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Special Issue "Redox Active Natural Products and Their Interaction with Cellular Signalling Pathways"

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

Deadline for manuscript submissions: closed (31 May 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Claus Jacob (Website)

Division of Bioorganic Chemistry, School of Pharmacy, University of Saarland, Campus, 66123 Saarbrücken, Germany
Phone: 00496813023129
Interests: reactive sulfur species in biology; redox active secondary metabolites and their potential uses in agricultural medicine; redox modulators (either natural or synthetic) as potential drugs and green pesticides; synthetic chemistry of sulfur, selenium, and tellurium agents; solubilization of redox active particles using nanotechnology; oligomeric natural products capable of controling protein function and enzyme activity

Special Issue Information

Dear Colleagues,

Redox active secondary metabolites from diverse plants, mushrooms, and microorganisms have recently attracted considerable interest because of their abundance in nature and often pronounced biological activity. Redox active organic sulfur compounds (OSCs) from plants like garlic, onions and mustard frequently exhibit distinct cytotoxic and antimicrobial activities. In contrast, polyphenols, such flavonoids and resveratrol, show antioxidant activities, are able to trigger various cellular signaling cascades, and also influence epigenomic processes.

Not surprisingly, many of these natural products may be useful in medicine and agriculture. In medicine, chemo-preventive and antioxidant activities are of particular interest; these qualities are especially useful for the (pre-emptive) treatment of an aging population. Because some of these natural products (and related compounds) also possess pronounced cytotoxic and antimicrobial properties, these products may potentially also be applied as antibiotics or fungicides. In agricultural research, the development of ecologically friendly plant protective agents, based on these redox active secondary metabolites, holds equal promise.

Various techniques have recently been developed and applied to understand the underlying biochemical processes responsible for these substances’ biological activities. These studies have revealed an often complex interplay of different intracellular redox events. These events result in the activation of a range of cellular signaling and response pathways. Such events may include, for instance, the activation of antioxidant pathways, the (mostly reversible) modification of key cysteine residues in proteins and enzymes of the cellular thiolstat, the up-regulation of reactive oxygen species, and epigenomic changes to the histones.

This Special Issue will therefore consider the latest developments in natural products research, with a particular focus on redox active secondary metabolites. The issue will take an interdisciplinary point of view and include the isolation and characterization of such compounds, the synthesis of artificial derivatives, and the respective biological activity observed for such products. To complete the emerging picture of redox active metabolites, the issue will also reflect on underlying cellular mechanisms and possible practical applications.

Prof. Dr. Claus Jacob
Guest Editor

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Submission

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed Open Access monthly journal published by MDPI.

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).

Keywords

  • cancer
  • green pesticides
  • infectious diseases
  • inflammatory diseases
  • macrophages
  • reactive sulfur species
  • redox modulators
  • secondary metabolites
  • selenium
  • tellurium
  • thiolstat

Published Papers (11 papers)

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Editorial

Jump to: Research, Review

Open AccessEditorial Special Issue: Redox Active Natural Products and Their Interaction with Cellular Signalling Pathways
Molecules 2014, 19(12), 19588-19593; doi:10.3390/molecules191219588
Received: 17 November 2014 / Accepted: 18 November 2014 / Published: 26 November 2014
Cited by 2 | PDF Full-text (183 KB) | HTML Full-text | XML Full-text
Abstract
During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, “natural” cosmetics and the issue of a sustainable and [...] Read more.
During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, “natural” cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature’s treasure chest of “green gold”. Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro-)organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic “sensor/effector” anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s) of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for “intracellular diagnostics”. In the case of redox active compounds, especially of Reactive Sulfur Species (RSS), such techniques have recently unraveled concepts such as the “cellular thiolstat”, yet considerably more research is required in order to gain a full understanding of why and how such compounds act—often selectively—in different organisms. Full article

Research

Jump to: Editorial, Review

Open AccessArticle Intracellular Diagnostics: Hunting for the Mode of Action of Redox-Modulating Selenium Compounds in Selected Model Systems
Molecules 2014, 19(8), 12258-12279; doi:10.3390/molecules190812258
Received: 13 June 2014 / Revised: 22 July 2014 / Accepted: 24 July 2014 / Published: 13 August 2014
Cited by 3 | PDF Full-text (2882 KB) | HTML Full-text | XML Full-text
Abstract
Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes [...] Read more.
Redox-modulating compounds derived from natural sources, such as redox active secondary metabolites, are currently of considerable interest in the field of chemoprevention, drug and phytoprotectant development. Unfortunately, the exact and occasionally even selective activity of such products, and the underlying (bio-)chemical causes thereof, are often only poorly understood. A combination of the nematode- and yeast-based assays provides a powerful platform to investigate a possible biological activity of a new compound and also to explore the “redox link” which may exist between its activity on the one side and its chemistry on the other. Here, we will demonstrate the usefulness of this platform for screening several selenium and tellurium compounds for their activity and action. We will also show how the nematode-based assay can be used to obtain information on compound uptake and distribution inside a multicellular organism, whilst the yeast-based system can be employed to explore possible intracellular mechanisms via chemogenetic screening and intracellular diagnostics. Whilst none of these simple and easy-to-use assays can ultimately substitute for in-depth studies in human cells and animals, these methods nonetheless provide a first glimpse on the possible biological activities of new compounds and offer direction for more complicated future investigations. They may also uncover some rather unpleasant biochemical actions of certain compounds, such as the ability of the trace element supplement selenite to induce DNA strand breaks. Full article
Open AccessArticle Cudarflavone B Provides Neuroprotection against Glutamate-Induced Mouse Hippocampal HT22 Cell Damage through the Nrf2 and PI3K/Akt Signaling Pathways
Molecules 2014, 19(8), 10818-10831; doi:10.3390/molecules190810818
Received: 21 May 2014 / Revised: 10 July 2014 / Accepted: 15 July 2014 / Published: 24 July 2014
Cited by 6 | PDF Full-text (846 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS) diseases such as Alzheimer’s disease, Parkinson’s disease, and ischemia. Nrf2 signaling-mediated heme oxygenase (HO)-1 expression acts against oxidants that are thought to play a key role in the pathogenesis [...] Read more.
Oxidative cell damage contributes to neuronal degeneration in many central nervous system (CNS) diseases such as Alzheimer’s disease, Parkinson’s disease, and ischemia. Nrf2 signaling-mediated heme oxygenase (HO)-1 expression acts against oxidants that are thought to play a key role in the pathogenesis of neuronal diseases. Cudraflavone B is a prenylated flavone isolated from C. tricuspidata which has shown anti-proliferative activity, mouse brain monoamine oxidase (MAO) inhibitory effects, apoptotic actions in human gastric carcinoma cells and mouse melanoma cells, and hepatoprotective activity. In this study, cudraflavone B showed neuroprotective effects and reactive oxygen species (ROS) inhibition against glutamate-induced neurotoxicity by inducing the expression of HO-1 in mouse hippocampal HT22 cells. Furthermore, cudraflavone B caused the nuclear accumulation of nuclear factor-E2-related factor 2 (Nrf2) and increased the promoter activity of antioxidant response elements (ARE) in mouse hippocampal HT22 cells. In addition, we found that the Nrf2-midiated HO-1 expression by cudraflavone B is involved in the cell protective response and ROS reductions, and cudraflavone B-induced expression of HO-1 was mediated through the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in HT22 cells. Our results demonstrated the potential application of naturally occurring cudraflavone B as a therapeutic agent from neurodegenerative disease. Full article
Open AccessArticle Plumbagin Modulates Leukemia Cell Redox Status
Molecules 2014, 19(7), 10011-10032; doi:10.3390/molecules190710011
Received: 3 June 2014 / Revised: 20 June 2014 / Accepted: 25 June 2014 / Published: 10 July 2014
Cited by 6 | PDF Full-text (1235 KB) | HTML Full-text | XML Full-text
Abstract
Plumbagin is a plant naphtoquinone exerting anti-cancer properties including apoptotic cell death induction and generation of reactive oxygen species (ROS). The aim of this study was to elucidate parameters explaining the differential leukemia cell sensitivity towards this compound. Among several leukemia cell [...] Read more.
Plumbagin is a plant naphtoquinone exerting anti-cancer properties including apoptotic cell death induction and generation of reactive oxygen species (ROS). The aim of this study was to elucidate parameters explaining the differential leukemia cell sensitivity towards this compound. Among several leukemia cell lines, U937 monocytic leukemia cells appeared more sensitive to plumbagin treatment in terms of cytotoxicity and level of apoptotic cell death compared to more resistant Raji Burkitt lymphoma cells. Moreover, U937 cells exhibited a ten-fold higher ROS production compared to Raji. Neither differential incorporation, nor efflux of plumbagin was detected. Pre-treatment with thiol-containing antioxidants prevented ROS production and subsequent induction of cell death by apoptosis whereas non-thiol-containing antioxidants remained ineffective in both cellular models. We conclude that the anticancer potential of plumbagin is driven by pro-oxidant activities related to the cellular thiolstat. Full article
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Open AccessArticle Xanthenedione Derivatives, New Promising Antioxidant and Acetylcholinesterase Inhibitor Agents
Molecules 2014, 19(6), 8317-8333; doi:10.3390/molecules19068317
Received: 12 May 2014 / Revised: 8 June 2014 / Accepted: 11 June 2014 / Published: 19 June 2014
Cited by 2 | PDF Full-text (357 KB) | HTML Full-text | XML Full-text
Abstract
Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce [...] Read more.
Natural and synthetic xanthone derivatives are well-known for their ability to act as antioxidants and/or enzyme inhibitors. This paper aims to present a successful synthetic methodology towards xanthenedione derivatives and the study of their aromatization to xanthones. Additionally their ability to reduce Fe(III), to scavenge DPPH radicals and to inhibit AChE was evaluated. The results demonstrated that xanthenedione derivative 5e, bearing a catechol unit, showed higher reduction capacity than BHT and similar to quercetin, strong DPPH scavenging activity (EC50 = 3.79 ± 0.06 µM) and it was also showed to be a potent AChEI (IC50 = 31.0 ± 0.09 µM) when compared to galantamine (IC50 = 211.8 ± 9.5 µM). Full article
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Review

Jump to: Editorial, Research

Open AccessReview Flavonoids as Important Molecules of Plant Interactions with the Environment
Molecules 2014, 19(10), 16240-16265; doi:10.3390/molecules191016240
Received: 30 May 2014 / Revised: 15 September 2014 / Accepted: 16 September 2014 / Published: 10 October 2014
Cited by 26 | PDF Full-text (1257 KB) | HTML Full-text | XML Full-text
Abstract
Flavonoids are small molecular secondary metabolites synthesized by plants with various biological activities. Due to their physical and biochemical properties, they are capable of participating in plants’ interactions with other organisms (microorganisms, animals and other plants) and their reactions to environmental stresses. [...] Read more.
Flavonoids are small molecular secondary metabolites synthesized by plants with various biological activities. Due to their physical and biochemical properties, they are capable of participating in plants’ interactions with other organisms (microorganisms, animals and other plants) and their reactions to environmental stresses. The majority of their functions result from their strong antioxidative properties. Although an increasing number of studies focus on the application of flavonoids in medicine or the food industry, their relevance for the plants themselves also deserves extensive investigations. This review summarizes the current knowledge on the functions of flavonoids in the physiology of plants and their relations with the environment. Full article
Open AccessReview Nopal Cactus (Opuntia ficus-indica) as a Source of Bioactive Compounds for Nutrition, Health and Disease
Molecules 2014, 19(9), 14879-14901; doi:10.3390/molecules190914879
Received: 10 July 2014 / Revised: 4 September 2014 / Accepted: 8 September 2014 / Published: 17 September 2014
Cited by 19 | PDF Full-text (832 KB) | HTML Full-text | XML Full-text
Abstract
Opuntia ficus-indica, commonly referred to as prickly pear or nopal cactus, is a dicotyledonous angiosperm plant. It belongs to the Cactaceae family and is characterized by its remarkable adaptation to arid and semi-arid climates in tropical and subtropical regions of the [...] Read more.
Opuntia ficus-indica, commonly referred to as prickly pear or nopal cactus, is a dicotyledonous angiosperm plant. It belongs to the Cactaceae family and is characterized by its remarkable adaptation to arid and semi-arid climates in tropical and subtropical regions of the globe. In the last decade, compelling evidence for the nutritional and health benefit potential of this cactus has been provided by academic scientists and private companies. Notably, its rich composition in polyphenols, vitamins, polyunsaturated fatty acids and amino acids has been highlighted through the use of a large panel of extraction methods. The identified natural cactus compounds and derivatives were shown to be endowed with biologically relevant activities including anti-inflammatory, antioxidant, hypoglycemic, antimicrobial and neuroprotective properties. The present review is aimed at stressing the major classes of cactus components and their medical interest through emphasis on some of their biological effects, particularly those having the most promising expected health benefit and therapeutic impacts. Full article
Open AccessReview 1,4-Naphthoquinones: From Oxidative Damage to Cellular and Inter-Cellular Signaling
Molecules 2014, 19(9), 14902-14918; doi:10.3390/molecules190914902
Received: 29 July 2014 / Revised: 2 September 2014 / Accepted: 11 September 2014 / Published: 17 September 2014
Cited by 15 | PDF Full-text (2377 KB) | HTML Full-text | XML Full-text
Abstract
Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others) to cellular and inter-cellular signaling processes [...] Read more.
Naphthoquinones may cause oxidative stress in exposed cells and, therefore, affect redox signaling. Here, contributions of redox cycling and alkylating properties of quinones (both natural and synthetic, such as plumbagin, juglone, lawsone, menadione, methoxy-naphthoquinones, and others) to cellular and inter-cellular signaling processes are discussed: (i) naphthoquinone-induced Nrf2-dependent modulation of gene expression and its potentially beneficial outcome; (ii) the modulation of receptor tyrosine kinases, such as the epidermal growth factor receptor by naphthoquinones, resulting in altered gap junctional intercellular communication. Generation of reactive oxygen species and modulation of redox signaling are properties of naphthoquinones that render them interesting leads for the development of novel compounds of potential use in various therapeutic settings. Full article
Open AccessReview Antioxidant Activity and Mechanisms of Action of Natural Compounds Isolated from Lichens: A Systematic Review
Molecules 2014, 19(9), 14496-14527; doi:10.3390/molecules190914496
Received: 28 May 2014 / Revised: 2 September 2014 / Accepted: 3 September 2014 / Published: 12 September 2014
Cited by 10 | PDF Full-text (838 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Chronic diseases such as cancer, diabetes, neurodegenerative and cardiovascular diseases are characterized by an enhanced state of oxidative stress, which may result from the overproduction of reactive species and/or a decrease in antioxidant defenses. The search for new chemical entities with antioxidant [...] Read more.
Chronic diseases such as cancer, diabetes, neurodegenerative and cardiovascular diseases are characterized by an enhanced state of oxidative stress, which may result from the overproduction of reactive species and/or a decrease in antioxidant defenses. The search for new chemical entities with antioxidant profile is still thus an emerging field on ongoing interest. Due to the lack of reviews concerning the antioxidant activity of lichen-derived natural compounds, we performed a review of the antioxidant potential and mechanisms of action of natural compounds isolated from lichens. The search terms “lichens”, “antioxidants” and “antioxidant response elements” were used to retrieve articles in LILACS, PubMed and Web of Science published until February 2014. From a total of 319 articles surveyed, 32 met the established inclusion and exclusion criteria. It was observed that the most common isolated compound studied was usnic acid, cited in 14 out of the 32 articles. The most often described antioxidant assays for the study of in vitro antioxidant activity were mainly DPPH, LPO and SOD. The most suggested mechanisms of action were scavenging of reactive species, enzymatic activation and inhibition of iNOS. Thus, compounds isolated from lichens are possible candidates for the management of oxidative stress, and may be useful in the treatment of chronic diseases. Full article
Open AccessReview Effect of Redox Modulating NRF2 Activators on Chronic Kidney Disease
Molecules 2014, 19(8), 12727-12759; doi:10.3390/molecules190812727
Received: 18 July 2014 / Revised: 6 August 2014 / Accepted: 12 August 2014 / Published: 20 August 2014
Cited by 26 | PDF Full-text (2967 KB) | HTML Full-text | XML Full-text
Abstract
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no [...] Read more.
Chronic kidney disease (CKD) is featured by a progressive decline of kidney function and is mainly caused by chronic diseases such as diabetes mellitus and hypertension. CKD is a complex disease due to cardiovascular complications and high morbidity; however, there is no single treatment to improve kidney function in CKD patients. Since biological markers representing oxidative stress are significantly elevated in CKD patients, oxidative stress is receiving attention as a contributing factor to CKD pathology. Nuclear factor erythroid-2 related factor 2 (NRF2) is a predominant transcription factor that regulates the expression of a wide array of genes encoding antioxidant proteins, thiol molecules and their generating enzymes, detoxifying enzymes, and stress response proteins, all of which can counteract inflammatory and oxidative damages. There is considerable experimental evidence suggesting that NRF2 signaling plays a protective role in renal injuries that are caused by various pathologic conditions. In addition, impaired NRF2 activity and consequent target gene repression have been observed in CKD animals. Therefore, a pharmacological intervention activating NRF2 signaling can be beneficial in protecting against kidney dysfunction in CKD. This review article provides an overview of the role of NRF2 in experimental CKD models and describes current findings on the renoprotective effects of naturally occurring NRF2 activators, including sulforaphane, resveratrol, curcumin, and cinnamic aldehyde. These experimental results, coupled with recent clinical experiences with a synthetic triterpenoid, bardoxolone methyl, have brought a light of hope for ameliorating CKD progression by preventing oxidative stress and maintaining cellular redox homeostasis. Full article
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Open AccessReview Allicin: Chemistry and Biological Properties
Molecules 2014, 19(8), 12591-12618; doi:10.3390/molecules190812591
Received: 23 June 2014 / Revised: 24 July 2014 / Accepted: 28 July 2014 / Published: 19 August 2014
Cited by 35 | PDF Full-text (3642 KB) | HTML Full-text | XML Full-text
Abstract
Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with a broad range of biological activities. Allicin is produced upon tissue damage from the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide) in a reaction that is catalyzed by the enzyme [...] Read more.
Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with a broad range of biological activities. Allicin is produced upon tissue damage from the non-proteinogenic amino acid alliin (S-allylcysteine sulfoxide) in a reaction that is catalyzed by the enzyme alliinase. Current understanding of the allicin biosynthetic pathway will be presented in this review. Being a thiosulfinate, allicin is a reactive sulfur species (RSS) and undergoes a redox-reaction with thiol groups in glutathione and proteins that is thought to be essential for its biological activity. Allicin is physiologically active in microbial, plant and mammalian cells. In a dose-dependent manner allicin can inhibit the proliferation of both bacteria and fungi or kill cells outright, including antibiotic-resistant strains like methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, in mammalian cell lines, including cancer cells, allicin induces cell-death and inhibits cell proliferation. In plants allicin inhibits seed germination and attenuates root-development. The majority of allicin’s effects are believed to be mediated via redox-dependent mechanisms. In sub-lethal concentrations, allicin has a variety of health-promoting properties, for example cholesterol- and blood pressure-lowering effects that are advantageous for the cardio-vascular system. Clearly, allicin has wide-ranging and interesting applications in medicine and (green) agriculture, hence the detailed discussion of its enormous potential in this review. Taken together, allicin is a fascinating biologically active compound whose properties are a direct consequence of the molecule’s chemistry. Full article

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