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Special Issue "Special Issue Dedicated to Late Professor Takuo Okuda, “Tannins and Related Polyphenols Revisited: Chemistry, Biochemistry and Biological Activities”"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (30 June 2018)

Special Issue Editors

Guest Editor
Prof. Dr. Hideyuki Ito

Faculty of Health and Welfare Science, Okayama Prefectural University, Kuboki, Soja, Okayama 719- 1197, Japan
Website | E-Mail
Interests: tannins; flavonoids; isolation and structure elucidation; biological activity; bioavailability; metabolites
Guest Editor
Prof. Dr. Tsutomu Hatano

Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan
Website | E-Mail
Phone: +81-86-251-7936
Fax: +81-86-251-7926
Interests: Natural product chemistry; Spectroscopic methods for structural analysis; Antibacterial effects of natural products
Guest Editor
Emeritus Prof. Dr. Takashi Yoshida

Faculty of Pharmaceutical Sciences, Okayama University, Tsushima-naka, Okayama, 700-8530, Japan
E-Mail
Interests: tannins; flavonoids; terpenoids; isolation and structure elucidation; biological activity; chemoprevention

Special Issue Information

Dear Colleagues,

Molecules is pleased to announce a memorial Special Issue, dedicated to Emeritus Professor Dr. Takuo Okuda at Okayama University, Japan, on the occasion of his passing away in December 2016, for his outstanding contribution in the research field of vegetable tannins and related polyphenols.

Prof. Okuda (born in 1927) was Professor of Medicinal Plants Chemistry at the Okayama University, in Japan, from 1970 to 1993. He was one of the pioneers of the chemistry of hydrolyzable tannins and related polyphenols in traditional medicinal plants in Japan, China, and South-East Asian countries. His prolific scientific activity is documented by more than 300 papers concerning the isolation and characterization of tannins and related polyphenolics in many plant species, including their diverse pharmacological functions beneficial to human health care, particularly to antioxidants, chemoprevention of life-related diseases such as cancers, diabetes, arteriosclerosis, and heart diseases. Prof. Okuda established fruitful collaborations with many pharmacologists, biochemists, and microbiologists. Prof. Okuda received the Tannin Award in the 4th Tannin Conference in 2004 (Philadelphia, USA), Groupe Polyphenol Medal in 2014 (Nagoya), for his achievements in the field of polyphenolic natural products.

This memorial Special Issue welcomes submission of previously unpublished manuscripts (original researches or reviews) on the investigation of tannins and biologically active polyphenolic compounds isolated from plants. We plan to receive submissions from April 2017 to the end of June 2018. Manuscripts will be published on an ongoing basis after being processed.

Prof. Dr. Hideyuki Ito
Prof. Dr. Tsutomu Hatano
Emeritus Prof. Dr. Takashi Yoshida
Guest Editors

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • New polyphenolic natural products
  • New tannins and flavonoids
  • Improved methodology of analysis
  • Biological activity
  • Bioavailability and metabolites
  • Structure elucidation
  • Organic synthesis
  • Mechanism of action

Published Papers (17 papers)

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Research

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Open AccessArticle Relationships between Structures of Condensed Tannins from Texas Legumes and Methane Production During In Vitro Rumen Digestion
Molecules 2018, 23(9), 2123; https://doi.org/10.3390/molecules23092123
Received: 26 June 2018 / Revised: 14 August 2018 / Accepted: 21 August 2018 / Published: 23 August 2018
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Abstract
Previous studies showed that a series of purified condensed tannins (CTs) from warm-season perennial legumes exhibited high variability in their modulation of methane production during in vitro rumen digestion. The molecular weight differences between these CTs did not provide correlation with either the
[...] Read more.
Previous studies showed that a series of purified condensed tannins (CTs) from warm-season perennial legumes exhibited high variability in their modulation of methane production during in vitro rumen digestion. The molecular weight differences between these CTs did not provide correlation with either the in vitro CH4 production or the ability to precipitate bovine serum albumin. In an effort to delineate other structure-activity relationships from these methane abatement experiments, the structures of purified CTs from these legumes were assessed with a combination of methanolysis, quantitative thiolysis, 1H-13C HSQC NMR spectroscopy and ultrahigh-resolution MALDI-TOF MS. The composition of these CTs is very diverse: procyanidin/prodelphinidin (PC/PD) ratios ranged from 98/2 to 2/98; cis/trans ratios ranged from 98/2 to 34/66; mean degrees of polymerization ranged from 6 to 39; and % galloylation ranged from 0 to 75%. No strong correlation was observed between methane production and the protein precipitation capabilities of the CT towards three different proteins (BSA, lysozyme, and alfalfa leaf protein) at ruminal pH. However, a strong non-linear correlation was observed for the inhibition of methane production versus the antioxidant activity in plant sample containing typical PC- and PD-type CTs. The modulation of methane production could not be correlated to the CT structure (PC/PD or cis/trans ratios and extent of galloylation). The most active plant in methane abatement was Acacia angustissima, which contained CT, presenting an unusual challenge as it was resistant to standard thiolytic degradation conditions and exhibited an atypical set of cross-peak signals in the 2D NMR. The MALDI analysis supported a 5-deoxy flavan-3-ol-based structure for the CT from this plant. Full article
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Open AccessArticle Green Tea Catechin Is an Alternative Immune Checkpoint Inhibitor that Inhibits PD-L1 Expression and Lung Tumor Growth
Molecules 2018, 23(8), 2071; https://doi.org/10.3390/molecules23082071
Received: 20 July 2018 / Revised: 15 August 2018 / Accepted: 16 August 2018 / Published: 18 August 2018
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Abstract
The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea catechin supports the role of immune checkpoint inhibitors was studied. We here report that (−)-epigallocatechin gallate (EGCG)
[...] Read more.
The anticancer activity of immune checkpoint inhibitors is attracting attention in various clinical sites. Since green tea catechin has cancer-preventive activity in humans, whether green tea catechin supports the role of immune checkpoint inhibitors was studied. We here report that (−)-epigallocatechin gallate (EGCG) inhibited programmed cell death ligand 1 (PD-L1) expression in non–small-cell lung cancer cells, induced by both interferon (IFN)-γ and epidermal growth factor (EGF). The mRNA and protein levels of IFN-γ–induced PD-L1 were reduced 40–80% after pretreatment with EGCG and green tea extract (GTE) in A549 cells, via inhibition of JAK2/STAT1 signaling. Similarly, EGF-induced PD-L1 expression was reduced about 37–50% in EGCG-pretreated Lu99 cells through inhibition of EGF receptor/Akt signaling. Furthermore, 0.3% GTE in drinking water reduced the average number of tumors per mouse from 4.1 ± 0.5 to 2.6 ± 0.4 and the percentage of PD-L1 positive cells from 9.6% to 2.9%, a decrease of 70%, in lung tumors of A/J mice given a single intraperitoneal injection of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). In co-culture experiments using F10-OVA melanoma cells and tumor-specific CD3+ T cells, EGCG reduced PD-L1 mRNA expression about 30% in F10-OVA cells and restored interleukin-2 mRNA expression in tumor-specific CD3+ T cells. The results show that green tea catechin is an immune checkpoint inhibitor. Full article
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Open AccessFeature PaperArticle Search of Neuroprotective Polyphenols Using the “Overlay” Isolation Method
Molecules 2018, 23(8), 1840; https://doi.org/10.3390/molecules23081840
Received: 30 June 2018 / Revised: 18 July 2018 / Accepted: 23 July 2018 / Published: 24 July 2018
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Abstract
Previous studies of the neuroprotective activity of polyphenols have used ununiform culture systems, making it difficult to compare their neuroprotective potency. We have established a new and simple method for preparing differentiated PC12 cells by removing the toxic coating step. Cells were induced
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Previous studies of the neuroprotective activity of polyphenols have used ununiform culture systems, making it difficult to compare their neuroprotective potency. We have established a new and simple method for preparing differentiated PC12 cells by removing the toxic coating step. Cells were induced to differentiate with the nerve growth factor (NGF) in a serum-free medium, without a medium change, but with a one-time overlay supplementation of NGF. The optimal inoculation density of the cells was 6–12 × 103 cells/cm2, and the presence of serum inhibited the differentiation. Neuroprotective activity could be quantified by the specific index (SI) value, that is, the ratio of the 50% cytotoxic concentration to the 50% effective concentration. Alkaline extract from the leaves of Sasa senanensis Rehder (SE), having had hormetic growth stimulation, showed the highest SI value, followed by epigallocatechin gallate. The SI value of curcumin and resveratrol was much lower. This simple overly method, that can prepare massive differentiated neuronal cells, may be applicable for the study of the differentiation-associated changes in intracellular metabolites, and the interaction between neuronal cells and physiological factors. Full article
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Open AccessArticle Exploiting Compositionally Similar Grape Marc Samples to Achieve Gradients of Condensed Tannin and Fatty Acids for Modulating In Vitro Methanogenesis
Molecules 2018, 23(7), 1793; https://doi.org/10.3390/molecules23071793
Received: 20 June 2018 / Revised: 12 July 2018 / Accepted: 18 July 2018 / Published: 20 July 2018
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Abstract
Ruminants produce large amounts of the greenhouse gas, methane, which can be reduced by supplementing feed with products that contain anti-methanogenic compounds, such as the solid winemaking by-product, grape marc. The aim of this study was to exploit compositional differences in grape marc
[...] Read more.
Ruminants produce large amounts of the greenhouse gas, methane, which can be reduced by supplementing feed with products that contain anti-methanogenic compounds, such as the solid winemaking by-product, grape marc. The aim of this study was to exploit compositional differences in grape marc to better understand the roles of condensed tannin and fatty acids in altering methanogenesis in a ruminant system. Grape marc samples varying in tannin extractability, tannin size and subunit composition, and fatty acid or tannin concentrations were selected and incubated in rumen fluid using an in vitro batch fermentation approach with a concentrate-based control. Four distinct experiments were designed to investigate the effects on overall fermentation and methane production. Generally, fatty acid concentration in grape marc was associated with decreased total gas volumes and volatile fatty acid concentration, whereas increased condensed tannin concentration tended to decrease methane percentage. Smaller, extractable tannin was more effective at reducing methane production, without decreasing overall gas production. In conclusion, fatty acids and tannin concentration, and tannin structure in grape marc play a significant role in the anti-methanogenic effect of this by-product when studied in vitro. These results should be considered when developing strategies to reduce methane in ruminants by feeding grape marc. Full article
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Open AccessArticle Convenient Synthesis and Physiological Activities of Flavonoids in Coreopsis lanceolata L. Petals and Their Related Compounds
Molecules 2018, 23(7), 1671; https://doi.org/10.3390/molecules23071671
Received: 31 March 2018 / Revised: 4 July 2018 / Accepted: 6 July 2018 / Published: 9 July 2018
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Abstract
Chalcones, flavanones, and flavonols, including 8-methoxybutin isolated from Coreopsis lanceolata L. petals, were successfully synthesized with total yields of 2–59% from O-methylpyrogallols using the Horner–Wadsworth–Emmons reaction as a key reaction. Aurones, including leptosidin, were also successfully synthesized with 5–36% total yields using the
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Chalcones, flavanones, and flavonols, including 8-methoxybutin isolated from Coreopsis lanceolata L. petals, were successfully synthesized with total yields of 2–59% from O-methylpyrogallols using the Horner–Wadsworth–Emmons reaction as a key reaction. Aurones, including leptosidin, were also successfully synthesized with 5–36% total yields using the Aldol condensation reaction as a key reaction. Each chalcone, flavanone, flavonol, and aurone with the 3,4-dihydroxy groups in the B-ring showed high antioxidant activity. Additionally, each of the chalcones, flavanones, flavonols, and aurones with the 2,4-dihydroxy groups in the B-ring showed an excellent whitening ability. Full article
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Open AccessFeature PaperArticle Direct Observation of Hydrangea Blue-Complex Composed of 3-O-Glucosyldelphinidin, Al3+ and 5-O-Acylquinic Acid by ESI-Mass Spectrometry
Molecules 2018, 23(6), 1424; https://doi.org/10.3390/molecules23061424
Received: 11 May 2018 / Revised: 7 June 2018 / Accepted: 9 June 2018 / Published: 12 June 2018
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Abstract
The blue sepal color of hydrangea is due to a metal complex anthocyanin composed of 3-O-glucosyldelphinidin (1) and an aluminum ion with the co-pigments 5-O-caffeoylquinic acid (2) and/or 5-O-p-coumaroylquinic acid (
[...] Read more.
The blue sepal color of hydrangea is due to a metal complex anthocyanin composed of 3-O-glucosyldelphinidin (1) and an aluminum ion with the co-pigments 5-O-caffeoylquinic acid (2) and/or 5-O-p-coumaroylquinic acid (3). The three components, namely anthocyanin, Al3+ and 5-O-acylquinic acids, are essential for blue color development, but the complex is unstable and only exists in an aqueous solution. Furthermore, the complex did not give analyzable NMR spectra or crystals. Therefore, many trials to determine the detailed chemical structure of the hydrangea-blue complex have not been successful to date. Instead, via experiments mixing 1, Al3+ and 2 or 3 in a buffered solution at pH 4.0, we obtained the same blue solution derived from the sepals. However, the ratio was not stoichiometric but fluctuated. To determine the composition of the complex, we tried direct observation of the molecular ion of the complex using electrospray-ionization mass spectrometry. In a very low-concentration buffer solution (2.0 mM) at pH 4.0, we reproduced the hydrangea-blue color by mixing 1, 2 and Al3+ in ratios of 1:1:1, 1:2:1 and 1:3:1. All solution gave the same molecular ion peak at m/z = 843, indicating that the blue solution has a ratio of 1:1:1 for the complex. By using 3, the observed mass number was m/z = 827 and the ratio of 1, 3 and Al3+ was also 1:1:1. A mixture of 1, 3-O-caffeoylquinic acid (4) and Al3+ did not give any blue color but instead was purple, and the intensity of the molecular ion peak at m/z = 843 was very low. These results strongly indicate that the hydrangea blue-complex is composed of a ratio of 1:1:1 for 1, Al3+ and 2 or 3. Full article
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Open AccessFeature PaperArticle Simultaneous Quantification of Ellagitannins and Related Polyphenols in Geranium thunbergii Using Quantitative NMR
Molecules 2018, 23(6), 1346; https://doi.org/10.3390/molecules23061346
Received: 18 May 2018 / Revised: 1 June 2018 / Accepted: 2 June 2018 / Published: 4 June 2018
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Abstract
Compared to commonly employed liquid chromatography-based methods, quantitative nuclear magnetic resonance (qNMR) is a recently developed method for accurate quantification of natural compounds in extracts. The simultaneous quantification of ellagitannins and the related polyphenols of Geranium thunbergii were studied using qNMR after a
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Compared to commonly employed liquid chromatography-based methods, quantitative nuclear magnetic resonance (qNMR) is a recently developed method for accurate quantification of natural compounds in extracts. The simultaneous quantification of ellagitannins and the related polyphenols of Geranium thunbergii were studied using qNMR after a short-term and long-term decoction. The qNMR fingerprint for quantifying ellagitannin was presented in this work. Geraniin was observed in the short-term decoction as a major component while corilagin was the major component of the long-term decoction. An aqueous acetone extract of G. thunbergii after long-term decoction was extracted with diethyl ether, ethyl acetate, and n-butanol. Corilagin was found as a major constituent in the ethyl acetate and n-butanol extracts. Furthermore, the contents of these polyphenols in G. thunbergii from six locations in Japan and three locations in China were quantified. The contents of geraniin and corilagin in G. thunbergii from Japan were higher than those from China. Our finding raised the possibility that qNMR can be effectively employed as a simple, accurate, and efficient method for quantification of ellagitannins in medicinal plants. Full article
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Open AccessArticle (−)-Epigallocatechin 3-Gallate Synthetic Analogues Inhibit Fatty Acid Synthase and Show Anticancer Activity in Triple Negative Breast Cancer
Molecules 2018, 23(5), 1160; https://doi.org/10.3390/molecules23051160
Received: 4 April 2018 / Revised: 2 May 2018 / Accepted: 10 May 2018 / Published: 11 May 2018
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Abstract
(−)-Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a
[...] Read more.
(−)-Epigallocatechin 3-gallate (EGCG) is a natural polyphenol from green tea with reported anticancer activity and capacity to inhibit the lipogenic enzyme fatty acid synthase (FASN), which is overexpressed in several human carcinomas. To improve the pharmacological profile of EGCG, we previously developed a family of EGCG derivatives and the lead compounds G28, G37 and G56 were characterized in HER2-positive breast cancer cells overexpressing FASN. Here, diesters G28, G37 and G56 and two G28 derivatives, monoesters M1 and M2, were synthesized and assessed in vitro for their cytotoxic, FASN inhibition and apoptotic activities in MDA-MB-231 triple-negative breast cancer (TNBC) cells. All compounds displayed moderate to high cytotoxicity and significantly blocked FASN activity, monoesters M1 and M2 being more potent inhibitors than diesters. Interestingly, G28, M1, and M2 also diminished FASN protein expression levels, but only monoesters M1 and M2 induced apoptosis. Our results indicate that FASN inhibition by such polyphenolic compounds could be a new strategy in TNBC treatment, and highlight the potential anticancer activities of monoesters. Thus, G28, G37, G56, and most importantly M1 and M2, are anticancer candidates (alone or in combination) to be further characterized in vitro and in vivo. Full article
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Open AccessArticle Preliminary Quality Evaluation and Characterization of Phenolic Constituents in Cynanchi Wilfordii Radix
Molecules 2018, 23(3), 656; https://doi.org/10.3390/molecules23030656
Received: 5 February 2018 / Revised: 5 March 2018 / Accepted: 12 March 2018 / Published: 14 March 2018
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Abstract
A new phenolic compound, 2-O-β-laminaribiosyl-4-hydroxyacetophenone (1), was isolated from Cynanchi Wilfordii Radix (CWR, the root of Cynanchum wilfordii Hemsley), along with 10 known aromatic compounds, including cynandione A (2), bungeisides-C (7) and –D (8
[...] Read more.
A new phenolic compound, 2-O-β-laminaribiosyl-4-hydroxyacetophenone (1), was isolated from Cynanchi Wilfordii Radix (CWR, the root of Cynanchum wilfordii Hemsley), along with 10 known aromatic compounds, including cynandione A (2), bungeisides-C (7) and –D (8), p-hydroxyacetophenone (9), 2′,5′-dihydroxyacetophenone (10), and 2′,4′-dihydroxyacetophenone (11). The structure of the new compound (1) was elucidated using spectroscopic methods and chemical methods. The structure of cynandione A (2), including a linkage mode of the biphenyl parts that remained uncertain, was unambiguously confirmed using the 2D 13C–13C incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum. Additionally, health issues related to the use of Cynanchi Auriculati Radix (CAR, the root of Cynanchum auriculatum Royle ex Wight) instead of CWR have emerged. Therefore, constituents present in methanolic extracts of commercially available CWRs and CARs were examined using UV-sensitive high-performance liquid chromatography (HPLC), resulting in common detection of three major peaks ascribed to cynandione A (2), p-hydroxyacetophenone (9), and 2′,4′-dihydroxyacetophenone (11). Thus, to distinguish between these ingredients, a thin-layer chromatography (TLC) method, combined with only UV irradiation detection, focusing on wilfosides C1N (12) and K1N (13) as marker compounds characteristic of CAR, was performed. Furthermore, we propose this method as a simple and convenient strategy for the preliminary distinction of CWR and CAR to ensure the quality and safety of their crude drugs. Full article
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Open AccessArticle Characterization of Condensed Tannins from Purple Prairie Clover (Dalea purpurea Vent.) Conserved as either Freeze-Dried Forage, Sun-Cured Hay or Silage
Molecules 2018, 23(3), 586; https://doi.org/10.3390/molecules23030586
Received: 1 February 2018 / Revised: 27 February 2018 / Accepted: 2 March 2018 / Published: 6 March 2018
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Abstract
Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the
[...] Read more.
Conservation methods have been shown to affect forage nutrient composition and value, but little information is available about the effect of forage conservation on plant condensed tannins (CT). The objective of this study was to assess the effects of conservation method on the concentration, chemical composition and biological activity of CT. Whole-plant purple prairie clover (PPC, Dalea purpurea Vent.) was harvested at full flower and conserved as freeze-dried forage (FD), hay (HAY) or silage (SIL). Concentration of CT in conserved PPC was determined by the butanol-HCl-acetone method. Structural composition, protein-precipitation capacity and anti-bacterial activity of CT isolated from conserved forage were determined by in situ thiolytic degradation followed by HPLC-MS analysis, a protein precipitation assay using bovine serum albumin and ribulose 1,5-disphosphate carboxylase as model proteins and by an Escherichia coli (E. coli) growth test, respectively. Conservation method had no effect on concentration of total CT, but ensiling decreased (p < 0.001) extractable CT and increased (p < 0.001) protein- and fiber-bound CT. In contrast, hay-making only increased (p < 0.01) protein-bound CT. Regardless of conservation method, epigallocatechin (EGC), catechin (C) and epicatechin (EC) were the major flavan-3-ol units, and gallocatechin (GC) was absent from both terminal and extension units of PPC CT. The SIL CT had the lowest (p < 0.001) EGC, but the highest (p < 0.01) EC in the extension units. Similarly, SIL CT exhibited a lower (p < 0.001) mean degree of polymerization (mDP), but higher (p < 0.001) procyanidins (PC) than FD or HAY CT. The protein-precipitating capacity of CT in conserved PPC ranked (p < 0.001) as FD > HAY > SIL. E. coli growth n M9 medium was inhibited by 25–100 µg/mL of CT isolated from FD, HAY and SIL (p < 0.05), but preservation method had no effect on the ability of CT to inhibit bacterial growth. The results demonstrated that ensiling decreased the extractability and protein-precipitating capacity of CT by increasing the proportions of PC. Purple prairie clover conserved as hay retained more biologically active CT than if it was conserved as silage. Full article
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Open AccessArticle Different Inhibitory Potencies of Oseltamivir Carboxylate, Zanamivir, and Several Tannins on Bacterial and Viral Neuraminidases as Assessed in a Cell-Free Fluorescence-Based Enzyme Inhibition Assay
Molecules 2017, 22(11), 1989; https://doi.org/10.3390/molecules22111989
Received: 23 October 2017 / Revised: 14 November 2017 / Accepted: 15 November 2017 / Published: 17 November 2017
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Abstract
Neuraminidase is a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying
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Neuraminidase is a key enzyme in the life cycle of influenza viruses and is present in some bacterial pathogens. We here assess the inhibitory potency of plant tannins versus clinically used inhibitors on both a viral and a bacterial model neuraminidase by applying the 2′-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA)-based activity assay. A range of flavan-3-ols, ellagitannins and chemically defined proanthocyanidin fractions was evaluated in comparison to oseltamivir carboxylate and zanamivir for their inhibitory activities against viral influenza A (H1N1) and bacterial Vibrio cholerae neuraminidase (VCNA). Compared to the positive controls, all tested polyphenols displayed a weak inhibition of the viral enzyme but similar or even higher potency on the bacterial neuraminidase. Structure–activity relationship analyses revealed the presence of galloyl groups and the hydroxylation pattern of the flavan skeleton to be crucial for inhibitory activity. The combination of zanamivir and EPs® 7630 (root extract of Pelargonium sidoides) showed synergistic inhibitory effects on the bacterial neuraminidase. Co-crystal structures of VCNA with oseltamivir carboxylate and zanamivir provided insight into bacterial versus viral enzyme-inhibitor interactions. The current data clearly indicate that inhibitor potency strongly depends on the biological origin of the enzyme and that results are not readily transferable. The therapeutic relevance of our findings is briefly discussed. Full article
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Open AccessArticle Characterization of Proanthocyanidin Oligomers of Ephedra sinica
Molecules 2017, 22(8), 1308; https://doi.org/10.3390/molecules22081308
Received: 14 July 2017 / Revised: 27 July 2017 / Accepted: 3 August 2017 / Published: 6 August 2017
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Abstract
Ephedra sinica, an important plant in Chinese traditional medicine, contains a complex mixture of proanthocyanidin oligomers as major constituents; however, only the minor components have been chemically characterized. In this study, oligomers with relatively large molecular weights, which form the main body
[...] Read more.
Ephedra sinica, an important plant in Chinese traditional medicine, contains a complex mixture of proanthocyanidin oligomers as major constituents; however, only the minor components have been chemically characterized. In this study, oligomers with relatively large molecular weights, which form the main body of the proanthocyanidin fractions, were separated by adsorption and size-exclusion chromatography. Acid-catalyzed degradation in the presence of mercaptoethanol or phloroglucinol led to the isolation of 18 fragments, the structures of which were elucidated from their experimental and TDDFT-calculated ECD spectra. The results indicated that (−)-epigallocatechin was the main extension unit, while catechin, the A-type epigallocatechin–gallocatechin dimer, and the A-type epigallocatechin homodimer, were identified as the terminal units. Among the degradation products, thioethers of gallocatechin with 3,4-cis configurations, a B-type prodelphinidin dimer, a prodelphinidin trimer with both A- and B-type linkages, and a prodelphinidin dimer with an α-substituted A-type linkage were new compounds. In addition, a phloroglucinol adduct of an A-type prodelphinidin dimer, a doubly-linked phloroglucinol adduct of epigallocatechin, and a unique product with a flavan-3-ol skeleton generated by the rearrangement of the aromatic rings were also isolated. Full article
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Open AccessArticle Chemical Composition, Antibacterial and Antifungal Activities of Crude Dittrichia viscosa (L.) Greuter Leaf Extracts
Molecules 2017, 22(7), 942; https://doi.org/10.3390/molecules22070942
Received: 12 May 2017 / Revised: 31 May 2017 / Accepted: 3 June 2017 / Published: 30 June 2017
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Abstract
The small amount of data regarding the antifungal activity of Dittrichia viscosa (L.) Greuter against dermatophytes, Malassezia spp. and Aspergillus spp., associated with the few comparative studies on the antimicrobial activity of methanolic, ethanolic, and butanolic extracts underpins the study herein presented. The
[...] Read more.
The small amount of data regarding the antifungal activity of Dittrichia viscosa (L.) Greuter against dermatophytes, Malassezia spp. and Aspergillus spp., associated with the few comparative studies on the antimicrobial activity of methanolic, ethanolic, and butanolic extracts underpins the study herein presented. The total condensed tannin (TCT), phenol (TPC), flavonoid (TFC), and caffeoylquinic acid (CQC) content of methanol, butanol, and ethanol (80% and 100%) extracts of D. viscosa were assessed and their bactericidal and fungicidal activities were evaluated. The antibacterial, anti-Candida and anti-Malassezia activities were evaluated by using the disk diffusion method, whereas the anti-Microsporum canis and anti-Aspergillus fumigatus activities were assessed by studying the toxicity effect of the extracts on vegetative growth, sporulation and germination. The methanolic extract contained the highest TPC and CQC content. It contains several phytochemicals mainly caffeoylquinic acid derivatives as determined by liquid chromatography with photodiode array and electrospray ionisation mass spectrometric detection (LC/PDA/ESI-MS) analysis. All extracts showed an excellent inhibitory effect against bacteria and Candida spp., whereas methanolic extract exhibited the highest antifungal activities against Malassezia spp., M. canis and A. fumigatus strains. The results clearly showed that all extracts, in particular the methanolic extract, might be excellent antimicrobial drugs for treating infections that are life threatening (i.e., Malassezia) or infections that require mandatory treatments (i.e., M. canis or A. fumigatus). Full article
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Review

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Open AccessFeature PaperReview Structural Revisions in Natural Ellagitannins
Molecules 2018, 23(8), 1901; https://doi.org/10.3390/molecules23081901
Received: 18 June 2018 / Revised: 9 July 2018 / Accepted: 17 July 2018 / Published: 30 July 2018
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Abstract
Ellagitannins are literally a class of tannins. Triggered by the oxidation of the phenolic parts on β-pentagalloyl-d-glucose, ellagitannins are generated through various structural conversions, such as the coupling of the phenolic parts, oxidation to highly complex structures, and the formation of
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Ellagitannins are literally a class of tannins. Triggered by the oxidation of the phenolic parts on β-pentagalloyl-d-glucose, ellagitannins are generated through various structural conversions, such as the coupling of the phenolic parts, oxidation to highly complex structures, and the formation of dimer and lager analogs, which expand the structural diversity. To date, more than 1000 natural ellagitannins have been identified. Since these phenolic compounds exhibit a variety of biological activities, ellagitannins have potential applications in medicine and health enhancement. Within the context of identifying suitable applications, considerations need to be based on correct structural features. This review describes the structural revisions of 32 natural ellagitannins, namely alnusiin; alnusnin A and B; castalagin; castalin; casuarinin; cercidinin A and B; chebulagic acid; chebulinic acid; corilagin; geraniin; isoterchebin; nobotanin B, C, E, G, H, I, J, and K; punicalagin; punicalin; punigluconin; roxbin B; sanguiin H-2, H-3, and H-6; stachyurin; terchebin; vescalagin; and vescalin. The major focus is on the outline of the initial structural determination, on the processes to find the errors in the structure, and on the methods for the revision of the structure. Full article
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Open AccessReview Vegetable Tannins Used in the Manufacture of Historic Leathers
Molecules 2018, 23(5), 1081; https://doi.org/10.3390/molecules23051081
Received: 28 March 2018 / Revised: 28 April 2018 / Accepted: 1 May 2018 / Published: 3 May 2018
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Abstract
In this review, a brief description of how animal skins were transformed in leathers in Europe using different vegetable tannins will be presented. Special attention will be dedicated to the description of the type of tannins and the characteristics of the most important
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In this review, a brief description of how animal skins were transformed in leathers in Europe using different vegetable tannins will be presented. Special attention will be dedicated to the description of the type of tannins and the characteristics of the most important type of historic leathers thus obtained. The text will also focus on the description of the techniques used in the identification of these tannins in historic objects: colorimetric tests and spectroscopic analysis. Full article
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Open AccessReview Tannins from Acacia mearnsii De Wild. Bark: Tannin Determination and Biological Activities
Molecules 2018, 23(4), 837; https://doi.org/10.3390/molecules23040837
Received: 7 March 2018 / Revised: 20 March 2018 / Accepted: 3 April 2018 / Published: 5 April 2018
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Abstract
The bark of Acacia mearnsii De Wild. (black wattle) contains significant amounts of water-soluble components acalled “wattle tannin”. Following the discovery of its strong antioxidant activity, a wattle tannin dietary supplement has been developed and as part of developing new dietary supplements, a
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The bark of Acacia mearnsii De Wild. (black wattle) contains significant amounts of water-soluble components acalled “wattle tannin”. Following the discovery of its strong antioxidant activity, a wattle tannin dietary supplement has been developed and as part of developing new dietary supplements, a literature search was conducted using the SciFinder data base for “Acacia species and their biological activities”. An analysis of the references found indicated that the name of Acacia nilotica had been changed to Vachellia nilotica, even though the name of the genus Acacia originated from its original name. This review briefly describes why and how the name of A. nilotica changed. Tannin has been analyzed using the Stiasny method when the tannin is used to make adhesives and the hide-powder method is used when the tannin is to be used for leather tanning. A simple UV method is also able to be used to estimate the values for both adhesives and leather tanning applications. The tannin content in bark can also be estimated using NIR and NMR. Tannin content estimations using pyrolysis/GC, electrospray mass spectrometry and quantitative 31P-NMR analyses have also been described. Tannins consists mostly of polyflavanoids and all the compounds isolated have been updated. Antioxidant activities of the tannin relating to anti-tumor properties, the viability of human neuroblastoma SH-SY5Y cells and also anti-hypertensive effects have been studied. The antioxidant activity of proanthocyanidins was found to be higher than that of flavan-3-ol monomers. A total of fourteen papers and two patents reported the antimicrobial activities of wattle tannin. Bacteria were more susceptible to the tannins than the fungal strains tested. Several bacteria were inhibited by the extract from A. mearnsii bark. The growth inhibition mechanisms of E. coli were investigated. An interaction between extracts from A. mearnsii bark and antibiotics has also been studied. The extracts from A. mearnsii bark inhibit the growth of cyanobacteria. Wattle tannin has the ability to inactivate α-amylase, lipase and glucosidase. In vivo experiments on anti-obesity and anti-diabetes were also reported. Several patents relating to these enzymes for anti-diabetes and anti-obesity are in the literature. In addition, studies on Acacia bark extract regarding its antitermite activities, inhibition of itching in atopic dermatitis and anti-inflammatory effects have also been reported. The growth of bacteria was inhibited by the extract from A. mearnsii bark, and typical intestinal bacteria such as E. coli, K. pneumoniae, P. vulgaris and S. marcescenes was also inhibited in vitro by extracts. Based on these results, the Acacia bark extract may inhibit not only the growth of these typical intestinal bacteria but also the growth of other types of intestinal bacteria such as Clostridium and Bacteroides, a so-called “bad bacteria”. If the tannin extract from A. mearnsii bark inhibits growth of these “bad bacteria” in vivo evaluation, the extracts might be usable as a new dietary supplement, which could control the human intestinal microbiome to keep the body healthy. Full article
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Open AccessReview Chemical and Biological Significance of Oenothein B and Related Ellagitannin Oligomers with Macrocyclic Structure
Molecules 2018, 23(3), 552; https://doi.org/10.3390/molecules23030552
Received: 5 February 2018 / Revised: 26 February 2018 / Accepted: 26 February 2018 / Published: 2 March 2018
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Abstract
In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal
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In 1990, Okuda et al. reported the first isolation and characterization of oenothein B, a unique ellagitannin dimer with a macrocyclic structure, from the Oenothera erythrosepala leaves. Since then, a variety of macrocyclic analogs, including trimeric–heptameric oligomers have been isolated from various medicinal plants belonging to Onagraceae, Lythraceae, and Myrtaceae. Among notable in vitro and in vivo biological activities reported for oenothein B are antioxidant, anti-inflammatory, enzyme inhibitory, antitumor, antimicrobial, and immunomodulatory activities. Oenothein B and related oligomers, and/or plant extracts containing them have thus attracted increasing interest as promising targets for the development of chemopreventive agents of life-related diseases associated with oxygen stress in human health. In order to better understand the significance of this type of ellagitannin in medicinal plants, this review summarizes (1) the structural characteristics of oenothein B and related dimers; (2) the oxidative metabolites of oenothein B up to heptameric oligomers; (3) the distribution of oenotheins and other macrocyclic analogs in the plant kingdom; and (4) the pharmacological activities hitherto documented for oenothein B, including those recently found by our laboratory. Full article
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