Terpenoids: natural inhibitors of NF-κB signaling with anti-inflammatory and anticancer potential

Traditional medicine has been a fertile source for revealing novel lead molecules for modern drug discovery. In plants, terpenoids represent a chemical defense against environmental stress and provide a repair mechanism for wounds and injuries. Interestingly, effective ingredients in several plant-derived medicinal extracts are also terpenoid compounds of monoterpenoid, sesquiterpenoid, diterpenoid, triterpenoid and carotenoid groups. Inflammatory diseases and cancer are typical therapeutic indications of traditional medicines. Thus folk medicine supports the studies which have demonstrated that plant-derived terpenoid ingredients can suppress nuclear factor-κB (NF-κB) signaling, the major regulator in the pathogenesis of inflammatory diseases and cancer.We review the extensive literature on the different types of terpenoid molecules, totalling 43, which have been verified both inhibiting the NF-κB signaling and suppressing the process of inflammation and cancer. It seems that during evolution, plants have established a terpene-based host defense which also represents a cornucopia of effective therapeutic compounds for common human diseases. Received 11 March 2008; received after revision 28 April 2008; accepted 29 April 2008     

Plants as a direct source of fuel

Summary Euphorbia lathyris, a plant which has been proposed as an energy farm candidate yields a total of 35% of its dry weight as simple organic extractables. Chemical analyses of the extracts show that 5% of the dry weight is a mixture of reduced terpenoids, in the form of triterpenoids, and 20% of the dry weight is simple sugars in the form of hexoses. The terpenoids can be converted to a gasoline-like substance and the sugars can be fermented to alcohol. Based on a biomass yield of about 25 dry tons ha^–1 year^–1, the total energy that can be obtained from this plant in the form of liquid fuels is 48 MJ ha^–1 year^–1, 26 MJ in the form of hydrocarbons and 22 MJ in the form of ethanol. A conceptual process study for the large scale recovery ofEuphorbia lathyris products indicates that this crop is a net energy producer. Several lines of investigation have been started to increase the hydrocarbon yield of this plant. Tissue cultures ofE. lathyris have been established and will be used for selection, with the aim of regenerating a superior plant. Biochemical studies have been initiated to elucidate regulation of terpenoid metabolism. Future plans include eventual genetic engineering to select the most desirable plant for hydrocarbon production.This work was supported by the Assistant Secretary for Conservation and Solar Energy, Office of Solar Energy, Solar Applications for Industry Division of the US Department of Energy under Contract No. W-7405-ENG-48.     

Stereochemistry of enzymic processes in the biosynthesis of pyrrolizidine alkaloids.

The harmonization of biosynthetic pathways with organic reaction mechanisms has relied heavily on stereochemical studies. The field of biosynthesis of pyrrolizidine alkaloids exemplifies these connections through a wide range of common organic reactions including oxidation condensation, and decarboxylation. Further, the applications of biogenetic concepts and enzyme-catalysed reactions to synthesis are illustrated. The results are exciting, not only for their intrinsic scientific interest, but because they point the way to using plant enzymes to recognise structurally modified biosynthetic intermediates and hence open routes to the synthesis of new compounds that would otherwise be difficult to obtain.     

Stereochemistry of enzymic processes in the biosynthesis of pyrrolizidine alkaloids

The harmonization of biosynthetic pathways with organic reaction mechanisms has relied heavily on stereochemical studies. The field of biosynthesis of pyrrolizidine alkaloids exemplifies these connections through a wide range of common organic reactions including oxidation, condensation, and decarboxylation. Further, the applications of biogenetic concepts and enzyme-catalysed reactions to synthesis are illustrated. The results are exciting, not only for their intrinsic scientific interest, but because they point the way to using plant enzymes to recognise structurally modified biosynthetic intermediates and hence open routes to the synthesis of new compounds that would otherwise be difficult to obtain.     

植物次生代谢研究

次生代谢是植物重要的生命活动,与植物的生长发育及其对环境的适应密切相关。同时次生代谢产物也是重要的药物和化工原料来源。次生代谢过程及代谢物的积累受到自身和环境中各种生物和非生物因素的调控。随着基因组和代谢组等组学技术的产生和发展,植物次生代谢研究获得了前所未有的机会。通过对代谢过程的深入了解,利用系统生物学方法开展预见性代谢工程将会成为未来的研究趋势。     

Polyamines in cell growth and cell death: molecular mechanisms and therapeutic applications

Polyamines are aliphatic cations with multiple functions and are essential for life. Cellular polyamine levels are regulated by multiple pathways such as synthesis from amino acid precursors, cellular uptake mechanisms that salvage polyamines from diet and intestinal microorganisms, as well as stepwise degradation and efflux. Investigations using polyamine biosynthetic inhibitors indicate that alterations in cellular polyamine levels modulate normal and cancer cell growth. Studies using transgenic mice overexpressing polyamine biosynthetic enzymes support a role of polyamines in carcinogenesis. Many, if not all, signal transduction pathways intersect with polyamine biosynthetic pathways and the regulation of intracellular polyamine levels. Direct binding of polyamines to DNA and their ability to modulate DNA-protein interactions appear to be important in the molecular mechanisms of polyamine action in cell proliferation. Consistent with the role of polyamines as facilitators of cell growth, several studies have shown their ability to protect cells from apoptosis. However, polyamines also have a role in facilitating cell death. The basis of these diverse cellular responses is currently not known. Cell death response might be partly mediated by the production of hydrogen peroxide during polyamine catabolism. In addition, the ability of polyamines to alter DNA-protein and protein-protein interactions might be disruptive to cellular functions, when abnormally high levels are accumulated due to defects in polyamine catabolic or efflux pathways. A large body of data indicates that polyamine pathway can be a molecular target for therapeutic intervention in several types cancers. Inhibitors of biosynthesis, polyamine analogues as well as oligonucleotide/polyamine analogue combinations are promising drug candidates for chemoprevention and/or treatment of cancer.     

Chemical studies on slow reacting substances/leukotrienes

The family of eicasanoids, biologically active metabolites of polyunsaturated C20 fatty acids such as arachidonic acid, has recently been enlarged by the recognition of a new biosynthetic pathway leading to the leukotrienes, including the compounds described two decades ago as 'slow reacting substances'. These biologically potent substances are involved in regulation of the immune response and also as mediators in various disease states. This account presents a brief history of this field, an overview of the biological relevance of leukotrienes, and a discussion of the investigations which led to the clarification of the molecular structures, pathway of biosynthesis and total chemical synthesis of the leukotrienes, including leukotrienes A, B, C, D and E (LTA-LTE). As a result of the synthetic work these rare substances are available for the first time in pure form and in quantities sufficient for biological and medical studies. Also reviewed are recent discoveries with regard to the development of inhibitors of leukotriene biosynthesis and anti-leukotrienes.     

Drimane sesquiterpenoids in MediterraneanDendrodoris nudibranchs: Anatomical distribution and biological role

Summary Two Mediterranean species ofDendrodoris nudibranchs have elaborated a very sophisticated defensive strategy against predators, involving the denovo biosynthesis of a series of drimane sesquiterpenoids, some of which are strongly ichthyodeterrent. Anatomical distribution of the drimane terpenoids in different sections and egg masses of the mollusc is reported, together with further studies aimed at finding out how the animals are protected against the noxious effects of their own allomones.Avila, C., F.P.I.-M.E.C. Spanish Fellowship (University of Barcelona) at the I.C.M.I.B.     

烯二炔类抗肿瘤抗生素的生物合成研究进展

烯二炔类抗生素以其独特的化学结构和强烈的抗肿瘤活性成为化学、生物和医药领域重点关注的对象。本文简要介绍了近年来关于烯二炔化合物的生物合成研究进展,以及运用组合生物合成的原理创造新型烯二炔结构类似物的前景。烯二炔类抗生素为我们研究复杂天然产物的生物合成提供了一个很好的模型,其基因和生化水平机制的阐明将进一步丰富组合生物合成的内容和手段,最终有利于发现和发展新型的抗肿瘤药物。     

New insights into short-chain prenyltransferases: structural features, evolutionary history and potential for selective inhibition

Isoprenoids form an extensive group of natural products involved in a number of important biological processes. Their biosynthesis proceeds through sequential 1′-4 condensations of isopentenyl diphosphate (C₅) with an allylic acceptor, the first of which is dimethylallyl diphosphate (C₅). The reactions leading to the production of geranyl diphosphate (C₁₀), farnesyl diphosphate (C₁₅) and geranylgeranyl diphosphate (C₂₀), which are the precursors of mono-, sesqui- and diterpenes, respectively, are catalyzed by a group of highly conserved enzymes known as short-chain isoprenyl diphosphate synthases, or prenyltransferases. In recent years, the sequences of many new prenyltransferases have become available, including those of several plant and animal geranyl diphosphate synthases, revealing novel mechanisms of product chain-length selectivity and an intricate evolutionary path from a putative common ancestor. Finally, there is considerable interest in designing inhibitors specific to short-chain prenyltransferases, for the purpose of developing new drugs or pesticides that target the isoprenoid biosynthetic pathway.     

Arabinogalactan-proteins: structure, expression and function

Arabinogalactan-proteins (AGPs) are a family of extensively glycosylated hydroxyproline-rich glycoproteins that are thought to have important roles in various aspects of plant growth and development. After a brief introduction to AGPs highlighting the problems associated with defining and classifying this diverse family of glycoproteins, AGP structure is described in terms of the protein component (including data from molecular cloning), carbohydrate component, processing of AGPs (including recent data on glycosylphosphatidylinositol membrane anchors) and overall molecular shape. Next, the expression of AGPs is examined at several different levels, from the whole plant to the cellular levels, using a variety of experimental techniques and tools. Finally, AGP function is considered. Although the existing functional evidence is not incontrovertible, it does clearly point to roles for AGPs in vegetative, reproductive, and cellular growth and development as well as programmed cell death and social control. In addition and most likely inextricably linked to their functions, AGPs are presumably involved in molecular interactions and cellular signaling at the cell surface. Some likely scenarios are discussed in this context. AGPs also have functions of real or potential commercial value, most notably as emulsifiers in the food industry and as potential immunological regulators for human health. Several important questions remain to be answered with respect to AGPs. Clearly, elucidating the unequivocal functions of particular AGPs and relating these functions to their respective structures and modes of action remain as major challenges in the years ahead.     

Acetyl-L-carnitine treatment stimulates oxygen consumption and biosynthetic function in perfused liver of young and old rats

The effect of treatment with acetyl-L-carnitine on hepatic mitochondrial respiration and biosynthetic function in perfused liver from young (90 days) and old (22-24 months) rats was studied. Rats were given a 1.5% (w/v) solution of acetyl-L-carnitine in their drinking water for 1 month and oxygen consumption together with the rate of gluconeogenesis, urea synthesis, and ketogenesis with and without added substrates were measured in perfused liver. Mitochondrial oxygen consumption was also assessed in liver homogenate and isolated mitochondria to determine the maximal capacity for oxidative phosphorylation. Acetyl-L-carnitine treatment almost completely restored the age-dependent decline in oxygen consumption, gluconeogenesis, urea synthesis, and ketogenesis found in perfused liver of old rats to the levels found in young rats. In addition, acetyl-L-carnitine treatment increased oxygen consumption and biosynthetic function in perfused liver from young rats. After acetyl-L-carnitine treatment, we found detectable 3-oxoacyl-CoA-transferase activity associated with a consumption of ketone bodies in young and old rats. Finally, oxygen consumption measured in homogenate and isolated mitochondria did not change with age and acetyl-L-carnitine treatment. Our results show that in perfused liver, acetyl-L-carnitine treatment slows the age-associated decline in mitochondrial respiration and biosynthetic function. In addition, treatment of young rats with acetyl-L-carnitine has a stimulating effect on liver metabolism, probably through an increase in ATP production. Received 25 October 2000; received after revision 14 December 2000; accepted 11 January 2001     

Boussingault versus ville: The social,political and scientific aspects of their disputes

A feature of mid-nineteenth century scientific debates in France on the subject of plant nutrition was the rivalry, at times acrimonious, between Jean Baptiste Boussingault and Georges Ville. It started in 1848 when Ville was demonstrator to Boussingault, who held one of the two chairs of agriculture at the Conservatoire des Arts et Métiers. A study of their disputes serves to illustrate their mutual incompatibility, exacerbated by the patronage extended to Ville by his step-brother, Louis Napoléon Bonaparte, afterwards Napoléon III. Their disputes were not merely the result of personal differences but also accompanied the development of two concepts of plant nutrition, namely the rôle of atmospheric nitrogen. and its possible assimilation by plants, and the chemical nature of plant nutrients, especially nitrates and phosphates.     

The metabolism and function of sphingolipids and glycosphingolipids

Sphingolipids and glycosphingolipids are emerging as major players in many facets of cell physiology and pathophysiology. We now present an overview of sphingolipid biochemistry and physiology, followed by a brief presentation of recent advances in translational research related to sphingolipids. In discussing sphingolipid biochemistry, we focus on the structure of sphingolipids, and their biosynthetic pathways – the recent identification of most of the enzymes in this pathway has led to significant advances and better characterization of a number of the biosynthetic steps, and the relationship between them. We then discuss some roles of sphingolipids in cell physiology, particularly those of ceramide and sphingosine-1-phosphate, and mention current views about how these lipids act in signal transduction pathways. We end with a discussion of sphingolipids and glycosphingolipids in the etiology and pathology of a number of diseases, such as cancer, immunity, cystic fibrosis, emphysema, diabetes, and sepsis, areas in which sphingolipids are beginning to take a central position, even though many of the details remain to be elucidated. Received 13 February 2007; received after revision 19 April 2007; accepted 26 April 2007     

In vivo occupation of estrogen receptors by hydroxylated metabolites of tamoxifen]

We report that after in vivo administration of (3H) tamoxifen, the cytosol and nuclear estrogen receptor sites of Rat uterus and Chicken oviduct are mostly occupied by polar metabolites. One of the major metabolites is 4-hydroxy-tamoxifen which we have identified by cocrystallisation withe non radioactive compound and which is known to display a high affinity for the estrogen receptor. In the Rat uterus, the proportion of the metabolites versus tamoxifen, increases with time with a maximum at 8 hrs. for the 4-hydroxy-tamoxifen. Other hydroxylated metabolites (M2) became predominant after 24 hrs. We propose that in vivo, the synthetic antiestrogens act mostly via their transformation into hydroxylated metabolites.     

Ion and metabolite transport in the chloroplast of algae: lessons from land plants

Chloroplasts are endosymbiotic organelles and play crucial roles in energy supply and metabolism of eukaryotic photosynthetic organisms (algae and land plants). They harbor channels and transporters in the envelope and thylakoid membranes, mediating the exchange of ions and metabolites with the cytosol and the chloroplast stroma and between the different chloroplast subcompartments. In secondarily evolved algae, three or four envelope membranes surround the chloroplast, making more complex the exchange of ions and metabolites. Despite the importance of transport proteins for the optimal functioning of the chloroplast in algae, and that many land plant homologues have been predicted, experimental evidence and molecular characterization are missing in most cases. Here, we provide an overview of the current knowledge about ion and metabolite transport in the chloroplast from algae. The main aspects reviewed are localization and activity of the transport proteins from algae and/or of homologues from other organisms including land plants. Most chloroplast transporters were identified in the green alga Chlamydomonas reinhardtii, reside in the envelope and participate in carbon acquisition and metabolism. Only a few identified algal transporters are located in the thylakoid membrane and play role in ion transport. The presence of genes for putative transporters in green algae, red algae, diatoms, glaucophytes and cryptophytes is discussed, and roles in the chloroplast are suggested. A deep knowledge in this field is required because algae represent a potential source of biomass and valuable metabolites for industry, medicine and agriculture.     

Melatonin,mitochondria, and the skin

The skin being a protective barrier between external and internal (body) environments has the sensory and adaptive capacity to maintain local and global body homeostasis in response to noxious factors. An important part of the skin response to stress is its ability for melatonin synthesis and subsequent metabolism through the indolic and kynuric pathways. Indeed, melatonin and its metabolites have emerged as indispensable for physiological skin functions and for effective protection of a cutaneous homeostasis from hostile environmental factors. Moreover, they attenuate the pathological processes including carcinogenesis and other hyperproliferative/inflammatory conditions. Interestingly, mitochondria appear to be a central hub of melatonin metabolism in the skin cells. Furthermore, substantial evidence has accumulated on the protective role of the melatonin against ultraviolet radiation and the attendant mitochondrial dysfunction. Melatonin and its metabolites appear to have a modulatory impact on mitochondrion redox and bioenergetic homeostasis, as well as the anti-apoptotic effects. Of note, some metabolites exhibit even greater impact than melatonin alone. Herein, we emphasize that melatonin–mitochondria axis would control integumental functions designed to protect local and perhaps global homeostasis. Given the phylogenetic origin and primordial actions of melatonin, we propose that the melatonin-related mitochondrial functions represent an evolutionary conserved mechanism involved in cellular adaptive response to skin injury and repair.     

The mode of antifungal action of plant, insect and human defensins

Defensins are small (~5 kDa), basic, cysteine-rich antimicrobial peptides that fulfill an important role in the innate immunity of their host by combating pathogenic invading micro-organisms. Defensins can inhibit the growth or virulence of microorganisms directly or can do so indirectly by enhancing the host's immune system. Because of their wide distribution in nature, defensins are believed to be ancient molecules with a common ancestor that arose more than a billion years ago. This review summarizes current knowledge concerning the mode of antifungal action of plant, insect and human defensins.