<Emphasis Type="Italic">Monascus purpureus</Emphasis>-fermented products and oral cancer: a review

Tobacco and alcohol consumption have been reported as major factors for the development of oral cancer. Edible fungi of the Monascus species have been used as traditional Chinese medicine in eastern Asia for several centuries. Monascus-fermented products have many functional secondary metabolites, including monacolin K, citrinin, ankaflavin, and monascin. In several recent studies performed in our laboratory, these secondary metabolites have shown anti-inflammatory, anti-oxidative, and anti-tumor activities. Many published studies have shown the efficacy of Monascus-fermented products in the prevention of numerous types of cancer. The current article discusses and provides evidence to support that Monascus-fermented metabolites may be developed as painting drugs for the mouth to prevent or cure oral carcinogenesis. This is a novel therapeutic approach focusing on tumor growth attenuation to improve patient survival and quality of life.     

Chemistry and biological activity of azoprenylated secondary metabolites

N-Prenyl secondary metabolites (isopentenylazo-, geranylazo-, farnesylazo- and their biosynthetic derivatives) represent a family of extremely rare natural products. Only in recent years have these alkaloids been recognized as interesting and valuable biologically active secondary metabolites. To date about 35 alkaloids have been isolated from plants mainly belonging to the Rutaceae family, and from fungi, bacteria, and/or obtained by chemical synthesis. These metabolites comprise anthranilic acid derivatives, diazepinones, and indole, and xanthine alkaloids. Many of the isolated prenylazo secondary metabolites and their semisynthetic derivatives are shown to exert valuable in vitro and in vivo anti-cancer, anti-inflammatory, anti-bacterial, anti-viral, and anti-fungal effects. The aim of this comprehensive review is to examine the different types of prenylazo natural products from a chemical, phytochemical and biological perspective.     

Development of Monascus fermentation technology for high hypolipidemic effect

Monascus species has been used as the traditional food fungus in Eastern Asia for several centuries. Monascus-fermented products are gradually developed as the popular functional food for the prevention of cardiovascular disease, but we know that culture condition affects the hypolipidemic effect of Monascus-fermented product. In the past, the cholesterol-lowering agent--monacolin K--is regarded as the most important hypolipidemic agent. Two natural yellow pigments--monascin and ankaflavin--are also proven as novel hypolipidemic agents in recent years. However, the hypolipidemic effect of Monascus-fermented product should contribute from monacolin K, monascin, ankaflavin, and other unknown functional ingredients. In addition to hypolipidemic effect, the safety concern of Monascus-fermented product is involved in the levels of mycotoxin--citrinin. The hypolipidemic effect and the production of these functional metabolites or mycotoxin are influenced by many factors such as the choice of culture substrates, carbon and nitrogen source, pH value, extra nutrients, and so on. Therefore, this review focused on the effect of various culture conditions and nutrients on the functional metabolites production, hypolipidemic effect as well as citrinin concentration, and further organized the fermentation technologies used by previous studies for the promotion of hypolipidemic effect and safety.     

Secondary Metabolites as Mediators of Trophic Interactions Among Antarctic Marine Organisms

Secondary metabolites are widespread among lower phyla and understandingtheir functional role(s) in the producing organism has beenunder study in recent decades. Considerable progress has beenmade in understanding chemical ecological interactions amongterrestrial organisms, and similar research in the marine realmhas been initiated in recent years. Polar regions are more difficultto access and thus progress has been slower. Nevertheless, theextreme and often unique marine environments surrounding Antarcticaas well as the many unusual trophic interactions in antarcticmarine communities might well be expected to select for novelsecondary metabolites and/or novel functional roles for secondarymetabolites. Indeed, recent studies have documented novel, chemically-mediatedinteractions between molluscs and amphipods, between algae,urchins and anemones, and between sponges and their predators.The Porifera are the dominant phylum on the McMurdo Sound benthos,and representatives of this phylum have been shown to elaboratesea star feeding deterrents, inhibitors of fouling or infectiousorganisms, and metabolites which mediate predation via moltinhibition. As a result of studies on Antarctic sponges, newinsights into functional roles of pigments and the ability ofsponges to sequester metabolites have been gained, and a newmechanism of chemical defense has been described. Herein wedescribe recent results of our studies of trophic interactionsbetween sponges and their predators that are mediated by specificsponge secondary metabolites. Moreover, we highlight unusualchemically-mediated interactions in antarctic marine invertebratesother than sponges.     

Marine natural pigments as potential sources for therapeutic applications

In recent years, marine natural pigments have emerged as a powerful alternative in the various fields of food, cosmetic, and pharmaceutical industries because of their excellent biocompatibility, bioavailability, safety, and stability. Marine organisms are recognized as a rich source of natural pigments such as chlorophylls, carotenoids, and phycobiliproteins. Numerous studies have shown that marine natural pigments have considerable medicinal potential and promising applications in human health. In this review, we summarize the marine natural pigments as potential sources for therapeutic applications, including: antioxidant, anticancer, antiangiogenic, anti-obesity, anti-inflammatory activities, drug delivery, photothermal therapy (PTT), photodynamic therapy (PDT), photoacoustic imaging (PAI), and wound healing. Marine natural pigments will offer a better platform for future theranostic applications.     

The alveolar macrophage

The alveolar macrophage is one of the few tissue macrophage populations readily accessible to study both in the human and in animals. Since harvesting of these cells by bronchoalveolar lavage was first described in 1961, alveolar macrophages have been extensively investigated. This population is the predominant cell type within the alveolus, and undoubtedly serves as the first line of host defense against inhaled organisms and soluble and particulate molecules. Early studies focussed on this endocytic role and delineated the cells' phagocytic and microbicidal capacities. More recent investigations demonstrated an extensive synthetic and secretory repertoire including lysozyme, neutral proteases, acid hydrolases and O2 metabolites. In addition, the complex immunoregulatory role of the macrophage has also been appreciated. These cells have been shown to produce a wide variety of pro- and anti-inflammatory agents including arachidonic acid metabolites of the cyclooxygenase and lipoxygenase pathways, cytokines which modulate lymphocyte function and factors which promote fibroblast migration and replication.     

Regulation of the biosynthesis of secondary metabolites in Streptomyces galbus

The effect of inhibiting and stimulating agents on the biosynthesis of secondary metabolites (actinomycin X and melanoid pigments) was studied in Streptomyces galbus as a function of the growth temperature. D-Valine was shown to inhibit actinomycin synthesis and to stimulate production of melanoid pigments. Tryptophan stimulated the synthesis of both actinomycin and melanoid pigments. The temperature of growth was found to regulate the biosynthesis of secondary metabolites by the culture. The organism synthesized actinomycin at 28 degrees C, but it switched to the production of melanoid pigments at 42 degrees C. This may be considered as a protective reaction of the organism to an increase in the temperature of the environment and in UV radiation which is possible under natural conditions as a consequence of temperature elevation. The paper presents a hypothetical scheme for the regulation of biosynthesis of actinomycin and melanoid pigments by temperature. According to the scheme, the culture synthesizes secondary metabolites from tryptophan to hydroxykynurenine via a general pathway which is then bifurcated: at 28 degrees C--through methylhydroxyanthranilic acid to actinocin to actinomycin; at 42 degrees C--through hydroxyanthranilic acid, o-aminophenol, pyrocatechol, and possibly, o-benzoquinone, to melanin.     

Kaurane and pimarane-type diterpenes from the Viguiera species inhibit vascular smooth muscle contractility

The research, development and use of natural products as therapeutic agents, especially those derived from plants, have been increasing in recent years. Despite the fact that plants provide a rich source of novel biologically active compounds, only a small percentage have been phytochemically investigated and studied for their medical potential. Viguiera is a genus that belongs to the family Asteraceae and to the sunflower tribe Heliantheae, which is widespread mostly in Mexico and in other areas of the Andes and upland areas of Brazil. A review on the secondary metabolites pointed out that sesquiterpene lactones and diterpenes, of the kaurane and pimarane-type, are the main compounds produced by these plants. Some reports have shown that kaurane- and pimarane-type diterpenes exert several biological activities such as anti-inflammatory action, antimicrobial and antispasmodic activities. Kaurenoic and pimaradienoic acids, which are the main secondary metabolites isolated by our research group from the roots of Viguiera robusta and V. arenaria, respectively, have been evaluated on vascular smooth muscle contractility. We showed that these diterpenoids are able to inhibit the vascular contractility mainly by blocking extracellular Ca(2+) influx. Additionally, in this review we discuss the structure-activity relationship of the diterpenes regarding their inhibitory activity on vascular contractility.     

Elevated γ-Aminobutyric Acid Levels Attenuate the Metabolic Response to Biateral Ischemia

Bilateral ischemia has been shown to alter the net brain levels of energy metabolites such as ATP, phosphocreatine, glucose, and glycogen. The amino acid neurotransmitter gamma-aminobutyric acid (GABA) exerts a tonic inhibitory influence on neural activity. The present studies were designed to evaluate the influence of elevated GABA levels on the metabolic sequelae of ischemia. The GABA transaminase inhibitor gamma-vinyl-GABA (GVG; vigabatrin) was administered to Mongolian gerbils before the production of a bilateral ischemic incident. GABA levels were elevated in all regions assayed. Levels of energy metabolites were also increased, an indication of reduced energy utilization. In control animals, in the absence of GVG, 1 min of bilateral ischemia produced decreases in the levels of all metabolites. In animals pretreated with GVG, the effects of 1 min of bilateral ischemia were attenuated. These data suggest that the level of ongoing activity may affect the response to an ischemic insult. Furthermore, GVG may have a clinical indication in reducing the effect of minor ischemic incidents.     

红曲菌次生代谢产物生物合成途径及相关基因的研究进展

红曲菌(Monascus spp.)是我国重要的药食两用微生物资源之一,能够产生天然食品添加剂红曲色素、降血酯活性物质Monacolin K等有益次生代谢产物,但也能分泌真菌毒素桔霉素(Citrinin),红曲菌及其相关产品的安全性由此受到质疑.因此,如何促进红曲菌有益代谢产物的产生,减少或抑制桔霉素的产生成为广大科研工作者研究的重点方向.近年来,红曲菌的分子生物学研究有了较快的发展,红曲菌次生代谢产物生物合成及其调控的研究是热点.本文重点介绍红曲色素、Monacolin K和桔霉素生物合成途径及相关基因的研究进展,以期为有效调控红曲菌次生代谢产物的产生、提高红曲产品的安全性提供参考和借鉴.     

植物次生代谢及其与环境的关系

人类对植物次生代谢产物（天然产物）的早期研究源于它们的应用价值,近些年来人们越来越认识到植物次生代谢产物广泛的生物学效应,开始重新评价这些化合物在植物生命活动以及生态系统中可能扮演的角色。植物的次生代谢是植物在长期进化中与环境（生物的和非生物的）相互作用的结果,次生代谢产物在植物提高自身保护和生存竞争能力、协调与环境关系上充当着重要的角色。介绍了植物次生代谢及其产物的特点,概述了植物次生代谢与温度、水分、光照、养分、CO2浓度、UV-B辐射、环境污染等非生物环境以及与化学防御、化感作用、菌根共生、微生物病害的关系。研究植物次生代谢与环境的关系,可以从更深的层次发掘植物与环境的内在联系,为全面、深入认识植物与环境的相互关系提供新的研究途径,同时也有利于人类更有效、合理地利用植物的次生代谢产物。     

Biophysical and biochemical characterization of active secondary metabolites from Aspergillus allahabadii

Fungal secondary metabolites are a diverse group of natural chemical products with physiological relevance. We aimed to identify bioactive secondary metabolites from Aspergillus allahabadii. We used “activity-guided fractionation” strategy for the isolation of secondary metabolites. Crude extracts showed good antibacterial activity. Two antibacterial secondary metabolites have been isolated from the crude extract. Chemical characterization of these compounds was performed using biophysical techniques (FT-IR, NMR, and mass spectrometry). Structural characterization confirmed these to be pyrone derivatives: 3-hydroxy 2-methyl 4-pyrone and 5-hydroxy-2-(hydroxymethyl)-4H-pyrone. These bioactive pyrone derivatives have been identified as maltol and kojic acid. From our initial observations, we infer that these pyrone derivatives have potent antimicrobial, antioxidant, antidiabetic, and mosquito larvicidal activities and no cytotoxicity. These compounds could have potential therapeutic and biomedical applications, but further mechanistic studies using animal models are very much necessary.     

Pigment chemistry, taxonomy and phylogeny of the Hypoxyloideae (Xylariaceae)

The Hypoxyloideae (Xylariaceae with Nodulisporium-like anamorphs) were evaluated by a morphological and HPLC-based chemotaxonomic survey of more than 2000 specimens and cultures. Conspecificity of recent records with ancient type specimens were established in many cases by HPLC, since their characteristic metabolites may remain stable for over 200 years. Most constitute novel natural products that were identified in the course of concurrent "mycochemical" studies. A comparison of HPLC profiles considering relationships within the Hypoxyloideae as inferred from the biogenesis of these pigments agreed fairly with concurrent molecular phylogenetic studies, based on sequences of actin, beta-tubulin, and 5.8S/ITS nrDNA genes. Anamorphic morphology and secondary metabolism of cultures agreed well at generic level and above. A combination of chemical and morphological traits is favored over PCR-based approaches for species discrimination, if only relatively few taxa of these diverse genera have been sequenced. An overview on the chemical structures and biological activities of the characteristic metabolites is provided, their ecological importance is discussed, and the utility of chemotaxonomy to support and predict phylogenetic relationships in the Hypoxyloidae is demonstrated. A polythetic approach is most useful to elucidate the phylogeny of the Xylariaceae. Chemotaxonomy to assess fungal biodiversity has considerable utility.     

Chemistry and pharmacology of oxyprenylated secondary plant metabolites

Oxyprenylated natural products (isopentenyloxy-, geranyloxy- and the less spread farnesyloxy- compounds and their biosynthetic derivatives) represent a family of secondary metabolites that have been considered for years just as biosynthetic intermediates of C-prenylated derivatives. Only in the last decade these natural products have been recognized as interesting and valuable biologically active phytochemicals. Up to now about 300 molecules have been isolated from plants mainly belonging to the families of Rutaceae and Compositae, comprising common edible vegetables and fruits. A wide variety of compounds containing a prenyloxy side chain have been isolated and these comprise alkaloids, coumarins, flavonoids, cinnamic acids, benzoic acids, phenols, alcohols, aldehydes, anthraquinones, chalcones, lignans, xanthones, aceto- and benzophenones and other more uncommon skeletons. Many of the isolated oxyprenylated natural products and their semisynthetic derivatives were shown to exert in vitro and in vivo remarkable anti-cancer, anti-inflammatory, anti-microbial and anti-fungal effects. The aim of this review is to examine in detail the different types of oxyprenylated natural compounds from a phytochemical and pharmacological point of view.     

Lipofuscin and lipofuscin-like substances

Lipofuscin is defined as being a yellowish brown, lipid-rich, heterogeneous, cytoplasmic granular pigment emitting an intense yellow autofluorescence when excited with ultraviolet light, which accumulates in various tissues of animals during their aging. It is believed that the pigments are derived from the reaction of some of reactive secondary products including malonaldehyde, formed during membranous lipid peroxidation, with amino groups of phospholipids and proteins, etc., and that these formations are accompanied by alteration of the membrane structure and inactivation of the enzymes. The fluorescence measurement of the pigments is widely used as a parameter of lipid peroxidation in vivo as well as in vitro. However, their origin, chemical structure, biological significance or fate has not as yet been fully elucidated. This article introduces and discusses the recent studies on these problems.     

Adventitious Roots and Secondary Metabolism

Plants are a rich source of valuable secondary metabolites and in the recent years plant cell, tissue and organ cultures have been developed as an important alternative sources for the production of these compounds. Adventitious roots have been successfully induced in many plant species and cultured for the production of high value secondary metabolites of pharmaceutical, nutraceutical and industrial importance. Adoption of elicitation methods have shown improved synthesis of secondary metabolites in adventitious root cultures. Development of large-scale culture methods using bioreactors has opened up feasibilities of production of secondary metabolites at the industrial levels. In the present review we summarize the progress made in recent past in the area of adventitious root cultures for the production of secondary metabolites.     

Adventitious Roots and Secondary Metabolism

Plants are a rich source of valuable secondary metabolites and in the recent years plant cell, tissue and organ cultures have been developed as an important alternative sources for the production of these compounds. Adventitious roots have been successfully induced in many plant species and cultured for the production of high- value secondary metabolites of pharmaceutical, nutraceutical and industrial importance. Adoption of elicitation methods have shown improved synthesis of secondary metabolites in adventitious root cultures. Development of large-scale culture methods using bioreactors has opened up feasibilities of production of secondary metabolites at the industrial levels. In the present review we summarize the progress made in recent past in the area of adventitious root cultures for the production of secondary metabolites.     

Function of MbtH homologs in nonribosomal peptide biosynthesis and applications in secondary metabolite discovery

Mycobacterium tuberculosis encodes mycobactin, a peptide siderophore that is biosynthesized by a nonribosomal peptide synthetase (NRPS) mechanism. Within the mycobactin biosynthetic gene cluster is a gene that encodes a 71-amino-acid protein MbtH. Many other NRPS gene clusters harbor mbtH homologs, and recent genetic, biochemical, and structural studies have begun to shed light on the function(s) of these proteins. In some cases, MbtH-like proteins are required for biosynthesis of their cognate peptides, and non-cognate MbtH-like proteins have been shown to be partially complementary. Biochemical studies revealed that certain MbtH-like proteins participate in tight binding to NRPS proteins containing adenylation (A) domains where they stimulate adenylation reactions. Expression of MbtH-like proteins is important for a number of applications, including optimal production of native and genetically engineered secondary metabolites produced by mechanisms that employ NRPS enzymes. They also may serve as beacons to identify gifted actinomycetes and possibly other bacteria that encode multiple functional NRPS pathways for discovery of novel secondary metabolites by genome mining.     

Mining novel biosynthetic machineries of secondary metabolites from actinobacteria

ABSTRACT

Secondary metabolites produced by actinobacteria have diverse structures and important biological activities, making them a useful source of drug development. Diversity of the secondary metabolites indicates that the actinobacteria exploit various chemical reactions to construct a structural diversity. Thus, studying the biosynthetic machinery of these metabolites should result in discovery of various enzymes catalyzing interesting and useful reactions. This review summarizes our recent studies on the biosynthesis of secondary metabolites from actinobacteria, including the biosynthesis of nonproteinogenic amino acids used as building blocks of nonribosomal peptides, the type II polyketide synthase catalyzing polyene scaffold, the nitrous acid biosynthetic pathway involved in secondary metabolite biosynthesis and unique cytochrome P450 catalyzing nitrene transfer. These findings expand the knowledge of secondary metabolite biosynthesis machinery and provide useful tools for future bioengineering.     

Biologically active secondary metabolites from marine cyanobacteria

Marine cyanobacteria are a rich source of complex bioactive secondary metabolites which derive from mixed biosynthetic pathways. Recently, several marine cyanobacterial natural products have garnered much attention due to their intriguing structures and exciting anti-proliferative or cancer cell toxic activities. Several other recently discovered secondary metabolites exhibit insightful neurotoxic activities whereas others are showing pronounced anti-inflammatory activity. A number of anti-infective compounds displaying activity against neglected diseases have also been identified, which include viridamides A and B, gallinamide A, dragonamide E, and the almiramides.