Phytochemistry Reviews (v.16, #6)

Carbazole alkaloids characterized by a heterocyclic aromatic basic skeleton are known from different organisms but do not represent a biogenetically homogenous group. The majority, comprising more than 330 derivatives, is derived from 3-methylcarbazole as common precursor and is designated as phytocarbazoles. They are nearly exclusively known from the four closely related plant genera Bergera (part of Murraya s. l.), Clausena, Glycosmis, and Micromelum of the family Rutaceae. Derived from anthranilic acid and malonyl-CoA the tricyclic basic skeleton is formed via a prenylated 2-quinolone intermediate. The following steps are speculated to involve the formation of 2-prenylindole and cyclization of the prenyl side chain to generate 3-methylcarbazole. Apart from different oxygenations and oxidations of the basic skeleton additional prenylations and geranylations contribute to the great structural diversity of phytocarbazoles which are grouped together according to their C13-, C18-, and C23-basic structures. Of taxonomic significance are the different oxidations of the characteristic C-3 methyl group leading to 3-formyl- and 3-carboxyl derivatives particularly accumulated in Clausena and Micromelum species. Predominant prenylation at C-5 is typical for Glycosmis and Micromelum, whereas in Clausena prenylation at different positions can contribute to an infrageneric grouping. Geranylation represents a characteristic biogenetic trend of Bergera. A wide variety of biological activities ranges from significant antimicrobial, antiprotozoal, and insecticidal properties to anti-inflammatory, antioxidative, antiplatelet aggregative, and anti-HIV activities. Of particular interest is the cytotoxicity of phytocarbazoles against various cancer cell lines, where some derivatives turned out to act as cell cycle inhibitors and apoptosis inducers. Especially the C23 derivative mahanine induced different cell-signaling pathways suggesting that it represents a multi-targeted and multi-functional compound that works on an array of different cancer types and has the potential to inhibit tumor growth in vivo.
Keywords: Carbazole alkaloids; Biogenetic trends; Biological activities; Rutaceae; Chemotaxonomy

Toad venom is regarded as the main source of bufadienolides; however, synthesis of these substances takes also place in a variety of other animal and plant organisms, including ethnomedicinal plants of the Kalanchoe genus. Chemically, bufadienolides are a group of polyhydroxy C-24 steroids and their glycosides, containing a six-membered lactone (α-pyrone) ring at the C-17β position. From the pharmacological point of view, bufadienolides might be a promising group of steroid hormones with cardioactive properties and anticancer activity. Most of the literature concerns bufadienolides of animal origin; however, the medicinal use of these compounds remains limited by their narrow therapeutic index and the risk of development of cardiotoxic effects. On the other hand, plants such as Kalanchoe are also a source of bufadienolides. Kalanchoe pinnata (life plant, air plant, cathedral bells), Kalanchoe daigremontiana (mother of thousands) and other Kalanchoe species are valuable herbs in traditional medicine of Asia and Africa. The present review focuses on the available data on chemical structures of 31 compounds, biological properties and prospects for therapeutic use of bufadienolides from Kalanchoe species. Furthermore, it presents some new investigational trends in research on curative uses of these substances.
Keywords: Bufadienolide; Kalanchoe ; Cytotoxicity; Cancer therapy; Ethnomedicine

Neuroprotective effects of paeoniflorin in neurodegenerative diseases of the central nervous system by Azadeh Manayi; Sahar Omidpanah; Davide Barreca; Silvana Ficarra; Maria Daglia; Seyed Fazel Nabavi; Seyed Mohammad Nabavi (1173-1181).
Paeoniflorin is a monoterpene glycoside, the β-glucoside of paeoniflorigenin. It is one of the major components of Radix Paeoniae, the herbal product obtained from Paeonia lactiflora Pall., a medicinal plant used in folk medicine, especially in Chinese Traditional Medicine, to treat several human ailments, including dementia and cognitive decline. The neuroprotective effects of paeoniflorin have been studied by many investigations showing that its beneficial effects may derive from its anti-inflammatory and anti-apoptotic properties, and its ability to promote neuronal survival. This review evaluates scientific evidence on the neuroprotective properties of paeoniflorin. On the basis of literature data, paeoniflorin seems to be a promising compound for the prevention and treatment of neurodegenerative disorders, though definitive recommendation requires further studies.
Keywords: Anti-inflammatory; Anti-apoptosis; Neuroprotection; Paoniflorine; Radix Paeoniae

For millennia, in the different cultures all over the world, plants have been extensively used as a source of therapeutic agents with wide-ranging medicinal applications, thus becoming part of a rational clinical and pharmacological investigation over the years. As bioactive molecules, plant-derived polyphenols have been demonstrated to exert many effects on human health by acting on different biological systems, thus their therapeutic potential would represent a novel approach on which natural product-based drug discovery and development could be based in the future. Many reports have provided evidence for the benefits derived from the dietary supplementation of polyphenols in the prevention and treatment of osteoporosis. Polyphenols are able to protect the bone, thanks to their antioxidant properties, as well as their anti-inflammatory actions by involving diverse signaling pathways, thus leading to bone anabolic effects and decreased bone resorption. This review is meant to summarize the research works performed so far, by elucidating the molecular mechanisms of action of polyphenols in a bone regeneration context, aiming at a better understanding of a possible application in the development of medical devices for bone tissue regeneration.
Keywords: Anti-inflammation; Antioxidant; Bone disease; Pathway; Polyphenols

Higher plants undergo a variety of stresses and to combat those stresses they acclimatize themselves by producing diverse secondary metabolites. These secondary metabolites also have a wide range of industrial applications and hence they serve as candidates for commercialization. Owing to the constraints faced by natural plant extraction, plant cell/tissue culture has emerged as an alternative platform for the in vitro production of value added bioactive secondary metabolites. Implementation of several productivity enhancement strategies, including elicitation, can overcome the limitations faced by plant cell technology that hampers its extensive commercialization. Elicitation is a technique that involves exogenous addition of elicitors (abiotic or biotic) in the growth medium which consequently triggers stress response with concomitant enhancement in secondary metabolite production. Elicitor induced stress results in the activation of several defense-related genes or inactivation of non-defense-related genes, transient phosphorylation/dephosphorylation of proteins, expression of enzymes whose information can be used to ascertain the biosynthetic pathways of many secondary metabolites. Furthermore, integration of transcriptomics, proteomics and metabolomics with system biology can aid in discovery of novel genes, transcriptional factors and several biosynthetic pathways which in turn can serve as a valuable tool for metabolic engineering and gene manipulation for enhancing the yield and productivity of secondary metabolites.
Keywords: Plant cell/tissue culture; Secondary metabolite; In vitro production; Yield/productivity enhancement; Biotic/abiotic elicitors

Bioactivities of Origanum vulgare L.: an update by Raffaele Pezzani; Sara Vitalini; Marcello Iriti (1253-1268).
Origanum vulgare L. is a plant species belonging to the Lamiaceae and native to the Mediterranean region and western Eurasia. This aromatic herb is widely used throughout the world as spice and medicinal plant, representing a remedy in various traditional healing systems. In particular, oregano essential oil, rich in C10 monoterpenes, has been extensively used and, consequently, investigated. This narrative review aims to provide an updated overview on the biological activities of O. vulgare and its main bioactive phytochemicals, considering both preclinical (in vitro and in vivo) and in human studies focused on anticancer, anti-inflammatory, antioxidant and antimicrobial activities.
Keywords: Biological activities; Crude extracts; Essential oil; Oregano; Preclinical studies

l-Canavanine: How does a simple non-protein amino acid inhibit cellular function in a diverse living system? by Paweł Staszek; Leslie A. Weston; Katarzyna Ciacka; Urszula Krasuska; Agnieszka Gniazdowska (1269-1282).
l-Canavanine (CAN) is a non-protein amino acid (NPAA) possessing toxic properties in both animal and plant systems. Upon treatment, this arginine structural analogue is typically incorporated into proteins by arginyl-tRNA synthetase, leading to rapid functional disruption of such “canavanyl proteins”. CAN is produced in many legumes including jack bean and lucerne (alfalfa) and is accumulated mainly in seeds and their newly germinating sprouts. It has been described as a potent allelochemical and its toxicity has been associated with autoimmunological diseases in humans or animals feeding on plants containing this NPAA. Application of CAN even at low concentration resulted in an inhibition of plant growth. When CAN was used as an anticancer agent, its mode of action appears to be associated with the synthesis of non-functional proteins in sensitive organisms, a similar mode of action to that of other simple NPAAs as meta-tyrosine. CAN toxicity in plants is also likely associated with the formation of non-functional proteins and its application has been shown to cause disruption of polyamine metabolism and formation of reactive nitrogen species including nitric oxide (NO). In higher plants, CAN has recently been used as a tool to study the regulation or modulation of polyamine–NO cross-talk. Comparing to other related NPAAs that impact cellular function in living plant and animal systems CAN seems to have the highest toxic properties. The aim of this review is to describe CAN specific activity and mode of action especially focused on higher plant systems.
Keywords: Arginine analogue; Plants; Toxicity