Antitumoral Effects of Fungal Natural Products on Chronic Myeloid Leukemia Models: What Do We Know so Far?

This handbook compiles authoritative information about fungal metabolites and their chemistry and biotechnology. The first in the reference work series “Phytochemicals”, and written by a team of international expert authors, this book provides reference information ranging from the description of fungal natural products, over their use e.g. as anticancer agents, to microbial synthesis, even spanning to the production of secondary metabolites on industrial scale. On the other hand it also describes global health issues related to aflatoxin production in foods and agriculture, including perspectives for detoxification. The handbook characterizes different compound classes derived from fungal secondary metabolites, like ergot alkaloids and aflatoxins. The discussion puts a special emphasis on how potentially useful compounds can be obtained and what applications they can find, on the one hand, and how potential dangers can be encountered on the other hand. The comprehensive chapters in this handbook will thus appeal to readers from diverse backgrounds in chemistry, biology, life sciences, and even medicine, who are working or planning to work with fungal (secondary) metabolites and their application. They provide the readers with rich sources of reference information on important topics in this field. The first authoritative summary and reference work on fungal (secondary) metabolites, their chemistry and biotechnological use and applications Covering aspects from beneficial use, to potential health issues of fungal metabolites Reference information for readers from various backgrounds: chemists, biologists, life scientists, medical scienti The biocontrol of plant pathogenic fungi includes two complementary approaches depending on whether the aim is to control soil-borne or air-borne pathogenic fungi. In the first case, natural biotic interactions within the indigenous microflora should be stimulated to regulate inoculum density and the infectious activity of pathogen populations. This strategy can be enhanced by inoculating one or more previously selected biocontrol agents. In the second case, one or more previously selected biocontrol agents can be sprayed on plant foliage to interfere with the development of the targeted pathogen through different mechanisms involving particular enzymes or metabolites. Selecting the most effective biological control agents implies (i) knowing the mechanisms of their interactions with the pathogens and (ii) checking that the environment in which the biocontrol agent is introduced will permit the expression of these mechanisms. The common thread of this chapter is the impressive diversity of metabolites and proteins produced by fungi and involved in interactions between pathogenic and nonpathogenic fungi. Many metabolites and proteins were discovered empirically or by chance a few decades ago, and what we knew about them was they inhibited the growth of pathogenic models on agar medium. Fungi producing these metabolites were not well-known fungal species and were not used as biocon- trol agents. However, the demonstration of their intense metabolic activity paved the way for more investigations in this area and led to deciphering the mechanisms of interactions between fungal strains. Thus, in recent years a large number of enzymes, signal molecules, secondary metabolites, large-size proteins, as well as new metabolic pathways have been revealed by genomics, and it is now possible to understand why some strains can control a given pathogen more than others or stimulate plant defense reactions. To date, the most studied fungi include many strains of the genus Trichoderma but also the species Chlonostachys rosea, Coniothyrium minitans, Verticillium biguttatum, and the oomycete Pythium oligandrum. All of them are successfully used as biocontrol agents. This chapter does not aim to provide a comprehensive catalog, but rather to associate these metabolites and proteins to the modes of action involved in pathogen control. The state of the art presented in this review suggests promising prospects for rational, appropriate, and effective use of the biocontrol potential offered by the huge diversity of fungal metab- olites and proteins.

Bioinformatics assisted construction of the link between biosynthetic gene clusters and secondary metabolites in fungi.

Cholix toxin (Cholix) is a novel ADP-ribosylating cytotoxin produced by Vibrio cholerae, which utilizes eukaryotic elongation factor 2 as a substrate and acts by a mechanism similar to that of diphtheria toxin and Pseudomonas exotoxin A. First it was found that Cholix-treated HeLa cells exhibited caspase-dependent apoptosis, whereas intestinal cells such as Caco-2, HCT116, and RKO did not. Here we investigated Cholix-induced cell death signaling pathways in HeLa cells. Cholix-induced cytochrome c release into cytosol was initiated by specific conformational changes of pro-apoptotic Bak associated with Bax. Silencing of bak/bax genes or bak gene alone using siRNA significantly suppressed cytochrome c release and caspase-7 activation, but not activation of caspases-3 and -9. Although pretreatment with a caspase-8 inhibitor (Z-IETD-FMK) reduced Cholix-induced cytochrome c release and activation of caspases-3, -7, and -9, cytotoxicity was not decreased. Pretreatment with Z-YVAD-FMK, which inhibits caspase-1, -4, and -5, suppressed not only cytochrome c release, activation of caspase-3, -7, -8, or -9, and PARP cleavage, but also cytotoxicity, indicating that caspase-1, -4, and -5 activation is initiated at an early stage of Cholix-induced apoptosis and promotes caspase-8 activation. These results show that the inflammatory caspases (caspase-1, -4, and -5) and caspase-8 are responsible for both mitochondrial signals and other caspase activation. In conclusion, we showed that Cholix-induced caspase activation plays an essential role in generation of apoptotic signals, which are mediated by both mitochondria-dependent and -independent pathways.

Higher fungi are a promising source of new bioactive natural products with great structural diversity, ranging from polyketides to terpenoids and alkaloids. Many of these structures are a challenge for synthetic organic chemists who have been inspired to develop new total syntheses. Nevertheless, reviews covering syntheses of fungal natural products are lacking. One aim of this review is to close this gap and to present a selection of more recent syntheses of fungal secondary metabolites from different structural classes. Secondly, this review intends to demonstrate that there are many more motivations for the synthesis of natural products than to confirm a proposed structure or to report the first total synthesis of a new natural product. Thirdly, this review is intended to stimulate the interest of organic chemists in the synthesis of fungal natural products. 1 History and Importance of (Fungal) Secondary Metabolites 2 Reasons for the Synthesis of Fungal Natural Products 3 Total Syntheses of Selected Fungal Natural Products 3.1 Terpenes 3.1.1 Sesquiterpenes 3.1.1.1 Polyquinanes 3.1.1.2 Drimanes 3.1.2 Diterpenes: Cyathanes 3.1.3 Terpenes Containing a Butenolide Moiety 3.2 Alkaloids 3.3 Natural Products Derived from the Shikimate Pathway 3.3.1 Pulvinic Acid Derivatives and Terphenyl Quinones 3.3.2 Shikimate Pathway Derived Macrolides 3.3.3 Strobilurins 3.4 Aromatic Polyketides 3.4.1 Quinones 3.4.2 Resorcylates and Catechols 3.5 Sugar Derivatives 4 Conclusion and Outlook

Review: [160 refs.

Piercing the armor of hepatobiliary cancer: Bcl-2 homology domain 3 (BH3) mimetics and cell death

Radiation affects several cellular and molecular processes, including double strand breakage and modifications of sugar moieties and bases. In outer space, protons are the primary radiation source that poses a range of potential health risks to astronauts. On the other hand, the use of proton irradiation for tumor radiation therapy is increasing, as it largely spares healthy tissues while killing tumor tissues. Although radiation-related research has been conducted extensively, the molecular toxicology and cellular mechanisms affected by proton irradiation remain poorly understood. Therefore, in this study, we irradiated rat lung epithelial cells with different doses of protons and investigated their effects on cell proliferation and death. Our data show an inhibition of cell proliferation in proton-irradiated cells with a significant dose-dependent activation and repression of reactive oxygen species and antioxidants glutathione and superoxide dismutase, respectively, compared with control cells. In addition, the activities of apoptosis-related genes such as caspase-3 and -8 were induced in a dose-dependent manner with corresponding increased levels of DNA fragmentation in proton-irradiated cells compared with control cells. Together, our results show that proton irradiation alters oxidant and antioxidant levels in cells to activate the apoptotic pathway for cell death.

Many drug discovery projects rely on commercial compounds to discover active leads. However, current commercial libraries, with mostly synthetic compounds, access a small fraction of the possible chemical diversity. Natural products, in contrast, possess a vast structural diversity and have proven to be an outstanding source of new drugs. Several chemoinformatic analyses of natural products have demonstrated their diversity and structural complexity. However, to our knowledge, the scaffold content and structural diversity of fungal secondary metabolites have never been studied. Herein, the scaffold diversity of 223 fungal metabolites was measured and compared to the diversity of approved drugs and commercial libraries for HTS containing natural, synthetic, and semi-synthetic compounds. In addition, the global diversity of the fungal isolates was assessed and compared to other reference data sets using Consensus Diversity Plots, a chemoinformatic tool recently developed. It was concluded that fungal secondary metabolites are cyclic systems with few ramifications and more diverse than the commercial libraries with natural products and semi-synthetic compounds. The fungal metabolites data set was one of the most structurally diverse, containing a large proportion of different and unique scaffolds not found in the other compound data sets including ChEMBL. Therefore, fungal metabolites offer a rich source of molecules suited for identifying diverse candidates for drug discovery.

Worldwide, antibiotics are among the most commonly used and misused drugs because of the perception in some practitioners and patients that antibiotic resistance is theoretical or only a minor risk. This review therefore aims to update knowledge and promote proper antibiotic prescription with the goal of optimizing use and halting the trend of rising resistance. A literature and internet (Medline, embase, HINARI and Cochrane data bases) search showed that prescription of antibiotics only when indicated following standard guidelines minimizes the incidence and spread of resistance. Mechanisms of resistance development include bacterial mutation or horizontal transfer from plasmids, transposons, integrons and gene cassettes between commensal organisms and potential pathogens by transduction, translocation, transposition, transformation or conjugation. Resistance may emerge following indiscriminate use of antibiotics, unhygienic conditions, poor drug handling and non-adherence. To halt resistance, priority areas include prudent use of antibiotics; development of antimicrobials with novel mechanisms of action; use of bioinformatics and genomic techniques to identify and study new targets of attack; use of alternatives to antibiotics such as bacteriophage-derived therapy or chemical agents that can block or reverse resistance pathways; use of agents in natural products, vaccines and pro-biotics as well as implementing public health strategies and education of the populace. In response, initiatives at the local, national and international levels are now directed towards promoting good antibiotic stewardship, infection control, sanitation and hygiene practices. Key words: Antibiotic, antimicrobials, prescription, resistance, contemporary, review

The ent-kaurane diterpenoids are widely distributed in China, some of which have high natural abundance in plants of Isodon, Pteris, Gnaphalium, Diplospora, Croton and some other species. These compounds exhibit significant anti-tumor, antibacterial and anti-inflammatory activities, which have attracted the attention of medicinal chemists. This review focuses on the recent advances in the research of derivatives, anti-tumor activity, mechanism of action, and structure-activity relationships of ent-kaurane diterpenoids. All of these will show the potential in the development of new antitumor agents in natural products.

Worldwide, antibiotics are among the most commonly used and misused drugs because of the perception in some practitioners and patients that antibiotic resistance is theoretical or only a minor risk. This review therefore aims to update knowledge and promote proper antibiotic prescription with the goal of optimizing use and halting the trend of rising resistance. A literature and internet (Medline, embase, HINARI and Cochrane data bases) search showed that prescription of antibiotics only when indicated following standard guidelines minimizes the incidence and spread of resistance. Mechanisms of resistance development include bacterial mutation or horizontal transfer from plasmids, transposons, integrons and gene cassettes between commensal organisms and potential pathogens by transduction, translocation, transposition, transformation or conjugation. Resistance may emerge following indiscriminate use of antibiotics, unhygienic conditions, poor drug handling and nonadherence. To halt resistance, priority areas include prudent use of antibiotics; development of antimicrobials with novel mechanisms of action; use of bioinformatics and genomic techniques to identify and study new targets of attack; use of alternatives to antibiotics such as bacteriophagederived therapy or chemical agents that can block or reverse resistance pathways; use of agents in natural products, vaccines and pro-biotics as well as implementing public health strategies and education of the populace. In response, initiatives at the local, national and international levels are now directed towards promoting good antibiotic stewardship, infection control, sanitation and hygiene practices.

Clinical experience suggests that drugs that interact with and damage DNA are useful in cancer chemotherapy (H. Umezawa , p. 43-72, in V. T. DeVita , Jr., and H. Busch [ed.], Methods in Cancer Research; Cancer Drug Development, vol. XVI, 1979). Prescreening systems for antitumor agents in natural products require assays that are exquisitely sensitive, since the active components are often produced in quantities of micrograms per milliliter or less. One assay used to identify agents that interact with DNA is the biochemical induction assay, utilizing Escherichia coli BR 513 (R. K. Elespuru and R. J. White, Cancer Res. 43:2819-2830, 1983). In this paper we describe a genetic modification of strain BR 513 that displays an expanded spectrum of activity. This strain may provide an improved prescreen for detecting natural products that interact with DNA.

DNA damage results in transcriptional induction of p53 target genes, including the cyclin-dependent kinase (CDK) inhibitor p21(Cip1) (CDKN1A) and the proapoptotic Bcl-2 family member p53 up-regulated modulator of apoptosis (PUMA). Depending on the cellular context, p21(Cip1) and PUMA mediate cell cycle arrest and apoptosis, respectively. By imposing cell cycle arrest at the expense of apoptosis, p21(Cip1) can sharply reduce the effectiveness of DNA-damaging anticancer agents in colorectal cancer cells. We investigated the link between cell cycle progression and the onset of apoptosis in DNA-damaged cells by analyzing the activation of the apoptotic cascade in p21(Cip1)-deficient HCT116 colorectal cancer cells. DNA damage induced a similar level of p53 activation and PUMA induction in p21(Cip1)-deficient cells compared with wild-type isogenic counterparts. p21(Cip1) did not act as a direct blocker of PUMA. However, only p21(Cip1)-deficient cells showed extensive cytochrome c release, mitochondrial membrane depolarization, and caspase activation. An increase in caspase activation occurred as these cells reached M-phase and incurred polyploidy. When ectopically expressed in p21(Cip1)-deficient HCT116 cells, p21(Cip1), its family member p27(Kip1), and the structurally unrelated CDK inhibitor p16(Ink4a) were similarly effective at causing cell cycle arrest and inhibiting DNA damage-induced apoptotic events such as cytochrome c release, mitochondrial membrane depolarization, and activation of the caspase cascade. These observations suggest that by blocking dysregulated cell cycle progression, CDK inhibitors can influence the sensitivity of the mitochondria to proapoptotic signals in DNA damage-induced cancer cells.

Fungi are amazing producers of natural products and thus they are crucial to the health and well-being of people throughout the world. Approximately 70,000 fungal species are recognized, although far more than 1 million are estimated to occur. Fungi can inhabit almost all the ecological niches in the world and are considered by their ability to create secondary metabolites or minor molecule natural products. Consequently, many of these secondary metabolites are not directly involved in the common growth, development, or reproduction of the fungi in which they occur, but rather may be essential in stress tolerance and ecological interactions with other organisms. Fungal secondary metabolites display a variety of biological activities and are of interest to the food, agrochemical, and pharmaceutical industries. The secondary metabolites produce from some common biosynthetic pathways, but the consequential intermediates undergo numerous enzyme-catalyzed reactions resulting in an extremely diverse group of chemical structures. Therefore, the bulk of these secondary metabolites are readily categorized on the basis of their biosynthetic origins as polyketides, alkaloids, terpenoids, nonribosomal peptides, and cyto-chalasins. These valuable molecules, recognized as nonribosomal peptides, are produced by a group of enzymes named nonribosomal peptide synthetases (NRPSs) that assemble diverse natural products including penicillin (antibacterial), beauvericin (anticancer), vancomycin (antibacterial), and peramine (anti-insect). Moreover, novel screening approaches based on innovative biological, chemical, and genetic methods have led to new fungal metabolites in recent years. This chapter highlights current knowledge about fungal natural products, including primary and secondary metabolites, their biosynthetic pathways, and brief examples of each class of compounds, including their bioactivity.

Decision letter: Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1