Publications by authors named "Nunziatina De Tommasi"

137 Publications

Limonoids from and : Heat Shock Protein 90 (Hsp90) Modulator Properties of Chisomicine D.

J Nat Prod 2021 Mar 4. Epub 2021 Mar 4.

Dipartimento di Farmacia, Università di Pisa, 56126 Pisa, Italy.

Nine new limonoids (-) were isolated from the stem bark of (-) and (-). Their structures were elucidated using 1D and 2D NMR and MS data and chemical methods as three A2,B,D--type limonoids (-), a mexicanolide (), three nomilin-type (-) limonoids, and two limonol derivatives ( and ). A DFT/NMR procedure was used to define the relative configurations of and . A surface plasmon resonance approach was used to screen the Hsp90 binding capability of the limonoids, and the A2,B,D--type limonoid 8-hydro-(8,9*)-dihydroxy-14,15-en-chisomicine A, named chisomicine D (), demonstrated the highest affinity. By means of mass spectrometry data, biochemical and cellular assays, and molecular docking, was found as a type of client-selective Hsp90 inhibitor binding to the C-terminus domain of the chaperone.
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http://dx.doi.org/10.1021/acs.jnatprod.0c01217DOI Listing
March 2021

Diterpenoids from Zhumeria majdae roots as potential heat shock protein 90 (HSP90) modulators.

Phytochemistry 2021 Feb 16;185:112685. Epub 2021 Feb 16.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano (SA), Italy. Electronic address:

Four undescribed and 17 known diterpenoids were isolated from the roots of Zhumeria majdae Rech.f. & Wendelbo. Using 1D and 2D NMR spectroscopy, ECD spectroscopy, and HRESIMS data analysis, the structures of the undescribed compounds were elucidated. The anti-proliferative activity of isolated compounds was evaluated against HeLa and MCF7 cancer cell lines. The binding affinity of all compounds to HSP90, one of the targets for the modern anticancer therapy, was investigated using surface plasmon resonance. The results demonstrated that lanugon Q interacted with the chaperone. To explain its mechanism of action, experimental and computational tests were also conducted.
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http://dx.doi.org/10.1016/j.phytochem.2021.112685DOI Listing
February 2021

Systematic Phytochemical Screening of Different Organs of and the Ovicidal Effect of Their Extracts to the Foodstuff Pest .

Molecules 2021 Feb 9;26(4). Epub 2021 Feb 9.

King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11481, Saudi Arabia.

In developing countries, crop deterioration is mainly caused by inappropriate storage conditions that promote insect infestation. Synthetic pesticides are associated with serious adverse effects on humans and the environment. Thus, finding alternative "green" insecticides is a very pressing need. (Aiton) Dryand (Apocynaceae) growing in Saudi Arabia was selected for this purpose. LC-MS/MS analysis was applied to investigate the metabolic composition of different extracts. Particularly, latex and leaves showed a high presence of cardenolides including calactin, uscharidin, 15β-hydroxy-calactin, 16β-hydroxy-calactin, and 12β-hydroxy-calactin. The ovicidal activity of the extracts from different plant organs (flowers, leaves, branches, roots), and of the latex, against (Walker) (Lepidoptera, Pyralidae) was assessed. Extracts of roots displayed the most potent activity with 50% of eggs not hatching at 10.000 ppm (1%).
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http://dx.doi.org/10.3390/molecules26040905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7916075PMC
February 2021

Recent Clinical and Preclinical Studies of Hydroxychloroquine on RNA Viruses and Chronic Diseases: A Systematic Review.

Molecules 2020 Nov 14;25(22). Epub 2020 Nov 14.

Department of Science, University of Basilicata, v.le dell'Ateneo Lucano 10, 85100 Potenza, Italy.

The rapid spread of the new Coronavirus Disease 2019 (COVID-19) has actually become the newest challenge for the healthcare system since, to date, there is not an effective treatment. Among all drugs tested, Hydroxychloroquine (HCQ) has attracted significant attention. This systematic review aims to analyze preclinical and clinical studies on HCQ potential use in viral infection and chronic diseases. A systematic search of Scopus and PubMed databases was performed to identify clinical and preclinical studies on this argument; 2463 papers were identified and 133 studies were included. Regarding HCQ activity against COVID-19, it was noticed that despite the first data were promising, the latest outcomes highlighted the ineffectiveness of HCQ in the treatment of viral infection. Several trials have seen that HCQ administration did not improve severe illness and did not prevent the infection outbreak after virus exposure. By contrast, HCQ arises as a first-line treatment in managing autoimmune diseases such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome. It also improves glucose and lipid homeostasis and reveals significant antibacterial activity.
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http://dx.doi.org/10.3390/molecules25225318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696151PMC
November 2020

Bioactive Ent-Kaurane Diterpenes Oridonin and Irudonin Prevent Cancer Cells Migration by Interacting with the Actin Cytoskeleton Controller Ezrin.

Int J Mol Sci 2020 Sep 29;21(19). Epub 2020 Sep 29.

Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", University of Salerno, Via Salvador Allende, 84081 Baronissi, Italy.

The ent-kaurane diterpene oridonin was reported to inhibit cell migration and invasion in several experimental models. However, the process by which this molecule exerts its anti-metastatic action has not been yet elucidated. In this article, we have investigated the anti-metastatic activity of Oridonin and of one homolog, Irudonin, with the aim to shed light on the molecular mechanisms underlying the biological activity of these ent-kaurane diterpenes. Cell-based experiments revealed that both compounds are able to affect differentiation and cytoskeleton organization in mouse differentiating myoblasts, but also to impair migration, invasion and colony formation ability of two different metastatic cell lines. Using a compound-centric proteomic approach, we identified some potential targets of the two bioactive compounds among cytoskeletal proteins. Among them, Ezrin, a protein involved in the actin cytoskeleton organization, was further investigated. Our results confirmed the pivotal role of Ezrin in regulating cell migration and invasion, and indicate this protein as a potential target for new anti-cancer therapeutic approaches. The interesting activity profile, the good selectivity towards cancer cells, and the lower toxicity with respect to Oridonin, all suggest that Irudonin is a very promising anti-metastatic agent.
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http://dx.doi.org/10.3390/ijms21197186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582544PMC
September 2020

Boosting the Synthesis of Pharmaceutically Active Abietane Diterpenes in Hairy Roots by Engineering the and Genes.

Front Plant Sci 2020 18;11:924. Epub 2020 Jun 18.

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

Abietane diterpenoids (ADs), synthesized in the roots of different species, such as aethiopinone, 1-oxoaethiopinone, salvipisone, and ferruginol, have a variety of known biological activities. We have shown that aethiopinone has promising cytotoxic activity against several human tumor cell lines, including the breast adenocarcinoma MCF7, HeLa, epithelial carcinoma, prostate adenocarcinoma PC3, and human melanoma A375. The low content of these compounds in natural sources, and the limited possibility to synthesize them chemically at low cost, prompted us to optimize the production of abietane diterpenoids by targeting genes of the methylerythritol phosphate (MEP) pathway, from which they are derived. Here, we report our current and ongoing efforts to boost the metabolic flux towards this interesting class of compounds in hairy roots (HRs). Silencing the gene encoding the -copalyl-diphosphate synthase gene (ent), acting at the lateral geranylgeranyl pyrophosphate (GGPP) competitive gibberellin route, enhanced the content of aethiopinone and other ADs in HRs, indicating indirectly that the GGPP pool is a metabolic constraint to the accumulation of ADs. This was confirmed by overexpressing the gene geranyl-geranyl diphosphate synthase) which triggered also a significant 8-fold increase of abietane diterpene content above the basal constitutive level, with a major boosting effect on aethiopinone accumulation in HRs. A significant accumulation of aethiopinone and other AD compounds was also achieved by overexpressing the CPPS gene (copalyl diphosphate synthase) pointing to this biosynthetic step as another potential metabolic target for optimizing the biosynthesis of this class of compounds. However, by co-expressing of and genes, albeit significant, the increase of abietane diterpenoids was less effective than that obtained by overexpressing the two genes individually. Taken together, the results presented here add novel and instrumental knowledge to a rational design of a hairy root-based platform to yield reliable amounts of aethiopinone and other ADs for a deeper understanding of their molecular pharmacological targets and potential future commercialization.
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http://dx.doi.org/10.3389/fpls.2020.00924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315395PMC
June 2020

A Herbal Mixture from Propolis, Pomegranate, and Grape Pomace Endowed with Anti-Inflammatory Activity in an In Vivo Rheumatoid Arthritis Model.

Molecules 2020 May 11;25(9). Epub 2020 May 11.

Dipartimento di Farmacia, Università di Pisa, 56126 Pisa, Italy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by the production of inflammatory factors. In order to overcome the side effects of currently used anti-inflammatory drugs, several attempts have been made to identify natural products capable of relieving RA symptoms. In this work, a herbal preparation consisting of propolis, pomegranate peel, and Aglianico grape pomace (PPP) extracts (4:1:1) was designed and evaluated for its effect on a murine collagen-induced arthritis (CIA) model. Firstly, the chemical contents of four different Italian propolis collected in the Campania region (Italy) were here reported for the first time. LC-MS analyses showed the presence of 38 constituents, identified in all propolis extracts, belonging to flavonoids and phenolic acids classes. The Pietradefusi extract was the richest one and thus was selected to design the PPP preparation for the in vivo assay. Our results highlight the impact of PPP on RA onset and progression. By using in vivo CIA models, the treatment with PPP resulted in a delayed onset of the disease and alleviated the severity of the clinical symptoms. Furthermore, we demonstrated that early PPP treatment was associated with a reduction in serum levels of IL-17, IL-1b, and IL-17-triggering cytokines.
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http://dx.doi.org/10.3390/molecules25092255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248927PMC
May 2020

Synergistic Anti Leukemia Effect of a Novel Hsp90 and a Pan Cyclin Dependent Kinase Inhibitors.

Molecules 2020 May 8;25(9). Epub 2020 May 8.

College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.

Acute myeloid leukemia (AML) is among the top four malignancies in Saudi nationals, and it is the top leukemia subtype worldwide. Resistance to available AML drugs requires the identification of new targets and agents. Hsp90 is one of the emerging important targets in AML, which has a central role in the regulation of apoptosis and cell proliferation through client proteins including the growth factor receptors and cyclin dependent kinases. The objective of the first part of this study is to investigate the putative Hsp90 inhibition activity of three novel previously synthesized quinazolines, which showed HL60 cytotoxicity and VEGFR2 and EGFR kinases inhibition activities. Using surface plasmon resonance, compound 1 (HAA) showed better Hsp90 inhibition compared to 17-AAG, and a docking study revealed that it fits nicely into the ATPase site. The objective of the second part is to maximize the anti-leukemic activity of HAA, which was combined with each of the eleven standard inhibitors. The best resulting synergistic effect in HL60 cells was with the pan cyclin-dependent kinases (CDK) inhibitor dinaciclib, using an MTT assay. Furthermore, the inhibiting effect of the Hsp90α gene by the combination of HAA and dinaciclib was associated with increased caspase-7 and TNF-α, leading to apoptosis in HL60 cells. In addition, the combination upregulated p27 simultaneously with the inhibition of cyclinD3 and CDK2, leading to abolished HL60 proliferation and survival. The actions of HAA propagated the apoptotic and cell cycle control properties of dinaciclib, showing the importance of co-targeting Hsp90 and CDK, which could lead to the better management of leukemia.
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http://dx.doi.org/10.3390/molecules25092220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248782PMC
May 2020

Antiprotozoal activity of diterpenoids isolated from Zhumeria majdae- absolute configuration by circular dichroism.

Daru 2020 Dec 11;28(2):455-462. Epub 2020 May 11.

Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran.

Purpose: Zhumeria majdae, a unique species of the Zhumeria genus, is an endemic Iranian plant in the Lamiaceae family. Phytochemical investigation and biological activity of this plant are rarely reported. The current study aimed to find new antiprotozoal compounds from the roots of Z. majdae and to determine the absolute configuration of isolated compounds by circular dichroism.

Methods: The extraction process from roots and aerial parts of Z. majdae was carried out by hexane, ethyl acetate and methanol followed by testing their antiprotozoal effects against Leishmania donovani, Trypanosoma brucei rhodesiense, T. cruzi, and Plasmodium falciparum, respectively. Structure elucidation was done using 1D and 2D NMR spectroscopy and HREIMS spectrometry. In addition, experimental and theoretical circular dichroism spectroscopy was used to establish absolute configuration.

Results: In comparison with aerial parts, the hexane extract from roots showed superior activity against T. b. rhodesiense, L. donovani and P. falciparum with IC values of 5.4, 1.6 and 2.1 μg/ml, respectively. From eight abietane-type diterpenoids identified in roots, six were reported for the first time in the genus Zhumeria. 11,14-dihydroxy-8,11,13-abietatrien-7-one (6) exhibited a promising biological activity against P. falciparum (IC 8.65 μM), with a selectivity index (SI) of 4.6, and lanugon Q (8) showed an IC value of 0.13 μM and SI of 15.4 against T. b. rhodesiense.

Conclusion: Altogether, according to the results, of 8 isolated compounds, dihydroxy-8,11,13-abietatrien-7-one (6) and lanugon Q (8) exhibited a promising activity against T. b. rhodesiense and P. falciparum. In conclusion, these compounds could be potential candidates for further analysis and may serve as lead compounds for the synthesis of antiprotozoal agents. Graphical abstract.
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http://dx.doi.org/10.1007/s40199-020-00345-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704868PMC
December 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

Antioxidant Activity of Compounds Isolated from Promotes Human Gingival Fibroblast Well-Being.

J Nat Prod 2020 03 7;83(3):626-637. Epub 2020 Feb 7.

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy.

Four new triterpenoid bidesmosidic saponins (-) and a sesquiterpenoid glucoside (), together with nine known phenolic compounds (-), were isolated from the fruits of . Their structures were elucidated using 1D and 2D NMR spectroscopy and mass spectrometry data. The antioxidant capability of the isolated compounds was evaluated in human gingival fibroblasts. Compound decreased ROS production and promoted cell proliferation. It also counteracted the cell cycle blockade induced by a low concentration of HO decreasing the expression of p21 and CDKN2A (p16). Compound decreased the expression of inflammatory cytokines (IL-6 and IL-8) in response to inflammatory stimuli, supporting its possible use in periodontitis lesions.
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http://dx.doi.org/10.1021/acs.jnatprod.9b01030DOI Listing
March 2020

Plants-Drifting from Farm to Food Applications, Phytotherapy, and Phytopharmacology.

Foods 2019 10 22;8(10). Epub 2019 Oct 22.

Department of Clinical Oncology, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong, China.

The genus includes about 500 different species and commonly grown in Europe, the United States, South Asia, and some northern areas of Iran and Pakistan. Leaves and fruits can be prepared as food flavorings, juices, and teas. Phytochemical analysis of these species has reported alkaloids, tannins, phenolic compounds and oleanolic acid, among others. Moreover, -cymene, limonene and ocimene as major compounds in essential oils were found by gas chromatography. is an important group of the plants having enormous potential in the food and pharmaceutical industry, since they possess several properties, including antioxidant, antimicrobial, anticancer activities. Here we would like to review the biological properties of the phytoconstituents of this genus. We emphasize the cultivation control in order to obtain the main bioactive compounds, the antioxidant and antimicrobial properties in order to apply them for food preservation and for treating several diseases, such as cancer, diabetes or Alzheimer. However, further study is needed to confirm the biological efficacy as well as, the toxicity.
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http://dx.doi.org/10.3390/foods8100522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836240PMC
October 2019

Modulatory Effects of Plant Polyphenols on Bone Remodeling: A Prospective View From the Bench to Bedside.

Front Endocrinol (Lausanne) 2019 23;10:494. Epub 2019 Jul 23.

Clinical Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

During the past, a more comprehensive knowledge of mechanisms implicated in bone resorption processes has driven researchers to develop a compound library of many small molecules that specifically interfere with the genesis of osteoclast precursors cells. Natural compounds that suppress osteoclast commitment may have therapeutic value in treating pathologies associated with bone resorption like osteoporosis, rheumatoid arthritis, bone metastasis, and periodontal disease. The present review is focused on the current knowledge on the polyphenols derived from plants that could be efficacious in suppressing osteoclast differentiation and bone resorption.
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http://dx.doi.org/10.3389/fendo.2019.00494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663995PMC
July 2019

Guaianolides from Ormenis mixta: Structural Insights and Evaluation of Their Anti-inflammatory Profile.

Planta Med 2019 Aug 4;85(11-12):947-956. Epub 2019 Jun 4.

Dipartimento di Farmacia, Università di Salerno, Fisciano (SA), Italy.

In this paper, the isolation of five new guaianolides (1:  - 5: ) and four (6:  - 9: ) known sesquiterpenes from aerial parts is reported. The structural determination of the guaianolides was obtained by NMR spectroscopic data, as well as MS experiments. Their relative configurations were assigned by a combined quantum mechanical/NMR approach, comparing the experimental C/H NMR chemical shift data and homonuclear coupling constants with the related predicted values. The isolates were assayed for their anti-inflammatory potential evaluating nitric oxide release and cyclooxygenase-2 expression in J774A.1 macrophages treated with lipopolysaccharide from . Our results indicated that, among the tested compounds, 1:  - 3: , and 7: were able to inhibit nitric oxide release, while all were able to inhibit cyclooxygenase-2 expression with different potencies.
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http://dx.doi.org/10.1055/a-0941-0364DOI Listing
August 2019

Enhancing the utility of J coupling constants in structural studies through optimized DFT analysis.

Chem Commun (Camb) 2019 May;55(41):5781-5784

Structure Elucidation Group, Analytical Research & Development, Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA.

Commonly used DFT methods for the calculation of 1JCH coupling constants have typically required the application of ad hoc correction factors, modification of functionals, or empirical scaling to improve the fit between predicted and experimental values. Here we demonstrate that highly accurate 1JCH coupling predictions can be obtained without such adjustments by careful selection of DFT methods for geometry optimization and J-coupling calculations (e.g. B3LYP/6-31G(d,p)(mixed)//mPW1PW/cc-pVTZ). The proposed method was cross-validated against a diverse set of 122 1JCH couplings and was successfully applied to the conformational and stereochemical analysis of strychnine and a previously unreported trachylobane diterpene natural product.
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http://dx.doi.org/10.1039/c9cc02469gDOI Listing
May 2019

High Yield of Bioactive Abietane Diterpenes in Salvia sclarea Hairy Roots by Overexpressing Cyanobacterial DXS or DXR Genes.

Planta Med 2019 Aug 26;85(11-12):973-980. Epub 2019 Apr 26.

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

Abietane diterpenoids, containing a quinone moiety, are synthesized in the roots of several species. Promising cytotoxicity and antiproliferative activities have been reported for these compounds in various cell and animal models. We have recently shown that aethiopinone, an o-naphto-quinone diterpene, produced in the roots of different species, is selectively cytotoxic against the A375 melanoma cell line. To enhance the synthesis of this abietane diterpenoid, we have engineered the plastidial 2-C-methyl-D-erythritol 4-phosphate-derived isoprenoid pathway in hairy roots by ectopic expression and plastid targeting of cyanobacterial genes encoding the 1-deoxy-D-xylulose 5-phosphate synthase or 1-deoxy-D-xylulose-5-phosphate reductoisomerase gene, the first two enzymatic steps of the plastidial MEP pathway, from which plant diterpenes primarily derive. Plastid-targeted expression of 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase proteins significantly enhanced the yield of aethiopinone by a 3-fold and about 6-fold increase, respectively. The accumulation of other abietane-type diterpenes (ferruginol, salvipisone, and carnosic acid), with interesting antiproliferative activity, was also increased. Compared to our previous data obtained by overexpressing the plant orthologous 1-deoxy-D-xylulose 5-phosphate synthase and 1-deoxy-D-xylulose-5-phosphate reductoisomerase genes in hairy roots, the results presented here confirm that the bacterial 1-deoxy-D-xylulose-5-phosphate reductoisomerase enzyme plays a major role than the DXS enzyme in the biosynthetic pathway of this class of compounds and that its ectopic expression does not conflict with active hairy root growth, resulting in a balanced trade-off between the transgenic hairy root final biomass and the increased content of o-naphto-quinone diterpenes, with interesting biological activities.
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http://dx.doi.org/10.1055/a-0895-5878DOI Listing
August 2019

Antiangiogenic Iridoids from Stachys ocymastrum and Premna resinosa.

Planta Med 2019 Aug 9;85(11-12):1034-1039. Epub 2019 Apr 9.

Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, Università degli Studi di Messina, Messina, Italy.

In this paper, the isolation of one new iridoid glucoside, 6-acetoxyipolamiide (1: ), and thirteen (2:  - 14: ) known congeners from two Lamiaceae species, and , leaf extracts is reported. The structural determination of the isolated compounds was performed by mono- and bidimensional NMR spectroscopic analysis as well as MS experiments. The isolates were assayed for their antiangiogenic activity by two models, zebrafish embryos and chick chorioallantoic membrane assays. The compounds with a significant antiangiogenic activity in both assays were -hydroxyipolamiide (2: ), ipolamiide (3: ), and buddlejoside A (8: ). 6---l-(3″--Methoxycinnamoyl-4″--acetyl)rhamnopyranosyl catalpol (13: ) and 6---l-(2″--caffeoyl)rhamnopyranosyl catalpol (6: ) showed the best antiangiogenic response on blood vessel growth in zebrafish embryos, whereas saccatoside (10: ) and 6---l-(2″- - : -methoxycinnamoyl-3″--acetyl)rhamnopyranosyl catalpol (14: ) resulted in a strong reduction of capillary formation in the chorioallantoic membrane assay.
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http://dx.doi.org/10.1055/a-0889-0412DOI Listing
August 2019

Fusicoccane Diterpenes from Hypoestes forsskaolii as Heat Shock Protein 90 (Hsp90) Modulators.

J Nat Prod 2019 03 6;82(3):539-549. Epub 2019 Mar 6.

Dipartimento di Farmacia , Università degli Studi di Salerno , Via Giovanni Paolo II 132 , 84084 Fisciano ( SA ), Italy.

Ten new (1-10) and six known (11-16) fusicoccane diterpenes were isolated from the roots of Hypoestes forsskaolii. The structural characterization of 1-10 was performed by spectroscopic analysis, including 1D and 2D NMR, ECD, and HRESIMS experiments. From a perspective of obtaining potential Hsp90α inhibitors, the isolates were screened by surface plasmon resonance measurements and their cytotoxic activity was assayed using Jurkat and HeLa cancer cells. Compound 6, 18-hydroxyhypoestenone, was shown to be the most active compound against Hsp90, and its interactions were studied also by biochemical and cellular assays and by molecular docking.
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http://dx.doi.org/10.1021/acs.jnatprod.8b00924DOI Listing
March 2019

Antiangiogenic Activity of Compounds Isolated from Anarrhinum pedatum.

J Nat Prod 2019 03 5;82(3):510-519. Epub 2019 Mar 5.

Dipartimento di Farmacia , Università di Pisa , Via Bonanno 33 , 56126 Pisa , Italy.

Ten new iridoid glycosides (1-10) and two new monoterpenoids (11 and 12), together with nine known compounds (13-21), were isolated from the n-butanol extract of the aerial parts of Anarrhinum pedatum. The structural characterization of all compounds was performed by spectroscopic analysis, including 1D and 2D NMR and HRESIMS experiments. The isolates were assayed for their antiangiogenic activity by two in vivo models, using zebrafish embryos and chicken chorioallantoic membranes (CAMs). The results showed that among the new compounds 6'- O-menthiafoloylmussaenosidic acid-11-(5- O-β-d-fructopyranosyl) ester (9) exhibited the most potent antiangiogenic activity in both the zebrafish embryos and CAM assays, reducing the growth of blood vessels. Antiangiogenic effects were also observed for the known compounds 6- O-nerol-8-oyl-antirrinoside (13), antirrinoside (14), 6- O- trans- and cis- p-coumaroyl antirrinoside (15), and (6 S)-2 E-2,6-dimethyl-6-hydroxyocta-2,7-dienoic acid β-glucopyranosyl ester (18).
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http://dx.doi.org/10.1021/acs.jnatprod.8b00893DOI Listing
March 2019

The anti-tumor diterpene oridonin is a direct inhibitor of Nucleolin in cancer cells.

Sci Rep 2018 11 13;8(1):16735. Epub 2018 Nov 13.

Università degli Studi di Salerno, Department of Pharmacy, Via Giovanni Paolo II, 84084, Fisciano, (SA), Italy.

The bioactive plant diterpene oridonin displays important pharmacological activities and is widely used in traditional Chinese medicine; however, its molecular mechanism of action is still incompletely described. In vitro and in vivo data have demonstrated anti-tumor activity of oridonin and its ability to interfere with several cell pathways; however, presently only the molecular chaperone HSP70 has been identified as a direct potential target of this compound. Here, using a combination of different proteomic approaches, innovative Cellular Thermal Shift Assay (CETSA) experiments, and classical biochemical methods, we demonstrate that oridonin interacts with Nucleolin, effectively modulating the activity of this multifunctional protein. The ability of oridonin to target Nucleolin and/or HSP70 could account for the bioactivity profile of this plant diterpene. Recently, Nucleolin has attracted attention as a druggable target, as its diverse functions are implicated in pathological processes such as cancer, inflammation, and viral infection. However, up to now, no small molecule as Nucleolin binders has been reported, thus our finding represents the first evidence of Nucleolin modulation by a small inhibitor.
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http://dx.doi.org/10.1038/s41598-018-35088-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6233161PMC
November 2018

New diterpenes from Salvia pseudorosmarinus and their activity as inhibitors of monoacylglycerol lipase (MAGL).

Fitoterapia 2018 Oct 18;130:251-258. Epub 2018 Sep 18.

Dipartimento di Farmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy; Centro Interdipartimentale di Ricerca "Nutraceutica e Alimentazione per la Salute", Università di Pisa, via del Borghetto 80, 56124 Pisa, Italy.

As a part of our ongoing research program on compounds from higher plants with lactate dehydrogenase (LDH) and monoacylglycerol lipase (MAGL) inhibitory activities, three new neoclerodane diterpene 12-deacetylsplendidin C (1), pseudorosmaricin (2), and 2-dehydroxysalvileucanthsin A (3) along with six known compounds were isolated from Salvia pseudorosmarinus aerial part extracts. Their structures were determined by spectroscopic and spectrometric techniques including 1D- and 2D NMR, and MS analyses. The isolated diterpenes were assayed for their inhibitory activity on LDH5 and MAGL, two enzymes covering key roles in the peculiar energetic metabolism of malignant tumours. All the assayed diterpenes showed negligible activity on LDH5, whereas the known jewenol A (4) displayed a moderate inhibition activity on MAGL, showing an IC value of 46.8μM and it proved to be a reversible MAGL inhibitor. Docking and molecular dynamic simulation studies where thus performed to evaluate the binding mode of 4 within MAGL.
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http://dx.doi.org/10.1016/j.fitote.2018.09.010DOI Listing
October 2018

Comparative Bioavailability of Two Diosmin Formulations after Oral Administration to Healthy Volunteers.

Molecules 2018 Aug 29;23(9). Epub 2018 Aug 29.

Dipartimento di Farmacia, Università di Salerno, via Giovanni Paolo II 132, 84084 Fisciano (SA), Italy.

Diosmin is a flavonoid commonly found in citrus fruits, largely used as adjuvant treatment for circulatory disorders, including chronic venous insufficiency (CVI) and hemorrhoids. Following oral administration, diosmin is not directly absorbed but must first be hydrolyzed into its aglycone, diosmetin, which is then absorbed into the systemic circulation. The aim of the current cross-over clinical study was to assess the pharmacokinetic profile of µSmin Plus, a micronized diosmin flavonoid complex standardized in diosmin and formulated with a buffering agent (tested formulation). The study compared this to unformulated micronized diosmin (reference), in 16 healthy volunteers. Plasma samples were analyzed by HPLC-MS and plasma diosmetin concentration was measured after deconjugation with β-glucuronidase. For the tested formulation area under the curve (AUC), and maximum plasma and time concentration (C; t) were found to be 298.4 ± 163.7, 50.3 ± 22.6 and 2.2 ± 2.9, respectively. AUC and C of the reference were 31.9 ± 100.4 and 2.4 ± 1.9, respectively. The tested formulation showed higher plasmatic concentrations of diosmetin in comparison to those obtained after the administration of unformulated micronized diosmin. The relative bioavailability was 9.4 greater for the tested formulation than in micronized diosmin. In conclusion, our data indicate that µSmin Plus was rapidly and well absorbed into systemic circulation and may therefore be ideally suitable to deliver diosmin in human interventional trials.
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http://dx.doi.org/10.3390/molecules23092174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225479PMC
August 2018

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

Coactivation of MEP-biosynthetic genes and accumulation of abietane diterpenes in Salvia sclarea by heterologous expression of WRKY and MYC2 transcription factors.

Sci Rep 2018 07 20;8(1):11009. Epub 2018 Jul 20.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II 134D, 80084, Fisciano, Italy.

Plant abietane diterpenoids (e.g. aethiopinone, 1- oxoaethiopinone, salvipisone and ferruginol), synthesized in the roots of several Salvia spp, have antibacterial, antifungal, sedative and anti-proliferative properties. Recently we have reported that content of these compounds in S. sclarea hairy roots is strongly depending on transcriptional regulation of genes belonging to the plastidial MEP-dependent terpenoid pathway, from which they mostly derive. To boost the synthesis of this interesting class of compounds, heterologous AtWRKY18, AtWRKY40, and AtMYC2 TFs were overexpressed in S. sclarea hairy roots and proved to regulate in a coordinated manner the expression of several genes encoding enzymes of the MEP-dependent pathway, especially DXS, DXR, GGPPS and CPPS. The content of total abietane diterpenes was enhanced in all overexpressing lines, although in a variable manner due to a negative pleiotropic effect on HR growth. Interestingly, in the best performing HR lines overexpressing the AtWRKY40 TF induced a significant 4-fold increase in the final yield of aethiopinone, for which we have reported an interesting anti-proliferative activity against resistant melanoma cells. The present results are also informative and instrumental to enhance the synthesis of abietane diterpenes derived from the plastidial MEP-derived terpenoid pathway in other Salvia species.
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http://dx.doi.org/10.1038/s41598-018-29389-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054658PMC
July 2018

Investigation of the Persistence of Penicillin G and Dihydrostreptomycin Residues in Milk of Lactating Buffaloes ( Bubalus bubalis) Using Ultra-High-Performance Liquid Chromatography and Tandem Mass Spectrometry.

J Agric Food Chem 2018 Jun 13;66(25):6388-6393. Epub 2018 Jun 13.

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

The purpose of this research was to evaluate the persistence of penicillin G and dihydrostreptomycin in milk of lactating buffaloes following intramuscular injection of procaine penicillin G (200000 IU/mL) and dihydrostreptomycin sulfate (250 mg/mL) every 24 h for 3 days. Milk samples were collected twice daily up to the 13th milking post-treatment and analyzed by ultra-high-performance liquid chromatography coupled to tandem mass spectrometry. The analytical method has been validated according to Commission Decision 2002/657/EC. The highest concentrations of penicillin G (275 μg kg) and dihydrostreptomycin (220.5 μg kg) were detected in the milk of the first milkings post-treatment, and levels were below the maximum residue limit of 4 and 200 μg kg in all treated buffaloes at milkings 12 and 2, respectively. The results of this study demonstrate that a nine-milking withdrawal time set for bovine milk was not adequate for depletion of penicillin G in lactating buffaloes.
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http://dx.doi.org/10.1021/acs.jafc.8b00229DOI Listing
June 2018

Limonoids from Aphanamixis polystachya Leaves and Their Interaction with Hsp90.

Planta Med 2018 Aug 15;84(12-13):964-970. Epub 2018 May 15.

Dipartimento di Farmacia, Università di Pisa, Pisa, Italy.

A phytochemical study of -hexane, CHCl, and CHCl-MeOH extracts of leaves led to the isolation of 10 compounds. Five of them turned out to be new natural compounds, including two mexicanolide-type (1, 2: ) and three polyoxyphragmalin-type (3: -5: ) limonoids, together with two known andirobin-type limonoids (6, 7: ) and three phenolic derivatives. The structures of the new compounds were established on the basis of spectroscopic methods to be 8-hydro-14,15-en-cabralin (1: ), 3-deacetyl-8-hydro-cabralin-14,15-en-3-one (2: ), 20,22-dihydroxy-21,23-dimethoxytetrahydrofuran khayanolide A (3: ), 1-deacetyl-3-dehydroxy-3-oxokhaysenelide E (4: ), and meliaphanamixin A (5: ). All compounds were isolated for the first time from this species. The ability of the isolated limonoids to interact with the molecular chaperone Hsp90 was tested. Compounds 6: and 7: were the most active.
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http://dx.doi.org/10.1055/a-0624-9538DOI Listing
August 2018

Toxicity of Crepis lacera in grazing ruminants.

BMC Vet Res 2018 Mar 7;14(1):74. Epub 2018 Mar 7.

Dipartimento di Medicina Veterinaria e Produzioni Animali, Università degli Studi di Napoli Federico II, via Delpino 1, 80137, Naples, Italy.

Background: Crepis lacera is a plant from the Asteraceae family that is common in the Mediterranean region. Farmers believe that this plant may be deadly to small ruminants in areas of southern Italy. However, scientific evidence is lacking, and no proof exists that C. lacera is toxic to ruminants. Necropsies conducted on four sheep revealed lesions in their livers and kidneys.

Results: In the current study, we described sheep poisoning and isolated secondary metabolites from Crepis lacera to assess the metabolites' biological activity both in vitro and in vivo. Phytochemical study of the aerial portions of Crepis lacera led to the isolation of five sesquiterpene lactones and two phenolic compounds. Cellular viability was evaluated in cell cultures of the bovine kidney cell line Madin Darby Bovine Kidney (MDBK) after incubation with phytochemicals. Our results showed that three sesquiterpene lactones, 8-epidesacylcynaropicrin-3-O-β-glucopyranoside (2), 8-epigrosheimin (3), and 8-β-hydroxydehydrozaluzanin C (4), were cytotoxic after 48 h of incubation. In addition, in the in vivo study, animals that received 1 mg/kg body weight (bw) of Crepis lacera extract and were then sacrificed after 48 h showed significant lesions in their liver, lungs and kidneys. These lesions were also found in rats that received 2 mg/kg bw of the same extract and sacrificed after 24 and 48 h.

Conclusions: These results validate the hypothesis that C. lacera is potentially dangerous when ingested in large quantities by grazing small domestic ruminants. Further studies are necessary to clarify the molecular mechanisms of Crepis spp. toxicity in animals.
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http://dx.doi.org/10.1186/s12917-018-1393-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5842513PMC
March 2018

Forssk. (Boraginaceae) extracts: chemical constituents, antioxidant activity and cytotoxic effect in human cancer cell lines.

Nat Prod Res 2019 Jun 12;33(12):1813-1818. Epub 2018 Feb 12.

a Unité de Recherche Valorisation des Ressources naturelles et Analyses physico-Chimiques et Biologiques , Université Frères Mentouri , Constantine , Algérie.

(Boraginaceae) is a perennial herb, growing in the Bechar region of Algeria, where it is traditionally used for skin diseases and tonsillitis. Herein, we report the isolation and characterization of sixteen secondary metabolites from the aerial part extracts. They include a sterol (), megastigman type nor-isoprenoids (, , , , , ), C-11 terpene lactones ( and ), and a monoterpene () from the chloroform extract (HB-C); monoterpene glucoside (), and phenolic compounds (-, , ) from the methanol one (HB-M). Their structures were elucidated by spectroscopic methods including 1D and 2D NMR experiments, and ESIMS analysis. HB-M showed a significant and concentration dependent scavenging activity against the radicals DPPH and ABTS related to the phenol derivatives (- and -), and HB-C inhibited the growth of colon cancer cell lines, mainly for the presence of the antiproliferative C-11 terpene lactones ( and ).
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http://dx.doi.org/10.1080/14786419.2018.1437433DOI Listing
June 2019

Accumulation of Polychlorinated Biphenyls in Mussels: A Proteomic Study.

J Food Prot 2018 02;81(2):316-324

1 Dipartimento di Medicina Veterinaria e Produzioni Animali, Settore di Tossicologia, Università degli Studi di Napoli "Federico II", Via F. Delpino, 1, 80137, Napoli, Italy (ORCID: http://orcid.org/0000-0001-8597-0724 [L.S.]).

Polychlorinated biphenyls (PCBs) are environmental pollutants of industrial origin that can contaminate food, mainly food of animal origin. Although production of PCBs has been banned in many countries since the 1980s, they are still present in the environment and are considered dangerous pollutants for human health. In fact, they can bioaccumulate in living organisms such as marine organisms because of their chemical and physical properties. New analytical approaches are useful to monitor the presence of such contaminants in seafood products and in the environment. In this work, we evaluate changes in protein expression of Mytilus galloprovincialis (Lam.) experimentally exposed to a PCB mixture and identify chemically specific protein expression signatures by using a proteomic approach. In particular, we identify 21 proteins whose levels of expression are sensibly modified after 3 weeks of exposure. The present work shows that a proteomic approach can be a useful tool to study alterations of protein expression in mussels exposed to PCBs and represents a first step toward the development of screening protocols to be used for biomonitoring surveys of fishery products.
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http://dx.doi.org/10.4315/0362-028X.JFP-17-148DOI Listing
February 2018

New Tirucallane-Type Triterpenoids from Guarea guidonia.

Planta Med 2018 Jul 16;84(9-10):716-720. Epub 2018 Jan 16.

Dipartimento di Medicina Veterinaria e Produzione Animale, Università di Napoli Federico II, Napoli, Italy.

The aerial parts of afforded three new tirucallane-type triterpenoids: 3,4--tirucalla-4(28),8(9),24(25)-trien-7α,11α-dihydroxy-21,23-epoxy-3,11-olide, named guareolide (1: ), 3,4--tirucalla-4(28),7(8),24(25)-trien-21-hydroxy-21,23-epoxy-3-oic acid, named guareoic acid A (2: ), and 3,4--tirucalla-4(28),7(8),24(25)-trien-21,23-epoxy-3-oic acid, named guareoic acid B (3: ), of which 1: possessed an unusual seven-membered lactone ring. Seven known terpenes were also isolated and characterized as flindissone, 7-acetyldihydronomilin, picroquassin E, boscartol C, and cneorubins A, B, and X. Their structures were determined by spectroscopic methods including one-dimensional and two-dimensional nuclear magnetic resonance analysis and high-resolution mass spectrometry. The isolates were investigated for their potential cytotoxic activity on Jurkat, HeLa, and MCF7 cancer cell lines. Flindissone and compound 2: showed an antiproliferative activity in all cell lines. Further studies revealed that flindissone, the most active compound, induced in Jurkat and HeLa cells both cytostatic and cytotoxic responses.
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http://dx.doi.org/10.1055/s-0044-100524DOI Listing
July 2018