:123-31. Epub 2016 Jan 18.

Department of Pharmaceutical Sciences, University of Eastern Piedmont "Amedeo Avogadro", L.go Donegani 2, 28100 Novara, Italy.

Oxybutynin hydrochloride (Oxy), the first choice drug used for the management of urinary incontinence, is available in different types of formulations. However, due to its better lipophylicity and permeability, Oxyfree base was used in the new topical formulations such as transdermal patch and gel. The presence of an unprecedented impurity (Oxy-EK) in transdermal patches led to reinvestigate the chemical stability of Oxyfree base in oxidative conditions assigning, to Oxy-EK, the structure of (3E)-4-(N,N-diethylamino)-2-oxo-3-buten-1-yl 1-cyclohexyl-1-phenylglycolate. Oxy-EK arises from the prototropic rearrangement of oxybutynin N-oxides leading to the formation of an enamino ketone function which shows a long-wavelength UV-absorption. The total synthesis of Oxy-EK was performed, allowing to propose it as the indicator of stability for oxidative degradation of Oxy free base in transdermal formulations. The presence in the structure of Oxy-EK of an α,β-unsaturated carbonyl function, a potential Michael acceptor, suggested the need of evaluating its possible mutagenic power. Accordingly, the Ames test was performed: at nontoxic concentrations, Oxy-EK did not increase the number of revertant colonies in all strains tested both in the absence and presence of the exogenous metabolic activator S9.
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http://dx.doi.org/10.1016/j.ejps.2016.01.015DOI Listing
March 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

Interaction of α-Hexylcinnamaldehyde with a Biomembrane Model: A Possible MDR Reversal Mechanism.

J Nat Prod 2015 May 20;78(5):1154-9. Epub 2015 Apr 20.

†Department of Drug Sciences, University of Catania, Viale A. Doria 6, 95125 Catania, Italy.

The ability of the naturally derived compound α-hexylcinnamaldehyde (1) to interact with biomembranes and to modulate their permeability has been investigated as a strategy to reverse multidrug resistance (MDR) in cancer cells. Dimyristoylphosphatidylcholine (DMPC) multilamellar vesicles (MLVs) were used as biomembrane models, and differential scanning calorimetry was applied to measure the effect of 1 on the thermotropic behavior of DMPC MLVs. The effect of an aqueous medium or a lipid carrier on the uptake of 1 by the biomembrane was also characterized. Furthermore, taking into account that MDR is strictly regulated by redox signaling, the pro-oxidant and/or antioxidant effects of 1 were evaluated by the crocin-bleaching assay, in both hydrophilic and lipophilic environments. Compound 1 was uniformly distributed in the phospholipid bilayers and deeply interacted with DMPC MLVs, intercalating among the phospholipid acyl chains and thus decreasing their cooperativity. The lipophilic medium allowed the absorption of 1 into the phospholipid membrane. In the crocin-bleaching assay, the substance produced no pro-oxidant effects in both hydrophilic and lipophilic environments; conversely, a significant inhibition of AAPH-induced oxidation was exerted in hydrophilic medium. These results suggest a possible role of 1 as a chemopreventive and chemosensitizing agent for fighting cancer.
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http://dx.doi.org/10.1021/acs.jnatprod.5b00152DOI Listing
May 2015