Publications by authors named "Angela Bisio"

35 Publications

The diterpene Manool extracted from Salvia tingitana lowers free radical production in retinal rod outer segments by inhibiting the extramitochondrial F F ATP synthase.

Cell Biochem Funct 2021 Jan 20. Epub 2021 Jan 20.

Dipartimento di Farmacia (DIFAR), Università di Genova, Genova, Italy.

Uncontrolled oxidative stress production, especially in the outer retina is one of the causes of retinal degenerations. Mitochondria are considered the principal source of oxidative stress. However, a Reactive Oxygen Intermediates (ROI) production in the retinal photoreceptor layer seems to depend also on the expression of an extramitochondrial oxidative phosphorylation (OxPhos) machinery in the rod outer segments (OS). In fact, OS conduct aerobic metabolism, producing ATP through oxygen consumption, although it is devoid of mitochondria. As diterpenes display an antioxidant effect, we have evaluated the effect Manool, extracted from Salvia tingitana, on the extramitochondrial OxPhos and the ROI production in the retinal rod OS. Results confirm that the OxPhos machinery is ectopically expressed in the OS and that F F -ATP synthase is a target of Manool, which inhibited the OS ATP synthesis, binding the F moiety with high affinity, as analysed by molecular docking. Moreover, the overall slowdown of OxPhos metabolism reduced the ROI production elicited in the OS by light exposure, in vitro. In conclusion, data are consistent with the antioxidant properties of Salvia spp., suggesting its ability to lower oxidative stress production, a primary risk factor for degenerative retinal diseases. SIGNIFICANCE OF THE STUDY: Here we show that Manool, a diterpene extracted from Salvia tingitana has the potential to lower the free radical production by light-exposed rod outer segments in vitro, by specifically targeting the rod OS F F -ATP synthase belonging to the extramitochondrial OxPhos expressed on the disk membrane. The chosen experimental model allowed to show that the rod OS is a primary producer of oxidative stress linked to the pathogenesis of degenerative retinal diseases. Data are also consistent with the antioxidant and anti-inflammatory action of Salvia spp., suggesting a beneficial effect also in vivo.
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http://dx.doi.org/10.1002/cbf.3618DOI Listing
January 2021

Sclareol modulates free radical production in the retinal rod outer segment by inhibiting the ectopic ff-atp synthase.

Free Radic Biol Med 2020 Nov 24;160:368-375. Epub 2020 Aug 24.

Dipartimento di Farmacia (DIFAR), Università di Genova, V.le Benedetto XV 3, 16132, Genova, Italy. Electronic address:

We have previously shown that the retinal rod outer segments (OS) produce reactive oxygen species in the function of illumination in vitro, establishing a relationship among the extra-mitochondrial oxidative phosphorylation and phototransduction. This source of oxidative stress in the OS can be modulated by polyphenols, acting as inhibitors of FF-ATP synthase. The present study aimed at exploring whether sclareol, a diterpene, interacts with FF-ATP synthase mitigating the light-induced free radical production in the rod OS. Characterization of bovine retinal sections was conducted by immunogold analysis. Reactive oxygen intermediates production, oxygen consumption, the activity of the four respiratory complexes and ATP synthesis were evaluated in purified bovine rod OS. Molecular docking analyses were also conducted. Sclareol reduced free radical production by light-exposed rod OS. Such antioxidant effect was associated with an inhibition of the respiratory complexes and oxygen consumption (OCR), in coupled conditions. Sclareol also inhibited the rod OS ATP synthetic ability. Since the inhibitor effect on respiratory complexes and OCR is not observed in uncoupled conditions, it is supposed that the modulating effect of sclareol on the ectopic oxidative phosphorylation in the rod OS targets specifically the FF-ATP synthase. This hypothesis is confirmed by the in silico molecular docking analyses, which shows that sclareol binds the F moiety of ATP synthase with high affinity. In conclusion, a beneficial effect of sclareol can be envisaged as a modulator of oxidative stress in the photoreceptor, a risk factor for the degenerative retinal diseases, suggestive of its potential beneficial action also in vivo.
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http://dx.doi.org/10.1016/j.freeradbiomed.2020.08.014DOI Listing
November 2020

Trace Elements in Edible Flowers from Italy: Further Insights into Health Benefits and Risks to Consumers.

Molecules 2020 Jun 23;25(12). Epub 2020 Jun 23.

Dipartimento di Farmacia, Università degli Studi di Genova, Viale Cembrano 4, 16148 Genova, Italy.

The use of edible flowers in cooking dates back to ancient times, but recently it is gaining success among the consumers, increasingly attentive to healthy and sustainable foods of high quality, without neglecting taste, flavour, and visual appeal. The present study aims to deepen the knowledge regarding the mineral composition of edible flowers, an aspect not widely investigated in scientific literature. The concentrations of Cd, Co, Cu, Fe, Mn, Ni, Pb, Sr, V, and Zn have been determined by Inductively Coupled Plasma Optical Emission Spectrometry (ICP OES) in flowers belonging to a wide variety of species. The study highlights that some floral species are characterized by significantly higher concentrations of certain trace elements, e.g., the flowers of for Mn, those of basil () and of pumpkins ( and ) for Cu and Sr, and those of orange daylily () for Ni. Potentially toxic elements are present at low concentrations, often below the limit of the detection for Cd, Co, Ni, V. In all samples, Cd and Pb are well below the maximum permitted levels in foodstuffs. It can be concluded that the edible flowers analyzed can be considered a good source of essential elements and do not present risks for the consumer health as for the mineral composition.
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http://dx.doi.org/10.3390/molecules25122891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355664PMC
June 2020

Antibacterial and ATP Synthesis Modulating Compounds from .

J Nat Prod 2020 04 17;83(4):1027-1042. Epub 2020 Mar 17.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy.

A surface extract of the aerial parts of afforded a nor-sesterterpenoid () and eight new sesterterpenoids (-̵), along with five known sesterterpenoids, five labdane and one abietane diterpenoid, one sesquiterpenoid, and four flavonoids. The structures of the new compounds were established by 1D and 2D NMR spectroscopy, HRESIMS, and VCD data and Mosher's esters analysis. The antimicrobial activity of compounds was evaluated against 30 human pathogens including 27 clinical strains and three isolates of marine origin for their possible implications on human health. The methyl ester of salvileucolide (), salvileucolide-6,23-lactone (), sclareol (), and manool () were the most active against Gram-positive bacteria. The compounds were also tested for the inhibition of ATP production in purified mammalian rod outer segments. Terpenoids , , , and inhibited ATP production, while only inhibited also ATP hydrolysis. Molecular modeling studies confirmed the capacity of to interact with mammalian ATP synthase. A significant reduction of ATP production in the presence of was observed in and isolates.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01024DOI Listing
April 2020

The novel diterpene 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone from Salvia corrugata shows complex cytotoxic activities against human breast epithelial cells.

Life Sci 2019 Sep 27;232:116610. Epub 2019 Jun 27.

Department of Integrated Oncological Therapies, IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Aims: The aim of this study was the characterization of the in vitro cytotoxic properties of a recently isolated diterpene compound, 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone (compound 1), extracted from Salvia corrugata, versus human cell lines.

Main Methods: We used as model study immortalized breast epithelial cells MCF10A and two ERBB2 breast cancer (BCa) cell lines, SKBR-3 and BT474. Compound 1 was isolated by methanolic extraction from regenerated shoots of Salvia corrugata Vahl, and purified by high pressure liquid chromatography (HPLC). Flow cytometry (FCM) was employed for cell cycle, apoptosis and reactive oxygen species (ROS) analysis. Cell morphology was assessed by immunofluorescence and transmission electron microscopy (TEM).

Key Findings: Compound 1 inhibited cell survival of all breast cell lines. In particular, compound 1 promoted cell cycle arrest in the G0/G1 phase and apoptosis along with impairment of the mitochondrial function, which was reflected in a gross alteration of the mitochondrial network structure. Furthermore, we also detected a potent activation of the ERK1/2 kinase, which suggested the induction of reactive oxygen species (ROS). Partial rescue of survival obtained with n-acetylcysteine (NAC) when coadminstered with compound 1 further supported a contribution of ROS mediated mechanisms to the growth-arrest and proapoptotic activity of compound 1 in both BCa cell lines. ROS production was indeed confirmed in SKBR-3.

Significance: Our findings show that compound 1 has a cytotoxic activity against both human normal and cancer cell lines derived from breast epithelia, which is mediated by ROS generation and mitochondrial damage.
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http://dx.doi.org/10.1016/j.lfs.2019.116610DOI Listing
September 2019

Phytochemistry of compounds isolated from the leaf-surface extract of Psiadia punctulata (DC.) Vatke growing in Saudi Arabia.

Phytochemistry 2018 Nov 24;155:191-202. Epub 2018 Aug 24.

Department of Veterinary Medicine and Animal Production, University of Napoli Federico II, Via Delpino 1, 80137, Napoli, Italy.

The surface extract of an accession of Psiadia punctulata (DC.) Vatke (Asteraceae) growing in Saudi Arabia was investigated for its phytochemical composition. A bio-guided investigation of the extract led to the isolation of thirteen ent-kaurane and trachylobane diterpenes and seventeen compounds previously described, including nine flavonoids and eight diterpenes. Three flavonoids and one ent-kaurane diterpene showed antimicrobial activity with MIC100 values ranging from 25 to 150 μg/ml. The extract showed antibacterial activity against Staphylococcus aureus (MIC = 180 μg/ml) and antifungal activity against Candida albicans (MIC = 130 μg/ml). The isolated 3',4',5,7-tetramethoxyflavone, at a concentration of 40 μg/ml, displayed the ability to reduce biofilm formation of S. aureus and C. albicans by 50% and 90% respectively.
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http://dx.doi.org/10.1016/j.phytochem.2018.08.003DOI Listing
November 2018

Cooperative antitumor activities of carnosic acid and Trastuzumab in ERBB2 breast cancer cells.

J Exp Clin Cancer Res 2017 11 3;36(1):154. Epub 2017 Nov 3.

Department of Integrated Oncological Therapies, IRCCS AOU - San Martino - IST, Largo Rosanna Benzi 10, 16132, Genoa, Italy.

Background: ERBB2 is overexpressed in up to 20-30% of human breast cancers (BCs), and it is associated with aggressive disease. Trastuzumab (Tz), a humanized monoclonal antibody, improves the prognosis associated with ERBB2-amplified BCs. However, the development of resistance remains a significant challenge. Carnosic acid (CA) is a diterpene found in rosemary and sage, endowed with anticancer properties. In this in vitro study, we have investigated whether Tz and CA have cooperative effects on cell survival of ERBB2 overexpressing (ERBB2) cells and whether CA might restore Tz sensitivity in Tz-resistant cells.

Methods: We have studied BC cell migration and survival upon CA and Tz treatment. In particular, migration ability was assessed by transwell assay while cell survival was assessed by MTT assay. In addition, we have performed cell cycle and apoptosis analysis by high-resolution DNA flow cytometry and annexin-V, resazurin and sytox blue staining by flow cytometry, respectively. The expression of proteins involved in cell cycle progression, ERBB2 signaling pathway, and autophagy was evaluated by immunoblot and immunofluorescence analysis. Cellular structures relevant to the endosome/lysosome and autophagy pathways have been studied by immunofluorescence and transmission electron microscopy.

Results: We report that, in ERBB2 BC cells, CA reversibly enhances Tz inhibition of cell survival, cooperatively inhibits cell migration and induces cell cycle arrest in G0/G1. These events are accompanied by ERBB2 down-regulation, deregulation of the PI3K/AKT/mTOR signaling pathway and up-regulation of both CDKN1A/p21 and CDKN1B/p27. Furthermore, we have demonstrated that CA impairs late autophagy and causes derangement of the lysosomal compartment as shown by up-regulation of SQSTM1/p62 and ultrastructural analysis. Accordingly, we have found that CA restores, at least in part, sensitivity to Tz in SKBR-3 Tz-resistant cell line.

Conclusions: Our data demonstrate the cooperation between CA and Tz in inhibiting cell migration and survival of ERBB2 BC cells that warrant further studies to establish if CA or CA derivatives may be useful in vivo in the treatment of ERBB2 cancers.
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http://dx.doi.org/10.1186/s13046-017-0615-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5670707PMC
November 2017

Antibacterial and Hypoglycemic Diterpenoids from Salvia chamaedryoides.

J Nat Prod 2017 02 10;80(2):503-514. Epub 2017 Feb 10.

Dipartimento di Farmacia, Università di Salerno , Via Giovanni Paolo II 132, 84084 Salerno, Italy.

A surface extract of the aerial parts of Salvia chamaedryoides afforded 13 diterpenes (1-13), with seven compounds (1, 3, 4, 7-9, 12) described for the first time. The structures of the new compounds were established using 1D and 2D NMR spectroscopic methods, HRESIMS, and ECD data. The potential hypoglycemic effects of the crude extract, fractions, and pure compounds from S. chamaedryoides were investigated by inhibition of α-glucosidase and α-amylase enzymes. The extract and its fractions showed a moderate dose-dependent inhibition; the pure compounds exhibited differential inhibitory activity against these two enzymes. Molecular modeling studies were also performed to suggest the interaction mode of compound 3 in the α-glucosidase enzyme active site. The antimicrobial activity of the purified compounds was investigated against 26 clinical pathogens. No activity was detected for the Gram-negative species tested nor on Candida albicans and C. glabrata, while variable susceptibilities were observed using Gram-positive staphylococcal and enterococcal species.
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http://dx.doi.org/10.1021/acs.jnatprod.6b01053DOI Listing
February 2017

Identification of as gerosuppressant agent by using an integrated senescence-screening assay.

Aging (Albany NY) 2016 12;8(12):3223-3240

Laboratory for Research and Development in Aging, Atrahasis S.r.l., 00189 Rome, Italy.

Cellular senescence is a stable cell cycle arrest that is the causative process of aging. The PI3K/AKT/mTOR pathway is implicated in the control of cellular senescence and inhibitors of this pathway have been successfully used for life span prolongation experiments in mammals. PTEN is the major regulator of the PI3K/AKT/mTOR pathway and loss of PTEN promotes a senescence response termed PICS. Here we report a novel-screening assay, for the identification of compounds that block different types of senescence response. By testing a library of more than 3000 natural and chemical compounds in PTEN deficient cells we have found that an extract from (SH), a native plant of Bolivia is a potent inhibitor of PICS. SH also decreases replicative and UV-mediated senescence in human primary fibroblasts and in a model of reconstructed human epidermis. Mechanistically, SH treatment affects senescence driven by UV by interfering with IL1-α signalling. Pre-clinical and clinical testing of this extract by performing toxicity and irritability evaluation also demonstrate the safety of SH extract for clinical use as anti-aging skin treatment.
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http://dx.doi.org/10.18632/aging.101076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5270665PMC
December 2016

Anti-inflammatory and analgesic activity of carnosol and carnosic acid in vivo and in vitro and in silico analysis of their target interactions.

Br J Pharmacol 2017 06 8;174(11):1497-1508. Epub 2016 Aug 8.

Department of Pharmacy, University of Salerno, Fisciano, Salerno, Italy.

Background And Purpose: The diterpenoids carnosol (CS) and carnosic acid (CA) from Salvia spp. exert prominent anti-inflammatory activities but their molecular mechanisms remained unclear. Here we investigated the effectiveness of CS and CA in inflammatory pain and the cellular interference with their putative molecular targets.

Experimental Approach: The effects of CS and CA in different models of inflammatory pain were investigated. The inhibition of key enzymes in eicosanoid biosynthesis, namely microsomal prostaglandin E synthase-1 (mPGES-1) and 5-lipoxygenase (5-LO) was confirmed by CS and CA, and we determined the consequence on the eicosanoid network in activated human primary monocytes and neutrophils. Molecular interactions and binding modes of CS and CA to target enzymes were analyzed by docking studies.

Key Results: CS and CA displayed significant and dose-dependent anti-inflammatory and anti-nociceptive effects in carrageenan-induced mouse hyperalgesia 4 h post injection of the stimuli, and also inhibited the analgesic response in the late phase of the formalin test. Moreover, both compounds potently inhibited cell-free mPGES-1 and 5-LO activity and preferentially suppressed the formation of mPGES-1 and 5-LO-derived products in cellular studies. Our in silico analysis for mPGES-1 and 5-LO supports that CS and CA are dual 5-LO/mPGES-1 inhibitors.

Conclusion And Implications: In summary, we propose that the combined inhibition of mPGES-1 and 5-LO by CS and CA essentially contributes to the bioactivity of these diterpenoids. Our findings pave the way for a rational use of Salvia spp., traditionally used as anti-inflammatory remedy, in the continuous expanding context of nutraceuticals.

Linked Articles: This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc.
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http://dx.doi.org/10.1111/bph.13545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5429324PMC
June 2017

Carnosic acid induces proteasomal degradation of Cyclin B1, RB and SOX2 along with cell growth arrest and apoptosis in GBM cells.

Phytomedicine 2016 Jun 6;23(7):679-85. Epub 2016 Apr 6.

IRCCS AOU - San Martino - IST, Largo Rosanna Benzi, 10, 16132 Genova, Italy. Electronic address:

Background: Carnosic acid (CA) is a diterpenoid found in Rosmarinus officinalis L. and Salvia officinalis L. as well as in many other Lamiaceae. This compound is reported to have antioxidant and antimicrobial properties. In addition, a number of reports showed that CA has a cytotoxic activity toward several cancer cell lines.

Purpose: The aim of this study was to establish whether CA has any specific antiproliferative effect toward human glioblastoma (GBM) cells and to analyze the molecular mechanisms involved.

Methods: We evaluated cell survival by MTT assay, apoptosis and DNA content by flow cytometry, protein expression and phosphorylation by immunoblot analyses.

Results: Our results showed that CA inhibited cell survival on both normal astrocytes and GBM cells. In GBM cells, in particular, CA caused an early G2 block, a reduction in the percentage of cells expressing Ki67, an enhanced expression of p21(WAF) and induced apoptosis. Furthermore, we showed that CA promoted proteasomal degradation of several substrate proteins, including Cyclin B1, retinoblastoma (RB), SOX2, and glial fibrillary acid protein (GFAP), whereas MYC levels were not modified. In addition, CA dramatically reduced the activity of CDKs.

Conclusion: In conclusion, our findings strongly suggest that CA promotes a profound deregulation of cell cycle control and reduces the survival of GBM cells via proteasome-mediated degradation of Cyclin B1, RB and SOX2.
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http://dx.doi.org/10.1016/j.phymed.2016.03.007DOI Listing
June 2016

Establishment and analysis of in vitro biomass from Salvia corrugata Vahl. and evaluation of antimicrobial activity.

Phytochemistry 2016 Feb 2;122:276-285. Epub 2016 Jan 2.

Dipartimento di Farmacia, Università di Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy.

Demethylfruticuline A and fruticuline A, the most abundant compounds from the surface extract of Salvia corrugata Vahl., have shown antibacterial, antitumor and cytotoxic activities. In order to obtain these icetexane diterpenes from in vitro cultures of S. corrugata, protocols were developed for callus production, micropropagation and shoot regeneration. Analysis of the regenerated shoots showed the presence of both icetexanes, micropropagated plants contained only fruticuline A, while the callus contained trace amounts of both diterpenes. The yield of fruticuline A was higher in the methanolic extract of regenerated shoots than in those of fresh leaves and fresh shoot tips. In addition to these diterpenes, the regenerated shoot and micropropagated plant extracts afforded seven other diterpenes, one icetexane and six abietanes, identified by UV, IR, 1D- and 2D-NMR and HR-MS analysis. Five compounds (19-acetoxy-7α-hydroxyroyleanone, 7β,20-epoxy-11,12,19-trihydroxyabieta-8,11,13-triene, 7,20-dihydrofruticuline A, 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone, 7β-ethoxy-6β,20:19,20-diepoxyroyleanone) were previously undescribed. Although the crude plant surface extract did not possess any antibacterial activity, methanolic extracts of in vitro tissues and two compounds, namely 7β-acetoxy-20-hydroxy-19,20-epoxyroyleanone and 7β-ethoxy-6β,20:19,20-diepoxyroyleanone, isolated in suitable amounts, were active in varying degrees against multidrug resistant clinical strains of Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis and Enterococcus faecium, displaying MIC values ranging from 32, 64 to 128μg/mL.
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http://dx.doi.org/10.1016/j.phytochem.2015.12.017DOI Listing
February 2016

Isolation of hydroxyoctaprenyl-1',4'-hydroquinone, a new octaprenylhydroquinone from the marine sponge Sarcotragus spinosulus and evaluation of its pharmacological activity on acetylcholine and glutamate release in the rat central nervous system.

Nat Prod Commun 2014 Nov;9(11):1581-4

Three polyprenyl-1',4'-hydroquinone derivatives, heptaprenyl-1',4'-hydroquinone (1), octaprenyl-1',4'-hydroquinone (2), and hydroxyoctaprenyl-1',4'- hydroquinone (3) were isolated from the marine sponge Sarcotragus spinosulus collected at Baia di Porto Conte, Alghero (Italy). Our findings indicate that the compounds isolated from S. spinosulus can significantly modulate the release of glutamate and acetylcholine in the rat hippocampus and cortex and might, therefore, represent the prototype of a new class of drugs regulating glutamatergic and cholinergic transmission in the mammalian central nervous system.
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November 2014

Antibacterial compounds from Salvia adenophora Fernald (Lamiaceae).

Phytochemistry 2015 Feb 27;110:120-32. Epub 2014 Nov 27.

Dipartimento di Farmacia, Università di Salerno, Via Giovanni Paolo II 132, 84084 Salerno, Italy.

From the aerial parts of Salvia adenophora Fernald four derivatives of 12-oxo-phytodienoic acid (1-4) together with five clerodane diterpenoids (5, 6, 8-10), and one known diterpene (7) have been isolated. Compounds 1-6 and 8-10 are described for the first time. The structures were established by extensive 1D, 2D NMR and HRESI-TOFMS spectroscopic methods. Finally, the absolute configuration has been established by comparing of experimental and quantum chemical calculation of ECD spectra. Despite a total lack of antimicrobial activity of the plant extract, hinting to the existence of antagonistic interactions in the crude material, three oxylipins (2-4) displayed a promising inhibition on Gram-positive multidrug-resistant clinical strains including Staphylococcus aureus, Streptococcus agalactiae and, particularly, Staphylococcus epidermidis, while the compounds 9 and 10 revealed a specific and strain-dependent activity against S. epidermidis. Interestingly, the inhibition provided by these compounds was independent of the resistance patterns of these pathogens to classic antibiotics. No action was reported on Gram-negative strains nor on Candida albicans. These results confirm that clerodanes and, particularly, prostaglandin-like compounds can be considered as interesting antimicrobial agents deserving further study.
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http://dx.doi.org/10.1016/j.phytochem.2014.10.033DOI Listing
February 2015

Cancer chemopreventive diterpenes from Salvia corrugata.

Phytochemistry 2013 Dec 10;96:257-64. Epub 2013 Oct 10.

Department of Pharmacy, University of Genoa, via Brigata Salerno 13, 16147 Genoa, Italy.

NMR and NP-HPLC-UV profiling of the exudate of Salvia corrugata revealed that its secondary metabolite composition was largely dominated by α-hydroxy-β-isopropyl-benzoquinone diterpenoids. Among them, four diterpenes not described previously were isolated and identified as fruticulin C (3), 7α-methoxy-19-acetoxy-royleanone (4), 7α,19-diacetoxy-royleanone (5), and 7-dehydroxy-conacytone (7). In addition, the known diterpenes fruticulin A (1), demethyl-fruticulin A (2) and 7α-O-methyl-conacytone (6) were also obtained. The isolated compounds were evaluated for their cancer chemopreventive activity by measuring quinone reductase induction activity and histone deacetylase inhibition. Three compounds (1, 2 and 5) showed promising activity.
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http://dx.doi.org/10.1016/j.phytochem.2013.09.011DOI Listing
December 2013

Sustainable production of biologically active molecules of marine based origin.

N Biotechnol 2013 Sep 3;30(6):839-50. Epub 2013 Apr 3.

Department of Applied Science, Limerick Institute of Technology, Limerick, Ireland; Shannon Applied Biotechnology Centre, Hartnett Enterprise Acceleration Centre, Limerick Institute of Technology, Limerick, Ireland.

The marine environment offers both economic and scientific potential which are relatively untapped from a biotechnological point of view. These environments whilst harsh are ironically fragile and dependent on a harmonious life form balance. Exploitation of natural resources by exhaustive wild harvesting has obvious negative environmental consequences. From a European industry perspective marine organisms are a largely underutilised resource. This is not due to lack of interest but due to a lack of choice the industry faces for cost competitive, sustainable and environmentally conscientious product alternatives. Knowledge of the biotechnological potential of marine organisms together with the development of sustainable systems for their cultivation, processing and utilisation are essential. In 2010, the European Commission recognised this need and funded a collaborative RTD/SME project under the Framework 7-Knowledge Based Bio-Economy (KBBE) Theme 2 Programme 'Sustainable culture of marine microorganisms, algae and/or invertebrates for high value added products'. The scope of that project entitled 'Sustainable Production of Biologically Active Molecules of Marine Based Origin' (BAMMBO) is outlined. Although the Union is a global leader in many technologies, it faces increasing competition from traditional rivals and emerging economies alike and must therefore improve its innovation performance. For this reason innovation is placed at the heart of a European Horizon 2020 Strategy wherein the challenge is to connect economic performance to eco performance. This article provides a synopsis of the research activities of the BAMMBO project as they fit within the wider scope of sustainable environmentally conscientious marine resource exploitation for high-value biomolecules.
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http://dx.doi.org/10.1016/j.nbt.2013.03.006DOI Listing
September 2013

Effects of the neoclerodane Hardwickiic acid on the presynaptic opioid receptors which modulate noradrenaline and dopamine release in mouse central nervous system.

Neurochem Int 2013 Mar 26;62(4):354-9. Epub 2013 Jan 26.

Department of Pharmacy, Pharmacology and Toxicology Section, University of Genoa, Italy.

We have comparatively investigated the effects of Hardwickiic acid and Salvinorin A on the K(+)-evoked overflow of [(3)H]noradrenaline ([(3)H]NA) and [(3)H]dopamine ([(3)H]DA) from mouse hippocampal and striatal nerve terminals, respectively. The K(+)-evoked overflow of [(3)H]DA was inhibited in presence of Salvinorin A (100 nM) but not in presence of Hardwickiic acid (100 nM). Hardwickiic acid (100 nM) mimicked Salvinorin A (100 nM) in facilitating K(+)-evoked hippocampal [(3)H]NA overflow and the two compounds were almost equipotent. Facilitation of [(3)H]NA overflow caused by 100 nM Hardwickiic acid was prevented by the κ-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 100 nM) and by the selective δ-opioid receptor (DOR) antagonist naltrindole (100 nM), but was not altered by 100 nM D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), a selective μ-opioid receptor (MOR) antagonist. We conclude that Hardwickiic acid modulates hippocampal [(3)H]NA overflow evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptor subtypes.
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http://dx.doi.org/10.1016/j.neuint.2013.01.016DOI Listing
March 2013

Chemical composition and antimicrobial activity of Salvia x jamensis essential oil.

Nat Prod Commun 2012 Sep;7(9):1237-40

Dipartimento di Scienze della Terra, della Vitae dell'Ambiente, Sezione di Biologia Vegetale, Università degli Studi di Urbino "Carlo Bo", Via Bramante 28 - 61029 Urbino (PU), Italy.

This is the first report about the composition of the essential oil of Salvia x jamensis. The major compounds identified by GC-MS were beta-caryophyllene (14.8 %), beta-pinene (6.8 %), caryophyllene oxide (6.0 %), delta-cadinene (5.5 %), alpha-pinene (5.2 %) and spatulenol (5.2 %). The oil showed antimicrobial activity against three Gram (+) bacteria: Bacillus cereus, Staphylococcus aureus, and S. epidermidis, and three Candida strains: C. albicans, C. glabrata and C. tropicalis, while it was inactive against three Gram (-) bacteria: Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae.
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September 2012

Salvia x jamensis J. Compton: Trichomes, essential oil constituents and cytotoxic-apoptotic activity.

Nat Prod Res 2013 2;27(17):1583-8. Epub 2012 Oct 2.

Dipartimento di Scienze della Terra, della Vita e dell'Ambiente, Sezione di Biologia Vegetale, Università degli Studi di Urbino "Carlo Bo", Urbino, Italy.

Salvia x jamensis J. Compton is a hybrid between Salvia greggii A. Gray and Salvia microphylla Kunt. In this study, we describe three hair types identified by Scanning Electron Microscopy. In the essential oil of the aerial parts of S. jamensis 56 different compounds were identified. The two main constituents were β-caryophyllene (14.8%) and β-pinene (6.8%). Cytotoxic-apoptotic activity of S. x jamensis essential oil has been investigated by using U937 cell line. The essential oil EC50 for cell number and for cell apoptosis have been shown to be 360 and 320 µg mL(-1), respectively. Among the constituents of the oil examined, only β-caryophyllene, β-pinene and α-pinene displayed cytotoxic and apoptotic activities. For the first time, it has been demonstrated that some of the pure constituents identified within S. x jamensis essential oil are responsible for its cytotoxic-apoptotic activity when properly combined.
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http://dx.doi.org/10.1080/14786419.2012.730044DOI Listing
April 2014

A chemical proteomics approach reveals Hsp27 as a target for proapoptotic clerodane diterpenes.

Mol Biosyst 2012 Oct;8(10):2637-44

Dipartimento di Scienze Farmaceutiche, Università di Pisa, via Bonanno 33, 56126 Pisa, Italy.

Clerodane diterpenoids are a class of naturally occurring molecules widely distributed in the Lamiaceae family. Neo-clerodane diterpenoids from Salvia ssp were recently described as compounds inhibiting the proliferation of human cancer cell lines. To gain new insights into molecular mechanism(s) underlying the antitumor potential of this class of compounds, we used a chemical proteomics approach to analyse the cellular interactome of hardwickiic acid (HAA) selected as a representative molecule. HAA was linked to an opportune 1,1'-carbonyldiimidazole modified by 1,12-dodecanediamine and then immobilized on a matrix support. The modified beads were then used as bait for fishing the potential partners of HAA in a U937 cell lysate. We identified heat shock protein 27 (Hsp27), an ATP-independent antiapoptotic chaperone characterized for its tumorigenic and metastatic properties and now referenced as a major therapeutic target in many types of cancer, as a major HAA partner. Here, we also report the study of HAA-Hsp27 interaction by means of a panel of chemical and biological approaches, including surface plasmon resonance measurements limited proteolysis, and biochemical assays. Our data suggest that HAA could provide a potential tool to develop strategies for the discovery of Hsp27 chemical inhibitors.
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http://dx.doi.org/10.1039/c2mb25171jDOI Listing
October 2012

Total phenolic content and antioxidant activity of Salvia spp. exudates.

Nat Prod Commun 2012 Feb;7(2):201-2

Dipartimento di Scienze della Terra, della Vitae dell'Ambiente (DiSTeVA) - Sez. Biologia Vegetale-Università degli Studi di Urbino "Carlo Bo", Via Bramante 28 - 61029, Urbino (PU), Italy.

The total phenolic content and antioxidant activity of 6 Salvia spp. exudates were measured to find new potential sources of natural antioxidants. Total phenolic content was assessed by a modified Prussian blue method, and the antioxidant activity by two methods: 1,1-diphenyl-2-picryl-hydrazyl (DPPH) radical scavenging capacity assay and lipoxygenase inhibitory assay. The total phenolic content ranged between 1.3 microg/mg DW (S. fallax) and 74.0 microg/mg DW (S. cacaliaefolia). In the DPPH test, S. cacaliaefolia was more effective than BHT, while in the inhibition of lipid peroxidation all the extracts presented good antioxidant capacity.
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February 2012

Phytotoxic clerodane diterpenes from Salvia miniata Fernald (Lamiaceae).

Phytochemistry 2011 Feb 2;72(2-3):265-75. Epub 2010 Dec 2.

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Università di Genova, Genova, Italy.

Our ongoing research to identify natural growth inhibitors with diterpene and triterpene skeletons exuding from the surface of the aerial parts of Salvia species led us to study Salvia miniata Fernald. Ten clerodane diterpenoids were found, along with three known diterpenes. Most of the isolated compounds from S. miniata inhibited the germination of Papaver rhoeas L. and Avena sativa L. in Petri dish experiments. Parallel results have been obtained in experiments carried out to evaluate the subsequent growth of the seedlings of the target species in the presence of the tested compounds.
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http://dx.doi.org/10.1016/j.phytochem.2010.11.011DOI Listing
February 2011

Demethyl fruticulin A (SCO-1) causes apoptosis by inducing reactive oxygen species in mitochondria.

J Cell Biochem 2010 Dec;111(5):1149-59

Centro Biotecnologie Avanzate, Genova, Italy.

Demethyl fruticulin A (SCO-1) is a compound found in Salvia corrugata leaves. SCO-1 was reported to induce anoikis in cell lines via the membrane scavenging receptor CD36. However, experiments performed with cells lacking CD36 showed that SCO-1 was able to induce apoptosis also via alternative pathways. To gain some insight into the biological processes elicited by this compound, we undertook an unbiased genomic approach. Upon exposure of glioblastoma tumor initiating cells (GBM TICs) to SCO-1 for 24 h, we observed a deregulation of the genes belonging to the glutathione metabolism pathway and of those belonging to the biological processes related to the response to stress and to chemical stimulus. On this basis, we hypothesized that the SCO-1 killing effect could result from the induction of reactive oxygen species (ROS) in the mitochondria. This hypothesis was confirmed by flow cytometry using MitoSOX, a mitochondria-selective fluorescent reporter of ROS, and by the ability of N-acetyl cysteine (NAC) to inhibit apoptosis when co-administered with SOC-1 to the GBM TICs. We further show that NAC also protects other cell types such as HeLa, MG-63, and COS-7 from apoptosis. We therefore propose that ROS production is the major molecular mechanism responsible for the pro-apoptotic effect induced by SCO-1. Consequently, SCO-1 may have a potential therapeutic value, which deserves further investigation in animal models.
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http://dx.doi.org/10.1002/jcb.22801DOI Listing
December 2010

New flavonoid glycosides from Vernonia ferruginea.

Nat Prod Commun 2009 Dec;4(12):1639-42

Dipartimento di Scienze Farmaceutiche, Università di Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.

Four new flavonoid glycosides, quercetin 3-O-beta-D-xylopyranosyl-(1-4)-beta-D-glucopyranoside, quercetin 3-O-beta-D-apiofuranosyl-(1-4)-beta-D-glucopyranoside, kaempferol 3-O-beta-D-apiofuranosyl-(1-4)-beta-D-glucopyranoside, and kaempferol 4'-methyl ether 3-O-beta-D-xylopyranoside, along with other known flavonoids and phenolic derivatives, were isolated from the leaves of Vernonia ferruginea Less. Their structures were established on the basis of detailed spectral analysis.
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December 2009

Phytotoxic activity of Salvia x jamensis.

Nat Prod Commun 2009 Dec;4(12):1621-30

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, University of Genoa, Genoa, Italy.

A study has been carried out on the surface exudate of Salvia x jamensis, which showed a significant phytotoxic activity against Papaver rhoeas L. and Avena sativa L.. Bioguided separation of the exudate yielded active fractions from which 3 beta-hydroxy-isopimaric acid (1), hautriwaic acid (2), betulinic acid (3), 7,8 beta-dihydrosalviacoccin (4), isopimaric acid (5), 14 alpha-hydroxy-isopimaric acid (7), 15,16-epoxy-7 alpha, 10 beta-dihydroxy-clerod-3,13(16),14-trien-17,12;18,19-diolide (8), cirsiliol (5,3',4'-trihydroxy-6,7-dimethoxyflavone, 9) and two new neoclerodane diterpenes (6 and 10) were isolated. The structures of 6 and 10 were identified as 15,16-epoxy-10 beta-hydroxy-clerod-3,13(16),14-trien-17,12;18,19-diolide and 15,16-epoxy-7 alpha,10-dihydroxy-clerod-2,13(16),14-trien-17,12;18,19-diolide respectively on the basis of spectroscopic data analysis. All compounds, but 7, 8 and 10, were active in inhibiting the germination of the tested species.
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December 2009

Preparation, characterisation and preliminary antitumour activity evaluation of a novel nanoparticulate system based on a cisplatin-hyaluronate complex and N-trimethyl chitosan.

Invest New Drugs 2011 Jun 29;29(3):443-55. Epub 2009 Dec 29.

Dipartimento di Chimica e Tecnologie Farmaceutiche ed Alimentari, Via Brigata Salerno 13, 16147, Genoa, Italy.

In this work, nanoparticles with a positive surface charge were prepared through the electrostatic interaction of a new cisplatin-hyaluronate complex with N-trimethyl chitosan (substitution degree of 85%). Mean particle diameter was approximately 195 nm. Drug loading of nanoparticles, which had a zeta potential of about 27 mV, was equal to 6% w/w. After 24 h, while the cisplatin-hyaluronate complex released approximately 60% w/w drug in phosphate buffered saline at pH 7.4, approximately 40% w/w of total cisplatin was released from nanoparticles. The same cumulative amounts of released drug were found after 48 h. These nanoparticles, as well as the starting cisplatin-hyaluronate complex, were active on all cell lines tested (P388, A2780, A549), with an antiproliferative activity similar to that of cisplatin. Apoptosis was markedly induced in A2780 cells by nanoparticles. In a preliminary in vivo experiment, the antitumour activity against a murine tumour (P388 cells) subcutaneously implanted in mice, resulted similar to that of cisplatin for nanoparticles whereas the starting complex showed a non-significant activity at the cisplatin dose tested. Body weight change of treated mice suggested a significantly better tolerance of the nanoparticles compared to cisplatin, after an initial brief period of acute toxicity higher than the parent drug. These results indicate that such a particulate system could be useful as a carrier for cisplatin delivery.
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http://dx.doi.org/10.1007/s10637-009-9373-yDOI Listing
June 2011

The administration of demethyl fruticulin A from Salvia corrugata to mammalian cells lines induces "anoikis", a special form of apoptosis.

Phytomedicine 2010 May 13;17(6):449-56. Epub 2009 Aug 13.

Stem Cell Laboratory, Advanced Biotechnology Center, Largo R. Benzi 10, 16132 Genova, Italy.

Recently demethyl fruticulin A was identified as the major diterpenoid component of the exudates produced by the trichomes of Salvia corrugata leafs. Given the documented apoptotic effects of some of the other known components of the exudates from Salvia species, we assessed if demethyl fruticulin A, once administered to mammalian cells, was involved in the onset of apoptosis and if its biological effects were exerted through the participation of a scavenger membrane receptor, CD36. Three model cell lines were chosen, one of which lacking CD36 expression. Functional availability of the receptor, or its transcriptional rate, were blocked/reduced with a specific antibody or by the administration of vitamin E. Immunodetection of cell cytoskeletal components and tunel analysis revealed that demethyl fruticulin A triggers the onset of anoikis, a special form of apoptosis induced by cell detachment from the substrate. Impairment of CD36 availability/transcription confirmed the receptor partial involvement in the intake of the substance and in anoikis, as also sustained by FACS analysis and by the downregulation of p95, a marker of anoikis, upon blockade of CD36 transcription. However, experiments with CD36-deficient cells suggested that alternate pathways, still to be determined, may take part in the biological effects exerted by demethyl fruticulin A.
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http://dx.doi.org/10.1016/j.phymed.2009.07.007DOI Listing
May 2010

Salvinorin A exerts opposite presynaptic controls on neurotransmitter exocytosis from mouse brain nerve terminals.

Neuropharmacology 2009 Oct-Nov;57(5-6):523-30. Epub 2009 Jul 21.

Department of Experimental Medicine, Pharmacology and Toxicology Section, University of Genoa, 16148 Genova, Italy.

We investigated the effects of salvinorin A on the basal and the 12 mM K(+)-evoked release of preloaded [(3)H]noradenaline ([(3)H]NA) and [(3)H]serotonin ([(3)H]5-HT) from mouse hippocampal nerve terminals (synaptosomes), as well as on the basal and 12mM K(+)-evoked release of preloaded [(3)H]dopamine ([(3)H]DA) from mouse striatal and prefrontal cortex (PFc) synaptosomes. Salvinorin A (0.1-1000 nM) failed to affect the basal release of amines, but inhibited the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]5-HT and [(3)H]DA. At the same concentration, salvinorin A facilitated the 12 mM K(+)-evoked, Ca(2+)-dependent, exocytotic-like release of [(3)H]NA. These effects could not be observed in pertussis toxin (PTx) entrapped synaptosomes. The broad spectrum kappa-opioid receptor (KOR) antagonist norbinaltorphimine (norBNI, 1-100 nM) antagonized the inhibition of [(3)H]5-HT and [(3)H]DA exocytosis as well as the facilitation of [(3)H]NA overflow induced by 100 nM salvinorin A. The KOR agonist U69593 (1-100 nM) mimicked salvinorin A in inhibiting [(3)H]5-HT and of [(3)H]DA exocytosis, its effect being prevented by norBNI, but leaving unchanged the K(+)-evoked release of [(3)H]NA. The effects of Salvinorin A on neurotransmitter exocytosis were not prevented by the selective mu opioid (MOR) receptor antagonist CTAP (10-100 nM), whereas facilitation of [(3)H]NA exocytosis, but not inhibition of [(3)H]5-HT and [(3)H]DA K(+)-evoked release, was counteracted by the delta opioid receptor (DOR) antagonist naltrindole (1-100 nM). We conclude that salvinorin A presynaptically modulates central NA, 5-HT, and DA exocytosis evoked by a mild depolarizing stimulus by acting at presynaptic opioid receptors having different pharmacological profiles.
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http://dx.doi.org/10.1016/j.neuropharm.2009.07.023DOI Listing
December 2009

First evidence for an anxiolytic effect of a diterpenoid from Salvia cinnabarina.

Nat Prod Commun 2009 Apr;4(4):469-72

Department of Experimental Pharmacology, University of Naples Federico II, via Domenico Montesano 49, 80131 Naples, Italy.

The potential anxiolytic and anti-depressive activity of CMP1 was studied in the elevated plus-maze test and in the forced swimming test. Furthermore, CMP1 sedative activity was evaluated in pentobarbital treated animals; the effect of CMP1 on spontaneous motor activity (total locomotion) was also evaluated. Our data show that CMP1, at doses that did not affect locomotion, was able to induce anxiolytic and sedative, but not anti-depressive effects. In conclusion, our results represent first evidence for an anxiolytic activity of this diterpenoid from Salvia cinnabarina.
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April 2009

Antimicrobial activity of the ornamental species Salvia corrugata, a potential new crop for extractive purposes.

J Agric Food Chem 2008 Nov;56(22):10468-72

Dipartimento di Chimica e Tecnologie Farmaceutiche e Alimentari, Universita di Genova, Genova, Italy.

As a part of our search for biologically active compounds from cultivated Salvia spp. we investigated Salvia corrugata Vahl. The activity of two isolated icetaxane diterpene quinones, fruticuline A and demethylfruticuline A, was assessed against 46 bacterial pathogens, mostly resistant to several primary antibiotics. The MIC for all the inhibited Gram-positive pathogens tested showed a very narrow distribution and ranged from 32 to 64 mg/L, regardless of their resistance patterns to other antibiotics. Demethylfruticuline A was shown to be highly bactericidal (>3 log(10) CFU decrease within 24 h) against Staphylococcus aureus and S. epidermidis and bacteriostatic against Enterococcus faecalis and E. faecium. Fruticuline A manifested bacteriostatic activity against all tested strains. S. corrugata can be viewed as an interesting source for these diterpenes, which, if well tolerated in vivo, may represent new medical agents useful for the treatment of serious infections caused by resistant Gram-positive pathogens.
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http://dx.doi.org/10.1021/jf802200xDOI Listing
November 2008