[Study on the growth, development and artificial propagation of Hypericum ascyron].

PubMed

Chen, Yu-mei; Zhang, Ke-qin; Song, Bai-jun; Zhao, Gui-ying; Wang, Zhen-hui; Wang, Li-mei; Chang, Wei-yi; Cong, Li-xin

2011-06-01

To explore the morphological changes, growth conditions and artificial propagation of Hypericum ascyron. The morphological changes were observed and recorded in the scene, the height and diameter of the plants were measured; the growth Verhaulst model was set up with the SPSS 17.0 software; the sexual reproduction and asexual reproduction were carried out in artificial cultivation. Hypericum ascyron started germinating in late April each year, branching in late May, flowering in late June, the period of full bearing was in early August, seeds were mature in early October. The Verhaulst models of the increase in the height (H), the quantity of leaf pairs (L) and the branching (B) were, H = 127.109/(1 + 23.744 x e(-0.062t)), L = 23.343/(1 + 11.303 x e(-0.062t)), B = 22.037/(1 + 73.068 x e(-0.068t)). The survival rate of whole graft and segmentation plant were 100% and 67.2% respectively on asexual reproduction; on the sexual reproduction, the seed germination rate was 15.2%, the survival rate of transplant seedlings was 36%. The period of growth and development of Hypericum ascyron is from April to October and it can be carried out artificial propagation.

Inhibition of MAO by fractions and constituents of hypericum extract.

PubMed

Bladt, S; Wagner, H

1994-10-01

The inhibition of monoamine oxidase (MAO) by six fractions from hypericum extract and three characteristic constituents (as pure substances) were analyzed in vitro and ex vivo to study the antidepressive mechanism of action. Rat brain homogenates were used as the in vitro model, while the ex vivo analysis was performed after intraperitoneal application of the test substances to albino rats. Massive inhibition of MAO-A could be shown with the total extract and all fractions only at the concentration of 10(-3) mol/L. At 10(-4) mol/L, one fraction rich in flavonoides showed an inhibition of 39%, and all other fractions demonstrated less than 25% inhibition. Using pure hypericin as well as in all ex vivo experiments, no relevant inhibiting effects could be shown. From the results it can be concluded that the clinically proven antidepressive effect of hypericum extract cannot be explained in terms of MAO inhibition.

Morphological and Phytochemical Diversity among Hypericum Species of the Mediterranean Basin

PubMed Central

Nürk, Nicolai M.; Crockett, Sara L.

2012-01-01

The genus Hypericum L. (St. John’s wort, Hypericaceae) includes more than 450 species that occur in temperature or tropical mountain regions of the world. Monographic work on the genus has resulted in the recognition and description of 36 taxonomic sections, delineated by specific combinations of morphological characteristics and biogeographic distribution. The Mediterranean Basin has been recognized as a hot spot of diversity for the genus Hypericum, and as such is a region in which many endemic species occur. Species belonging to sections distributed in this area of the world display considerable morphological and phytochemical diversity. Results of a cladistic analysis, based on 89 morphological characters that were considered phylogenetically informative, are given here. In addition, a brief overview of morphological characteristics and the distribution of pharmaceutically relevant secondary metabolites for species native to this region of the world are presented. PMID:22662020

[The HMPC monograph on Hypericum: Background, development, contents].

PubMed

Länger, Reinhard

2010-12-01

The adoption of the EU community monograph on Hypericum constitutes a milestone in the process of harmonisation of herbal medicinal products within the European Community. The assessment of the published clinical data revealed that for two types of extracts the evidence of the efficacy in mild to moderate depressive episodes compared to placebo or standard medication was found to be acceptable. Additionally, a sufficient efficacy in relapse prophylaxis could be demonstrated for these two herbal preparations. For some other dry extracts, the efficacy in the short-term treatment of symptoms in mild depressive disorders was found to be substantiated. Short-term treatment with preparations containing low amounts of hyperforin did not increase cytochrome P450 enzyme activity. Therefore the oral administration of traditional herbal preparations is restricted to two weeks. In the case that an applicant demonstrates that the daily intake of hyperforin is below 1 mg the warnings on interactions may be omitted in traditional herbal medicinal products. Additionally the cutaneous administration of traditional liquid herbal preparations for the traditional use in symptomatic treatment of minor inflammations of the skin and as an aid in healing minor wounds was included in the monograph.

Bioactive xanthones from the roots of Hypericum perforatum (common St John's Wort)

USDA-ARS?s Scientific Manuscript database

In contemporary western alternative medicine, extracts of the inflorescences and upper stem leaves of Hypericum perforatum L. (common St. John’s Wort; Clusiaceae) are taken orally for the treatment of mild to moderate depression and applied topically to promote wound-healing. Numerous researchers h...

Hypericum species in the Páramos of Central and South America: a special focus upon H. irazuense Kuntze ex N. Robson

PubMed Central

Crockett, Sara; Eberhardt, Marianne; Kunert, Olaf; Schühly, Wolfgang

2010-01-01

Knowledge about members of the flowering plant family Clusiaceae occurring in the tropical mountain regions of the world is limited, in part due to endemism and restricted distributions. High altitude vegetation habitats (Páramos) in Central and South America are home to numerous native Hypericum species. Information related to the phytochemistry of páramo Hypericum, as well as ecological factors with the potential to influence chemical defenses in these plants, is briefly reviewed. Results of the phytochemical analysis of Hypericum irazuense, a species collected in the páramo of the Cordillera de Talamanca in Costa Rica, are presented. Lastly, guidelines for the viable and sustainable collections of plant material, to facilitate future investigations of these interesting plants, are given. PMID:21151765

Evaluation of the cytotoxic effect and antibacterial, antifungal, and antiviral activities of Hypericum triquetrifolium Turra essential oils from Tunisia

PubMed Central

2013-01-01

Background A number of bio-active secondary metabolites have been identified and reported for several Hypericum species. Many studies have reported the potential use of the plant extracts against several pathogens. However, Hypericum triquetrifolium is one of the least studied species for its antimicrobial activity. The aim of the present study was to evaluate the cytotoxic effect of the essential oils of Hypericum triquetrifolium as well as their antimicrobial potential against coxsakievirus B3 and a range of bacterial and fungal strains. Methods The essential oils of Hypericum triquetrifolium harvested from five different Tunisian localities (Fondouk DJedid, Bou Arada, Bahra, Fernana and Dhrea Ben Jouder) were evaluated for their antimicrobial activities by micro-broth dilution methods against bacterial and fungal strains. In addition, the cytotoxic effect and the antiviral activity of these oils were carried out using Vero cell lines and coxsakievirus B3. Results The results showed a good antibacterial activities against a wide range of bacterial strains, MIC values ranging between 0.39-12.50 mg/ml and MBC values between 1.56-25.0 mg/ml. In addition, the essential oils showed promising antifungal activity with MIC values ranging between 0.39 μg/mL and 12.50 μg/mL; MFC values ranged between 3.12 μg/mL and 25.00 μg/mL; a significant anticandidal activity was noted (MIC values comprised between 0.39 μg/mL and 12.50 μg/mL). Although their low cytotoxic effect (CC50 ranged between 0.58 mg/mL and 12.00 mg/mL), the essential oils did not show antiviral activity against coxsakievirus B3. Conclusion The essential oils obtained from Hypericum triquetrifolium can be used as antimicrobial agents and could be safe at non cytotoxic doses. As shown for the tested essential oils, comparative analysis need to be undertaken to better characterize also the antimicrobial activities of Hypericum triquetrifolium extracts with different solvents as well as their

Acetic acid acts as an elicitor exerting a chitosan-like effect on xanthone biosynthesis in Hypericum perforatum L. root cultures.

PubMed

Valletta, Alessio; De Angelis, Giulia; Badiali, Camilla; Brasili, Elisa; Miccheli, Alfredo; Di Cocco, Maria Enrica; Pasqua, Gabriella

2016-05-01

Acetic acid acts as a signal molecule, strongly enhancing xanthone biosynthesis in Hypericum perforatum root cultures. This activity is specific, as demonstrated by the comparison with other short-chain monocarboxylic acids. We have recently demonstrated that Hypericum perforatum root cultures constitutively produce xanthones at higher levels than the root of the plant and that they respond to chitosan (CHIT) elicitation with a noteworthy increase in xanthone production. In the present study, CHIT was administered to H. perforatum root cultures using three different elicitation protocols, and the increase in xanthone production was evaluated. The best results (550 % xanthone increase) were obtained by subjecting the roots to a single elicitation with 200 mg l(-1) CHIT and maintaining the elicitor in the culture medium for 7 days. To discriminate the effect of CHIT from that of the solvent, control experiments were performed by administering AcOH alone at the same concentration used for CHIT solubilization. Unexpectedly, AcOH caused an increase in xanthone production comparable to that observed in response to CHIT. Feeding experiments with (13)C-labeled AcOH demonstrated that this compound was not incorporated into the xanthone skeleton. Other short-chain monocarboxylic acids (i.e., propionic and butyric acid) have little or no effect on the production of xanthones. These results indicate that AcOH acts as a specific signal molecule, able to greatly enhance xanthone biosynthesis in H. perforatum root cultures.

Inhibition of Prostaglandin E2 Production by Anti-inflammatory Hypericum perforatum Extracts and Constituents in RAW264.7 Mouse Macrophage Cells

PubMed Central

Hammer, Kimberly D. P.; Hillwig, Matthew L.; Solco, Avery K. S.; Dixon, Philip M.; Delate, Kathleen; Murphy, Patricia A.; Wurtele, Eve S.; Birt, Diane F.

2008-01-01

Hypericum perforatum (Hp) is commonly known for its antiviral, antidepressant, and cytotoxic properties, but traditionally Hp was also used to treat inflammation. In this study, the anti-inflammatory activity and cytotoxicity of different Hp extractions and accessions and constituents present within Hp extracts were characterized. In contrast to the antiviral activity of Hp, the anti-inflammatory activity observed with all Hp extracts was light-independent. When pure constituents were tested, the flavonoids, amentoflavone, hyperforin, and light-activated pseudohypericin, displayed anti-inflammatory activity, albeit at concentrations generally higher than the amount present in the Hp extracts. Constituents that were present in the Hp extracts at concentrations that inhibited the production of prostaglandin E2 (PGE2) were pseudohypericin and hyperforin, suggesting that they are the primary anti-inflammatory constituents along with the flavonoids, and perhaps the interactions of these constituents and other unidentified compounds are important for the anti-inflammatory activity of the Hp extracts. PMID:17696442

A review of issues of nomenclature and taxonomy of Hypericum perforatum L. and Kew's Medicinal Plant Names Services.

PubMed

Dauncey, Elizabeth Anne; Irving, Jason Thomas Whitley; Allkin, Robert

2017-10-16

To review which names are used to refer to Hypericum perforatum L. in health regulation and medicinal plant references, and the potential for ambiguity or imprecision. Structured searches of Kew's Medicinal Plant Names Services Resource, supplemented with other online bibliographic resources, found that the scientific name Hypericum perforatum L. is used consistently in the literature, but variation between subspecies is rarely considered by researchers. Research is still published using only the common name 'St John's wort' despite it being imprecise; at least 80 other common names are also used for this plant in multiple languages. Ambiguous and alternative plant names can lead to ineffective regulation, misinterpretation of literature, substitution of raw material or the failure to locate all published research. Kew's Medicinal Plant Names Services (MPNS) maps all names used for each plant in medicinal plant references onto current taxonomy, thereby providing for disambiguation and comprehensive access to the regulations and references that cite that plant, regardless of the name used. MPNS also supplies the controlled vocabulary for plant names now required for compliance with a new standard (Identification of Medicinal Products, IDMP) adopted by medicines regulators worldwide. © 2017 Royal Pharmaceutical Society.

Biological evaluation of hyperforin and its hydrogenated analogue on bacterial growth and biofilm production.

PubMed

Schiavone, Brigida Immacolata Pia; Rosato, Antonio; Marilena, Muraglia; Gibbons, Simon; Bombardelli, Ezio; Verotta, Luisella; Franchini, Carlo; Corbo, Filomena

2013-09-27

Bacterial biofilms are organized communities of microorganisms, embedded in a self-produced matrix, growing on a biotic surface and resistant to many antimicrobial agents when associated with a medical device. These biofilms require the development of new strategies for the prevention and treatment of infectious disease, including the potential use of natural products. One interesting natural product example is Hypericum, a plant genus that contains species known to have antimicrobial properties. The major constituent of Hypericum perforatum is an unstable compound named hyperforin (1); for this reason it was not believed to play a significant role in the pharmacological effects. In this investigation a hydrogenated hyperforin analogue (2) was tested on several ATCC and clinical isolate strains, in their planktonic and biofilm form (Staphylococcus aureus, MRSA, and Enterococcus faecalis). Compound 2 was effective against planktonic and biofilm cultures, probably due to higher stability, showing the percentage of cells killed in the range from 45% to 52%. These results are noteworthy from the point of view of future development of these polyprenylated phloroglucinols as potential antibiotics.

Life span effects of Hypericum perforatum extracts on Caenorhabditis elegans under heat stress.

PubMed

Kılıçgün, Hasan; Göksen, Gülden

2012-10-01

The beneficial effects of antioxidants in plants are mainly extrapolated from in vitro studies or short-term dietary supplementation studies. Due to cost and duration, relatively little is known about whether dietary antioxidants are beneficial in whole animals' life span or not. To address this question, under heat stress (35°C), Hypericum perforatum was extracted with petroleum ether and the nematodes Caenorhabditis elegans exposed to three different extract concentrations (1mg/mL, 0.1mg/mL, 0.01mg/mL) of H. perforatum. We report that Hypericum perforatum extracts did not increase life span and slow aging related increase in C. elegans. Moreover, one fraction (1mg/mL) increased declines of C. elegans life span and thermotolerance. Given this mounting evidence for life span role of H. perforatum in the presence of heat stress in vivo, the question whether H. perforatum acts as a prooxidant or an antioxidant in vivo under heat stress arises.

Life span effects of Hypericum perforatum extracts on Caenorhabditis elegans under heat stress

PubMed Central

Kılıçgün, Hasan; Göksen, Gülden

2012-01-01

Background: The beneficial effects of antioxidants in plants are mainly extrapolated from in vitro studies or short-term dietary supplementation studies. Due to cost and duration, relatively little is known about whether dietary antioxidants are beneficial in whole animals’ life span or not. Materials and Methods: To address this question, under heat stress (35°C), Hypericum perforatum was extracted with petroleum ether and the nematodes Caenorhabditis elegans exposed to three different extract concentrations (1mg/mL, 0.1mg/mL, 0.01mg/mL) of H. perforatum. Results: We report that Hypericum perforatum extracts did not increase life span and slow aging related increase in C. elegans. Moreover, one fraction (1mg/mL) increased declines of C. elegans life span and thermotolerance. Conclusion: Given this mounting evidence for life span role of H. perforatum in the presence of heat stress in vivo, the question whether H. perforatum acts as a prooxidant or an antioxidant in vivo under heat stress arises. PMID:24082638

A Perspective on Hypericum perforatum Genetic Transformation

PubMed Central

Hou, Weina; Shakya, Preeti; Franklin, Gregory

2016-01-01

Hypericum perforatum (St John's wort) is a reservoir of diverse classes of biologically active and high value secondary metabolites, which captured the interest of both researchers and the pharmaceutical industry alike. Several studies and clinical trials have shown that H. perforatum extracts possess an astounding array of pharmacological properties. These properties include antidepressant, anti-inflammatory, antiviral, anti-cancer, and antibacterial activities; and are largely attributed to the naphtodianthrones and xanthones found in the genus. Hence, improving their production via genetic manipulation is an important strategy. In spite of the presence of contemporary genome editing tools, genetic improvement of this genus remains challenging without robust transformation methods in place. In the recent past, we found that H. perforatum remains recalcitrant to Agrobacterium tumefaciens mediated transformation partly due to the induction of plant defense responses coming into play. However, H. perforatum transformation is possible via a non-biological method, biolistic bombardment. Some research groups have observed the induction of hairy roots in H. perforatum after Agrobacterium rhizogenes co-cultivation. In this review, we aim at updating the available methods for regeneration and transformation of H. perforatum. In addition, we also propose a brief perspective on certain novel strategies to improve transformation efficiency in order to meet the demands of the pharmaceutical industry via metabolic engineering. PMID:27446112

Antinociceptive activity of Hypericum caprifoliatum and Hypericum polyanthemum (Guttiferae).

PubMed

Viana, A F; Heckler, A P; Fenner, R; Rates, S M K

2003-05-01

The aim of the present study was to assess the analgesic activity of the aerial parts of two Hypericum species native to Southern Brazil, H. caprifoliatum and H. polyanthemum. The antinociceptive effect of the H. polyanthemum cyclohexane extract (POL; 180 mg/kg) and of the H. caprifoliatum methanol (MET) and cyclohexane (CH) extracts (90 mg/kg) was evaluated in the hot-plate (ip and po) and writhing (po) tests using male Swiss CF1 mice weighing 22-27 g (N = 10 per group). All extracts displayed antinociceptive effects in the hot-plate test (MET ip = 48%, MET po = 39%, CH ip = 27%, CH po = 50%, POL ip = 74%, and POL po = 49% compared to control). Pretreatment with naloxone (2.5 mg/kg, sc) abolished the effects of CH and POL, and partially prevented the analgesia induced by MET administered by the ip (but not by the po) route. POL and CH (po) significantly reduced the number of writhes induced by acetic acid, while MET was ineffective in this regard. We conclude that the antinociceptive effects of the H. caprifoliatum (CH) and H. polyanthemum (POL) hexane extracts seem to be mediated by the opioid system. Moreover, the antinociceptive activity of the H. caprifoliatum MET extract seems to depend on at least two chemical substances (or groups of substances) with distinct pharmacokinetic profiles and mechanisms of action. Only the naloxone-insensitive component of MET activity showed good bioavailability following oral administration.

Downstream processing of hyperforin from Hypericum perforatum root cultures.

PubMed

Haas, Paul; Gaid, Mariam; Zarinwall, Ajmal; Beerhues, Ludger; Scholl, Stephan

2018-05-01

Hyperforin is a major metabolite of the medicinal plant Hypericum perforatum (St. John's Wort) and has recently been found in hormone induced root cultures. The objective of this study is to identify a downstream process for the production of a hyperforin-rich extract with maximum extraction efficiency and minimal decomposition. The maximum extraction time was found to be 60min. The comparison of two equipment concepts for the extraction and solvent evaporation was performed employing two different solvents. While the rotary mixer showed better results for the extraction efficiency than a stirred vessel, the latter set-up was able to handle larger volumes but did not meet all process requirements. For the evaporation the prompt evaporation of the extraction agent using nitrogen stripping led to minor decomposition. In a 5L stirred vessel, the highest specific extraction of hyperforin was 4.3mg hyperforin/g dry weight bio material. Parameters for the equipment design for extraction and solvent evaporation were determined based on the experimental data. Copyright © 2017 Elsevier B.V. All rights reserved.

Leishmanicidal activity of lipophilic extracts of some Hypericum species.

PubMed

Dagnino, Ana Paula; Barros, Francisco Maikon Corrêa de; Ccana-Ccapatinta, Gari Vidal; Prophiro, Josiane Somariva; Poser, Gilsane Lino von; Romão, Pedro R T

2015-01-15

Leishmaniasis has emerged as the third most prevalent parasite-borne disease worldwide after malaria and filariasis, with about 350 million people at risk of infection. Antileishmanial drugs currently available have various limitations, mainly because of the parasite resistance and side effects. The search of new antileishmanial drugs is ventured throughout the world. The purpose of this study was to assess the leishmanicidal activity of lipophilic extracts of eight Hypericum species against promastigote forms of Leishmania (Leishmania) amazonensis. The dried and powered materials of aerial parts of H. andinum Gleason, H. brevistylum Choisy, H. caprifoliatum Cham. & Schltdl., H. carinatum Griseb., H. linoides A. St.-Hil., H. myrianthum Cham. & Schltdl., H. polyanthemum Klotzsch ex Reichardt and H. silenoides Juss. were extracted by static maceration with n-hexane. Extracts were evaporated to dryness under reduced pressure and stored at -20°C until biological evaluation and HPLC analysis. The metabolites investigated were dimeric phloroglucinol derivatives, benzophenones and benzopyrans. The yields were expressed as mean of three injections in mg of compound per g of extract (mg/g extract). The effect of Hypericum species on the viability of infective forms of L. (L.) amazonensis was determined using a hemocytometer. Amphotericin B was used as a standard drug. The 50% inhibitory concentration (IC50) values for each extract were determined by linear regression analysis. The cytotoxic effects of extracts were assessed on peritoneal macrophages of BALB/c mice by MTT assay. The concentration that causes 50% of macrophage cytotoxicity (CC50) was determined by linear regression analysis. The selectivity index (SI) of the extracts was determined considering the following equation: CC50 against mammalian cells/IC50 against L. amazonensis. We demonstrated that H. carinatum, H. linoides and H. polyanthemum were able to kill the parasites in a dose dependent manner. These

Biosynthesis of hyperforin and adhyperforin from amino acid precursors in shoot cultures of Hypericum perforatum.

PubMed

Karppinen, Katja; Hokkanen, Juho; Tolonen, Ari; Mattila, Sampo; Hohtola, Anja

2007-04-01

Hyperforin and adhyperforin contribute to the antidepressant effects of Hypericum perforatum. The involvement of branched-chain amino acids in the biosynthesis of hyperforin and adhyperforin was demonstrated in H. perforatum shoot cultures. L-[U-(13)C(5)]Valine and L-[U-(13)C(6)]isoleucine, upon administration to the shoot cultures, were incorporated into acyl side chain of hyperforin and adhyperforin, respectively. Feeding the shoot cultures with unlabelled L-isoleucine at a concentration of 2mM induced a 3.7-fold increase in the production of adhyperforin. The addition of 3mM L-threonine, a precursor of isoleucine, stimulated a 2.0-fold increase in the accumulation of adhyperforin. The administration of L-valine at concentrations of 0-5mM had no stimulating effect on the hyperforin production in H. perforatum shoot cultures.

Do early changes in the HAM-D-17 anxiety/somatization factor items affect treatment outcome among depressed outpatients? Comparison of two controlled trials of St John’s Wort (Hypericum Perforatum) versus an SSRI

PubMed Central

Bitran, Stella; Farabaugh, Amy H; Ameral, Victoria E; LaRocca, Rachel A; Clain, Alisabet J; Fava, Maurizio; Mischoulon, David

2011-01-01

Objective To assess whether early changes in HAM-D-17 anxiety/somatization items predict remission in two controlled studies of hypericum perforatum (St. John’s wort) versus an SSRI for major depressive disorder (MDD). Methods The Hypericum Depression Trial Study Group (NIMH) study randomized 340 subjects to hypericum, sertraline, or placebo for 8 weeks. The MGH study randomized 135 subjects to hypericum, fluoxetine, or placebo for 12 weeks. We examined whether remission was associated with early changes in anxiety/somatization symptoms. Results In the NIMH study, significant associations were observed between remission and early improvement in the anxiety-psychic item (sertraline arm), somatic-gastrointestinal item (hypericum arm), and somatic symptoms-general (placebo arm). None of the three treatment arms of the MGH study showed significant associations between anxiety/somatization symptoms and remission. When both study samples were pooled, we found associations for anxiety-psychic (SSRI arm), somatic-gastrointestinal and hypochondriasis (hypericum arm), and anxiety-psychic and somatic symptoms-general (placebo arm). In the entire sample, remission was associated with improvement in the anxiety-psychic, somatic-gastrointestinal, and somatic symptoms-general items. Conclusions The number and type of anxiety/somatization items associated with remission varied depending on the intervention. Early scrutiny of the HAM-D-17 anxiety/somatization items may help predict remission of MDD. PMID:21278577

Do early changes in the HAM-D-17 anxiety/somatization factor items affect the treatment outcome among depressed outpatients? Comparison of two controlled trials of St John's wort (Hypericum perforatum) versus a SSRI.

PubMed

Bitran, Stella; Farabaugh, Amy H; Ameral, Victoria E; LaRocca, Rachel A; Clain, Alisabet J; Fava, Maurizio; Mischoulon, David

2011-07-01

To assess whether early changes in Hamilton Depression Rating Scale-17 anxiety/somatization items predict remission in two controlled studies of Hypericum perforatum (St John's wort) versus selective serotonin reuptake inhibitors for major depressive disorder. The Hypericum Depression Trial Study Group (National Institute of Mental Health) randomized 340 patients to Hypericum, sertraline, or placebo for 8 weeks, whereas the Massachusetts General Hospital study randomized 135 patients to Hypericum, fluoxetine, or placebo for 12 weeks. The investigators examined whether remission was associated with early changes in anxiety/somatization symptoms. In the National Institute of Mental Health study, significant associations were observed between remission and early improvement in the anxiety (psychic) item (sertraline arm), somatic (gastrointestinal item; Hypericum arm), and somatic (general) symptoms (placebo arm). None of the three treatment arms of the Massachusetts General Hospital study showed significant associations between anxiety/somatization symptoms and remission. When both study samples were pooled, we found associations for anxiety (psychic; selective serotonin reuptake inhibitors arm), somatic (gastrointestinal), and hypochondriasis (Hypericum arm), and anxiety (psychic) and somatic (general) symptoms (placebo arm). In the entire sample, remission was associated with the improvement in the anxiety (psychic), somatic (gastrointestinal), and somatic (general) items. The number and the type of anxiety/somatization items associated with remission varied depending on the intervention. Early scrutiny of the Hamilton Depression Rating Scale-17 anxiety/somatization items may help to predict remission of major depressive disorder.

Antimicrobial and cytotoxic constituents from native Cameroonian medicinal plant Hypericum riparium.

PubMed

Tala, Michel Feussi; Talontsi, Ferdinand Mouafo; Zeng, Guang-Zhi; Wabo, Hippolyte Kamdem; Tan, Ning-Hua; Spiteller, Michael; Tane, Pierre

2015-04-01

Bioassay guided fractionation of Hypericum riparium leaves extract has resulted in the isolation and characterization of three new compounds namely chipericumin E (1), hyperenone C (3), and hyperixanthone (5), together with twenty known compounds. Their structures were elucidated based on comprehensive interpretation of spectroscopic and spectrometric data. Compounds 1-4, and 6-8 displayed moderate antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and cytotoxic effects on the human gastric cell line BGC-823 with IC50 values ranging from 6.54 to 18.50μM. Copyright © 2015 Elsevier B.V. All rights reserved.

Distinct Hypericum perforatum L. total extracts exert different antitumour activity on erythroleukemic K562 cells.

PubMed

Valletta, Elena; Rinaldi, Annamaria; Marini, Mario; Franzese, Ornella; Roscetti, Gianna

2018-05-22

Total flower extracts of Hypericum perforatum L. obtained with 3 different solvent systems were tested on tumour cell line cultures by comparing two groups of plants harvested in different times and places. The extracts, characterized according to the spectroscopic profile and the hypericin content, were tested on the growth and apoptotic death of K562 cells, a human erythroleukemic cell line. Growth and apoptosis were analysed by viable cell count, flow cytometry, and fluorescence microscopy at 6, 24, and 48 hr of culture following 1 hr exposure to the extracts under investigation. Here, we show that Hypericum extracts are able to reduce the growth of K562 cells and induce different degrees and kinetics of apoptosis according to the group of plants of origin. Also, we highlighted interesting differences in terms of efficacy among the extracts, with some samples losing their effectiveness along the culture time and others able to maintain or even increase their efficacy. Furthermore, the data herein obtained confirm the role of non hypericin compounds that are present in different proportions in the two plant groups and in the extracts analysed. Copyright © 2018 John Wiley & Sons, Ltd.

Identification of light-independent inhibition of human immunodeficiency virus-1 infection through bioguided fractionation of Hypericum perforatum

PubMed Central

Maury, Wendy; Price, Jason P; Brindley, Melinda A; Oh, ChoonSeok; Neighbors, Jeffrey D; Wiemer, David F; Wills, Nickolas; Carpenter, Susan; Hauck, Cathy; Murphy, Patricia; Widrlechner, Mark P; Delate, Kathleen; Kumar, Ganesh; Kraus, George A; Rizshsky, Ludmila; Nikolau, Basil

2009-01-01

Background Light-dependent activities against enveloped viruses in St. John's Wort (Hypericum perforatum) extracts have been extensively studied. In contrast, light-independent antiviral activity from this species has not been investigated. Results Here, we identify the light-independent inhibition of human immunodeficiency virus-1 (HIV-1) by highly purified fractions of chloroform extracts of H. perforatum. Both cytotoxicity and antiviral activity were evident in initial chloroform extracts, but bioassay-guided fractionation produced fractions that inhibited HIV-1 with little to no cytotoxicity. Separation of these two biological activities has not been reported for constituents responsible for the light-dependent antiviral activities. Antiviral activity was associated with more polar subfractions. GC/MS analysis of the two most active subfractions identified 3-hydroxy lauric acid as predominant in one fraction and 3-hydroxy myristic acid as predominant in the other. Synthetic 3-hydroxy lauric acid inhibited HIV infectivity without cytotoxicity, suggesting that this modified fatty acid is likely responsible for observed antiviral activity present in that fraction. As production of 3-hydroxy fatty acids by plants remains controversial, H. perforatum seedlings were grown sterilely and evaluated for presence of 3-hydroxy fatty acids by GC/MS. Small quantities of some 3-hydroxy fatty acids were detected in sterile plants, whereas different 3-hydroxy fatty acids were detected in our chloroform extracts or field-grown material. Conclusion Through bioguided fractionation, we have identified that 3-hydroxy lauric acid found in field grown Hypericum perforatum has anti-HIV activity. This novel anti-HIV activity can be potentially developed into inexpensive therapies, expanding the current arsenal of anti-retroviral agents. PMID:19594941

Root cultures of Hypericum perforatum subsp. angustifolium elicited with chitosan and production of xanthone-rich extracts with antifungal activity.

PubMed

Tocci, Noemi; Simonetti, Giovanna; D'Auria, Felicia Diodata; Panella, Simona; Palamara, Anna Teresa; Valletta, Alessio; Pasqua, Gabriella

2011-08-01

Hypericum perforatum is a well-known medicinal plant which contains a wide variety of metabolites, including xanthones, which have a wide range of biological properties, including antifungal activity. In the present study, we evaluated the capability of roots regenerated from calli of H. perforatum subsp. angustifolium to produce xanthones. Root biomass was positively correlated with the indole-3-butyric acid concentration, whereas a concentration of 1 mg l(-1) was the most suitable for the development of roots. High auxin concentrations also inhibited xanthone accumulation. Xanthones were produced in large amounts, with a very stable trend throughout the culture period. When the roots were treated with chitosan, the xanthone content dramatically increased, peaking after 7 days. Chitosan also induced a release of these metabolites into the culture. The maximum accumulation (14.26 ± 0.62 mg g(-1) dry weight [DW]) and release (2.64 ± 0.13 mg g(-1) DW) of xanthones were recorded 7 days after treatment. The most represented xanthones were isolated, purified, and spectroscopically characterized. Antifungal activity of the total root extracts was tested against a broad panel of human fungal pathogen strains (30 Candida species, 12 Cryptococcus neoformans, and 16 dermatophytes); this activity significantly increased when using chitosan. Extracts obtained after 7 days of chitosan treatment showed high antifungal activity (mean minimum inhibitory concentration of 83.4, 39.1, and 114 μg ml(-1) against Candida spp., C. neoformans, and dermatophytes, respectively). Our results suggest that root cultures can be considered as a potential tool for large-scale production of extracts with stable quantities of xanthones.

Impact of origin and biological source on chemical composition, anticholinesterase and antioxidant properties of some St. John's wort species (Hypericum spp., Hypericaceae) from the Central Balkans.

PubMed

Božin, Biljana; Kladar, Nebojša; Grujić, Nevena; Anačkov, Goran; Samojlik, Isidora; Gavarić, Neda; Conić, Branislava Srđenović

2013-09-25

The study shows the influence of the origin of plant material and biological source on the in vitro antioxidant (neutralization of DPPH and OH radical, nitric oxide, and inhibition of lipid peroxidation) and anticholinesterase activity of chemically characterized and quantified ethanol extracts of ten St. John's wort samples. The investigated samples were: five Hypericum perforatum species representatives collected at different localities, one commercial sample of Hyperici herba purchased at a local market and four Hypericum species autochtonous to the Balkan Peninsula (H. maculatum subsp. immaculatum, H. olympicum, H. richeri subsp. grisebachii and H. barbatum). All the examined extracts exhibited notable antioxidant potential, but in most of the cases indigenous Hypericum species expressed stronger effects compared to the original source of the drug, H. perforatum. The changes in the content of phenolic compounds, especially flavonoids, hyperforin and hypericin, related to the source of the drug affected the investigated activities. Since all of the investigated species have shown prominent inhibition of acetylcholinesterase in vitro activity, they could be further investigated as potential substances in preventing of Alzheimer's disease.

Xanthones from roots, hairy roots and cell suspension cultures of selected Hypericum species and their antifungal activity against Candida albicans.

PubMed

Zubrická, Daniela; Mišianiková, Anna; Henzelyová, Jana; Valletta, Alessio; De Angelis, Giulia; D'Auria, Felicia Diodata; Simonetti, Giovanna; Pasqua, Gabriella; Čellárová, Eva

2015-11-01

Highest xanthone contents were found in Hypericum pulchrum and H. annulatum untransformed roots. The best anti- Candida activity was obtained for hairy roots extracts of H. tetrapterum clone 2 ATCC 15834. Extracts of root cultures, hairy roots and cell suspensions of selected Hypericum spp. were screened for the presence of xanthones and tested for their antifungal activity against Candida albicans strain ATCC 10231. At least one of the following xanthones, 5-methoxy-2-deprenylrheediaxanthone; 1,3,6,7-tetrahydroxyxanthone; 1,3,5,6-tetrahydroxyxanthone; paxanthone; kielcorin or mangiferin was identified in methanolic extracts of the untransformed root cultures. The highest total xanthone content, with five xanthones, was found in untransformed H. pulchrum and H. annulatum root cultures. Hairy roots and the controls of H. tetrapterum contained 1,7-dihydroxyxanthone, while hairy root cultures and the corresponding controls of H. tomentosum contained toxyloxanthone B, 1,3,6,7- and 1,3,5,6-tetrahydroxyxanthone. Two xanthones, cadensin G and paxanthone, were identified in cell suspension cultures of H. perforatum. Their content increased about two-fold following elicitation with salicylic acid. The anti-Candida activity of the obtained extracts ranged from MIC 64 to >256 µg ml(-1). Among the extracts of Hypericum untransformed roots, the best antifungal activity was obtained for extracts of H. annulatum grown under CD conditions. Extracts of hairy roots clones A4 and 7 ATCC15834 of H. tomentosum and clone 2 ATCC15834 of H. tetrapterum displayed inhibition of 90% of Candida growth with 256 μg ml(-1). Extracts from chitosan-elicitated cells did not show antifungal activity.

Nephrotoxicity of Natural Products.

PubMed

Nauffal, Mary; Gabardi, Steven

2016-01-01

The manufacture and sale of natural products constitute a multi-billion dollar industry. Nearly a third of the American population admit to using some form of complementary or alternative medicine, with many using them in addition to prescription medications. Most patients fail to inform their healthcare providers of their natural product use and physicians rarely inquire. Annually, thousands of natural product-induced adverse events are reported to Poison Control Centers nationwide. Natural product manufacturers are not responsible for proving safety and efficacy, as the FDA does not regulate them. However, concerns exist surrounding the safety of natural products. This review provides details on natural products that have been associated with renal dysfunction. We have focused on products that have been associated with direct renal injury, immune-mediated nephrotoxicity, nephrolithiasis, rhabdomyolysis with acute renal injury, hepatorenal syndrome, and common adulterants or contaminants that are associated with renal dysfunction. The potential for natural products to cause renal dysfunction is justifiable. It is imperative that natural product use be monitored closely in all patients. Healthcare practitioners must play an active role in identifying patients using natural products and provide appropriate patient education. © 2016 S. Karger AG, Basel.

Polar Constituents and Biological Activity of the Berry-Like Fruits from Hypericum androsaemum L.

PubMed Central

Caprioli, Giovanni; Alunno, Alessia; Beghelli, Daniela; Bianco, Armandodoriano; Bramucci, Massimo; Frezza, Claudio; Iannarelli, Romilde; Papa, Fabrizio; Quassinti, Luana; Sagratini, Gianni; Tirillini, Bruno; Venditti, Alessandro; Vittori, Sauro; Maggi, Filippo

2016-01-01

Hypericum androsaemum, also known as Tutsan, is a small evergreen shrub common in the Mediterranean basin where it is traditionally used as diuretic and hepatoprotective herbal drug. This plant possesses the peculiarity to produce fleshy and berry-like fruits that ripen from red to shiny black. In the present work, the chemical constituents of methanolic extracts and infusions of red and black fruits were analyzed by HPLC, and correlated with their antioxidant properties which were evaluated by the DPPH, β-Carotene/linoleic acid, and hypochlorous acid tests. In addition, the red pigment of the fruit was isolated by column chromatography and structurally elucidated by NMR. Results showed that H. androsaemum fruits contain high amounts of shikimic and chlorogenic acids, while their color was given by a tetraoxygenated-type xanthone, reported for the first time in Hypericum species. The red berries infusion gave the highest content of total phenolic compounds, DPPH, and hypochlorous acid scavenging activity, and β-carotene bleaching. Cytotoxicity of the berries extracts on three human tumor cell lines (malignant melanoma, breast adenocarcinoma, and colon carcinoma) was evaluated by MTT assay, and relevant inhibition on colon carcinoma cells (IC50 value of 8.4 μg/mL) was found. Finally, the effects of red berries extract on the immune system were evaluated by peripheral blood mononuclear cell (PBMC) proliferation assay that revealed a strong stimulation on lymphocytes at low doses (0.4–6 μg/mL). PMID:26973675

Molecular Cloning and Characterization of a Xanthone Prenyltransferase from Hypericum calycinum Cell Cultures.

PubMed

Fiesel, Tobias; Gaid, Mariam; Müller, Andreas; Bartels, Joana; El-Awaad, Islam; Beuerle, Till; Ernst, Ludger; Behrends, Sönke; Beerhues, Ludger

2015-08-27

In plants, prenylation of metabolites is widely distributed to generate compounds with efficient defense potential and distinct pharmacological activities profitable to human health. Prenylated compounds are formed by members of the prenyltransferase (PT) superfamily, which catalyze the addition of prenyl moieties to a variety of acceptor molecules. Cell cultures of Hypericum calycinum respond to elicitor treatment with the accumulation of the prenylated xanthone hyperxanthone E. A cDNA encoding a membrane-bound PT (HcPT) was isolated from a subtracted cDNA library and transcript preparations of H. calycinum. An increase in the HcPT transcript level preceded hyperxanthone E accumulation in cell cultures of H. calycinum treated with elicitor. The HcPT cDNA was functionally characterized by expression in baculovirus-infected insect cells. The recombinant enzyme catalyzed biosynthesis of 1,3,6,7-tetrahydroxy-8-prenylxanthone through regiospecific C-8 prenylation of 1,3,6,7-tetrahydroxyxanthone, indicating its involvement in hyperxanthone E formation. The enzymatic product shared significant structural features with the previously reported cholinesterase inhibitor γ-mangostin. Thus, our findings may offer a chance for semisynthesis of new active agents to be involved in the treatment of Alzheimer's disease.

Natural-Product-Derived Carbon Dots: From Natural Products to Functional Materials.

PubMed

Zhang, Xinyue; Jiang, Mingyue; Niu, Na; Chen, Zhijun; Li, Shujun; Liu, Shouxin; Li, Jian

2018-01-10

Nature provides an almost limitless supply of sources that inspire scientists to develop new materials with novel applications and less of an environmental impact. Recently, much attention has been focused on preparing natural-product-derived carbon dots (NCDs), because natural products have several advantages. First, natural products are renewable and have good biocompatibility. Second, natural products contain heteroatoms, which facilitate the fabrication of heteroatom-doped NCDs without the addition of an external heteroatom source. Finally, some natural products can be used to prepare NCDs in ways that are very green and simple relative to traditional methods for the preparation of carbon dots from man-made carbon sources. NCDs have shown tremendous potential in many fields, including biosensing, bioimaging, optoelectronics, and photocatalysis. This Review addresses recent progress in the synthesis, properties, and applications of NCDs. The challenges and future direction of research on NCD-based materials in this booming field are also discussed. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hyperascyrones A-H, polyprenylated spirocyclic acylphloroglucinol derivatives from Hypericum ascyron Linn.

PubMed

Zhu, Hucheng; Chen, Chunmei; Liu, Junjun; Sun, Bin; Wei, Guangzheng; Li, Yan; Zhang, Jinwen; Yao, Guangmin; Luo, Zengwei; Xue, Yongbo; Zhang, Yonghui

2015-07-01

Eight polyprenylated spirocyclic acylphloroglucinol derivatives (PSAPs), hyperascyrones A-H, were isolated from the aerial parts of Hypericum ascyron Linn., together with six known analogs. Their structures were established by spectroscopic analyses including HRESIMS, 1D and 2D NMR, and their absolute configurations were determined by electronic circular dichroism calculations (ECD, Gaussian 09). Structures of previously reported tomoeones C, D, G, and H were revised. Hyperascyrones A-H were evaluated for their cytotoxic and anti-HIV-1 activities, with hyperascyrones C and G exhibiting significant cytotoxicities against HL-60 cell lines with IC50 values of 4.22 and 8.36 μM, respectively. In addition, the chemotaxonomic significance of these compounds was also discussed. Copyright © 2015 Elsevier Ltd. All rights reserved.

Secondary Metabolites of Hypericum leptophyllum Hochst., an Endemic Turkish Species

PubMed Central

Camas, Necdet; Radusiene, Jolita; Stanius, Zydrunas; Caliskan, Omer; Cirak, Cuneyt

2012-01-01

In the present study, the presence of the phloroglucinol derivative hyperforin, the naphthodianthrones hypericin and pseudohypericin, the phenylpropane chlorogenic acid and the flavonoids rutin, hyperoside, kaempferol, isoquercetine, quercitrine, and quercetine was investigated in Hypericum leptophyllum Hochst., an endemic Turkish species for the first time. The aerial parts representing a total of 30 individuals were collected at full flowering and dissected into floral, leaf, and stem tissues. After being dried at room temperature, the plant materials were assayed for secondary metabolite concentrations by HPLC. Aerial plant parts accumulated chlorogenic acid, hyperoside, isoquercetine, quercitrine, and quercetine, but they did not accumulate hyperforin, hypericin, pseudohypericin, rutin, and kaempferol. Accumulation levels of the detected compounds varied with plant tissues. Such kind of data could be useful for elucidation of the chemotaxonomical significance of the corresponding compounds and phytochemical evaluation of this endemic species. PMID:22649295

Hyperforin accumulates in the translucent glands of Hypericum perforatum.

PubMed

Soelberg, Jens; Jørgensen, Lise Bolt; Jäger, Anna K

2007-06-01

Hypericum perforatum contains the therapeutically important compounds hypericin and hyperforin. Hypericin is known to accumulate in the dark glands. This investigation aimed to determine the accumulation site of hyperforin. Dark and translucent glands as well as non-secretory tissue in leaves were manually isolated under the microscope. Hyperforin content was quantified by UV HPLC. Secretory structures were surveyed anatomically. The hyperforin content of intact leaves was found to be about 3 mg g(-1) fresh tissue, whereas a content of about 7 mg g(-1) fresh material was found in isolated translucent glands. Hyperforin was found only to occur in minute amounts in dark glands (approx. 0.4 mg g(-1) fresh tissue). In non-secretory tissue no hyperforin was detected. The accumulation of hyperforin detected in the translucent glands supports the proposed hypothesis that hyperforin is synthesized by the same biosynthetic machinery as monoterpenes in the chloroplasts of cells delimiting the gland.

Hyperforin Accumulates in the Translucent Glands of Hypericum perforatum

PubMed Central

Soelberg, Jens; Jørgensen, Lise Bolt; Jäger, Anna K.

2007-01-01

Background and Aims Hypericum perforatum contains the therapeutically important compounds hypericin and hyperforin. Hypericin is known to accumulate in the dark glands. This investigation aimed to determine the accumulation site of hyperforin. Methods Dark and translucent glands as well as non-secretory tissue in leaves were manually isolated under the microscope. Hyperforin content was quantified by UV HPLC. Secretory structures were surveyed anatomically. Key Results The hyperforin content of intact leaves was found to be about 3 mg g−1 fresh tissue, whereas a content of about 7 mg g−1 fresh material was found in isolated translucent glands. Hyperforin was found only to occur in minute amounts in dark glands (approx. 0·4 mg g−1 fresh tissue). In non-secretory tissue no hyperforin was detected. Conclusions The accumulation of hyperforin detected in the translucent glands supports the proposed hypothesis that hyperforin is synthesized by the same biosynthetic machinery as monoterpenes in the chloroplasts of cells delimiting the gland. PMID:17468113

Natural and engineered biosynthesis of fluorinated natural products.

PubMed

Walker, Mark C; Chang, Michelle C Y

2014-09-21

Both natural products and synthetic organofluorines play important roles in the discovery and design of pharmaceuticals. The combination of these two classes of molecules has the potential to be useful in the ongoing search for new bioactive compounds but our ability to produce site-selectively fluorinated natural products remains limited by challenges in compatibility between their high structural complexity and current methods for fluorination. Living systems provide an alternative route to chemical fluorination and could enable the production of organofluorine natural products through synthetic biology approaches. While the identification of biogenic organofluorines has been limited, the study of the native organisms and enzymes that utilize these compounds can help to guide efforts to engineer the incorporation of this unusual element into complex pharmacologically active natural products. This review covers recent advances in understanding both natural and engineered production of organofluorine natural products.

Chronic consumption of Hypericum humifusum leaf extracts impairs epididymis spermatozoa characters in association with oxidative stress in adult male Wistar rats.

PubMed

Hammami, Imen; Ali, Ridha Ben; Nahdi, Afef; Kallech-Ziri, Olfa; Boussada, Marwa; El May, Ahmed; El May, Michèle Véronique

2017-09-01

Recently, there has been increasing interest in Hypericum (Hypericaceae) genus. The first part of the present study focused on the phytochemical analysis of the methanolic and aqueous extracts of Hypericum humifusum leaves. The second part of the study investigated the effect of Hypericum humifusum leaf extracts on male reproductive parameters. 30 male rats were grouped into control (1mL/rat, distilled water), treated by 200mg/kg body weight (bw) aqueous extract (A200), 400mg/kg bw aqueous extract (A400), 10mg/kg bw methanolic extract (M10) and 20mg/kg bw methanolic extract (M20) groups. The phytochemical analysis revealed the presence of tannins, flavonoids, steroids, carbohydrates, and phenolic compounds. After thirty-day treatment, body and reproductive organs were weighed. Testes in all rat groups were processed for biochemical assays and histopathological examinations. Epididymis sperm analyses were also performed. Testicular tissue homogenate samples were used for Malondialdehyde (MDA), catalase and superoxide dismutase (SOD) measurements. We showed that Hh extracts induced a severe seminiferous tubular damage with an increase in the percentage of empty seminiferous tubules. Epididymis sperm analysis revealed a significant reduction in density and viability of sperm with alteration of spermatozoa morphology. Also, we found that Hh leaf extracts decreased plasma total cholesterol, HDL-cholesterol and triglycerides levels. These results were associated with an increase of MDA levels and a decrease of catalase and SOD activities in testis tissues. Our finding revealed that chronic consumption of Hh extracts induces disruption of normal spermatogenesis by alteration of sperm density, viability, and morphology. This action may be due to an inhibition of the antioxidant-defense system. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Differential accumulation of hyperforin and secohyperforin in Hypericum perforatum tissue cultures.

PubMed

Charchoglyan, Armen; Abrahamyan, Arusyak; Fujii, Isao; Boubakir, Zakia; Gulder, Tobias A M; Kutchan, Toni M; Vardapetyan, Hrachik; Bringmann, Gerhard; Ebizuka, Yutaka; Beerhues, Ludger

2007-11-01

Hyperforin is a pharmacologically active constituent of Hypericum perforatum (St. John's wort). In vitro cultures of this medicinal plant were found to contain hyperforin and three related polyprenylated acylphloroglucinol derivatives. The accumulation of these compounds was coupled to shoot regeneration, with secohyperforin being the major constituent in morphogenic cultures. The structure of secohyperforin was elucidated online by LC-DAD, -MS, and -NMR. In multiple shoot cultures, the ratio of hyperforin to secohyperforin was strongly influenced by the phytohormones N6-benzylaminopurine (BAP) and naphthalene-1-acetic acid (NAA). While increasing concentrations of BAP stimulated the formation of hyperforin, increasing concentrations of NAA elevated the level of secohyperforin. No differential stimulation was observed after elicitor treatment. Hyperforin and secohyperforin are proposed to arise from a branch point in the biosynthetic pathway.

A comparative study on the effects of Hypericum Perforatum and passion flower on the menopausal symptoms of women referring to Isfahan city health care centers.

PubMed

Fahami, Fariba; Asali, Zahra; Aslani, Abolfazl; Fathizadeh, Nahid

2010-01-01

With regard to an increase in the life expectancy for women and the consistency of the menopause age, a significant portion of women's age is passed after the menopause. Menopause is considered as a critical and sensitive period due to the changes and the disorders that are involved in it. Vasomotor symptoms, sleep disorders and psycho-mental changes are among the most prevalent symptoms of this period. Hormone therapy is a common treatment and it involves some problems for most individuals. The purpose of this study was to comparatively examine the effects of two herbal medications, Hypericum Perforatum and Passion Flower, on menopause symptoms. This study was of a clinical-experimental type which was done in 1388 in Isfahan. The sample included 59 menopausal women who had the conditions for entering into the study. The individuals were selected via simple sampling and were assigned randomly into two groups of Hypericum Perforatum treatment group (30 women) and Passion Flower group (29 women). The required data were filled out through interview, Personal Characteristics Questionnaire, and Cooperman's Index for menopause symptoms in three stages of pre-intervention, the third week of intervention, and the sixth week of intervention. The results were analyzed by descriptive and inferential statistical methods and the statistical software of SPSS. The findings showed that the average score of menopause symptoms in two treatment groups of Hypericum Perforatum and Passion Flower had a significant decrease throughout the third and the sixth weeks of study (p < 0.05). In addition, there was no statistically significant difference between the two groups and both herbs equally resulted in a decrease in the menopause symptoms scores (p > 0.05). With regard to the effects of Hypericum Perforatum and Passion Flower on treating menopause precocious symptoms (vasomotor signs, insomnia, depression, anger, headache, etc.), these two herbs can be used as an alternative treatment

Induction of phenolic compounds in Hypericum perforatum L. cells by Colletotrichum gloeosporioides elicitation.

PubMed

Conceição, Luis F R; Ferreres, Federico; Tavares, Rui M; Dias, Alberto C P

2006-01-01

Changes in phenolic metabolism after elicitation with Colletotrichum gloeosporioides (CG) has been studied in Hypericum perforatum L. (HP) cell suspension cultures. Soluble phenolics were analysed by HPLC-DAD and HPLC-DAD-MS/MS. HP cultures elicited with the CG elicitor showed a significant increase in xanthone accumulation. Xanthone accumulation increased twelve fold when the cells were primed with methyl-jasmonate (MeJ) or salicylic acid (SA), before elicitation. HP cultures exposed only to MeJ produced a set of flavonoids, the flavones which represent a substantial part (approx. 40%) of the total flavonoids accumulated in these cells. The possible importance of xanthones as a component of defence mechanism of HP against biotic stress is discussed.

Cinnamate:CoA ligase initiates the biosynthesis of a benzoate-derived xanthone phytoalexin in Hypericum calycinum cell cultures.

PubMed

Gaid, Mariam M; Sircar, Debabrata; Müller, Andreas; Beuerle, Till; Liu, Benye; Ernst, Ludger; Hänsch, Robert; Beerhues, Ludger

2012-11-01

Although a number of plant natural products are derived from benzoic acid, the biosynthesis of this structurally simple precursor is poorly understood. Hypericum calycinum cell cultures accumulate a benzoic acid-derived xanthone phytoalexin, hyperxanthone E, in response to elicitor treatment. Using a subtracted complementary DNA (cDNA) library and sequence information about conserved coenzyme A (CoA) ligase motifs, a cDNA encoding cinnamate:CoA ligase (CNL) was isolated. This enzyme channels metabolic flux from the general phenylpropanoid pathway into benzenoid metabolism. HcCNL preferred cinnamic acid as a substrate but failed to activate benzoic acid. Enzyme activity was strictly dependent on the presence of Mg²⁺ and K⁺ at optimum concentrations of 2.5 and 100 mM, respectively. Coordinated increases in the Phe ammonia-lyase and HcCNL transcript levels preceded the accumulation of hyperxanthone E in cell cultures of H. calycinum after the addition of the elicitor. HcCNL contained a carboxyl-terminal type 1 peroxisomal targeting signal made up by the tripeptide Ser-Arg-Leu, which directed an amino-terminal reporter fusion to the peroxisomes. Masking the targeting signal by carboxyl-terminal reporter fusion led to cytoplasmic localization. A phylogenetic tree consisted of two evolutionarily distinct clusters. One cluster was formed by CoA ligases related to benzenoid metabolism, including HcCNL. The other cluster comprised 4-coumarate:CoA ligases from spermatophytes, ferns, and mosses, indicating divergence of the two clades prior to the divergence of the higher plant lineages.

The safety of St John's wort (Hypericum perforatum) in pregnancy and lactation: A systematic review of rodent studies.

PubMed

Avila, Catharine; Whitten, Dawn; Evans, Sue

2018-04-30

Herbal products are popular among women during the perinatal period. St John's wort (SJW), Hypericum perforatum, is a common remedy for mild depression, a problem prevalent in this population. Although the safety of herbal products must be investigated, ethical issues constrain intervention studies in humans. Hence, animal studies often inform clinical decisions. The objective of this study is to systematically review rodent studies assessing the safety of SJW during the perinatal period. A literature search to November 10, 2017, identified 10 rodent studies that met a priori inclusion criteria. Study quality was evaluated according to both the Systematic Review Centre for Laboratory animal Experimentation tool for assessing bias and recommendations for appropriate reporting of herbal medicine research. Significant methodological limitations were found in each of the studies reviewed. These limitations include the lack of botanical verification and omission of extract characterization, inadequate explanation of dosage rationale, and absence of bias limiting protocols. Critical appraisal with contemporary tools indicates that each of the reviewed studies lacks appropriate rigour, rendering the results unreliable. Despite this, these papers are used in the rationale for recommending or contraindicating SJW during pregnancy and lactation. Copyright © 2018 John Wiley & Sons, Ltd.

Variation of hyperforin in Hypericum montbretii during its phenological cycle.

PubMed

Cirak, C; Radusiene, J

2007-11-01

Hypericum montbretii, a perennial herbaceous plant from Turkish flora has a great pharmaceutical potential with its well-documented chemical content. In the present study, morphogenetic and phenological variations of hyperforin were investigated in this species for the first time. Wild growing plants were harvested at vegetative, floral budding, full flowering, fresh fruiting, and mature fruiting stages and dissected into stem, leaf and reproductive tissues and assayed for hyperforin by HPLC method. Phenological changes in hyperforin content were found to be significant. After decreasing at floral budding slightly, hyperforin concentration in whole shoots increased with advancing of plant development and the highest level was reached at fresh fruiting. Among different parts of the plant, reproductive tissues namely green capsules and full opened flowers accumulated significantly higher amount of hyperforin when compared to stems and leaves. Such kind of data could be useful for elucidation of the chemotaxonomical significance of hyperforin and phytochemical evaluation of H. montbretii.

Integrating fossils, phylogenies, and niche models into biogeography to reveal ancient evolutionary history: the case of Hypericum (hypericaceae).

PubMed

Meseguer, Andrea S; Lobo, Jorge M; Ree, Richard; Beerling, David J; Sanmartín, Isabel

2015-03-01

In disciplines such as macroevolution that are not amenable to experimentation, scientists usually rely on current observations to test hypotheses about historical events, assuming that "the present is the key to the past." Biogeographers, for example, used this assumption to reconstruct ancestral ranges from the distribution of extant species. Yet, under scenarios of high extinction rates, the biodiversity we observe today might not be representative of the historical diversity and this could result in incorrect biogeographic reconstructions. Here, we introduce a new approach to incorporate into biogeographic inference the temporal, spatial, and environmental information provided by the fossil record, as a direct evidence of the extinct biodiversity fraction. First, inferences of ancestral ranges for those nodes in the phylogeny calibrated with the fossil record are constrained to include the geographic distribution of the fossil. Second, we use fossil distribution and past climate data to reconstruct the climatic preferences and potential distribution of ancestral lineages over time, and use this information to build a biogeographic model that takes into account "ecological connectivity" through time. To show the power of this approach, we reconstruct the biogeographic history of the large angiosperm genus Hypericum, which has a fossil record extending back to the Early Cenozoic. Unlike previous reconstructions based on extant species distributions, our results reveal that Hypericum stem lineages were already distributed in the Holarctic before diversification of its crown-group, and that the geographic distribution of the genus has been relatively stable throughout the climatic oscillations of the Cenozoic. Geographical movement was mediated by the existence of climatic corridors, like Beringia, whereas the equatorial tropical belt acted as a climatic barrier, preventing Hypericum lineages to reach the southern temperate regions. Our study shows that an

Integrating Fossils, Phylogenies, and Niche Models into Biogeography to Reveal Ancient Evolutionary History: The Case of Hypericum (Hypericaceae)

PubMed Central

Meseguer, Andrea S.; Lobo, Jorge M.; Ree, Richard; Beerling, David J.; Sanmartín, Isabel

2015-01-01

In disciplines such as macroevolution that are not amenable to experimentation, scientists usually rely on current observations to test hypotheses about historical events, assuming that “the present is the key to the past.” Biogeographers, for example, used this assumption to reconstruct ancestral ranges from the distribution of extant species. Yet, under scenarios of high extinction rates, the biodiversity we observe today might not be representative of the historical diversity and this could result in incorrect biogeographic reconstructions. Here, we introduce a new approach to incorporate into biogeographic inference the temporal, spatial, and environmental information provided by the fossil record, as a direct evidence of the extinct biodiversity fraction. First, inferences of ancestral ranges for those nodes in the phylogeny calibrated with the fossil record are constrained to include the geographic distribution of the fossil. Second, we use fossil distribution and past climate data to reconstruct the climatic preferences and potential distribution of ancestral lineages over time, and use this information to build a biogeographic model that takes into account “ecological connectivity” through time. To show the power of this approach, we reconstruct the biogeographic history of the large angiosperm genus Hypericum, which has a fossil record extending back to the Early Cenozoic. Unlike previous reconstructions based on extant species distributions, our results reveal that Hypericum stem lineages were already distributed in the Holarctic before diversification of its crown-group, and that the geographic distribution of the genus has been relatively stable throughout the climatic oscillations of the Cenozoic. Geographical movement was mediated by the existence of climatic corridors, like Beringia, whereas the equatorial tropical belt acted as a climatic barrier, preventing Hypericum lineages to reach the southern temperate regions. Our study shows that an

Natural Products and HIV/AIDS.

PubMed

Cary, Daniele C; Peterlin, B Matija

2018-01-01

The study of natural products in biomedical research is not a modern concept. Many of the most successful medical therapeutics are derived from natural products, including those studied in the field of HIV/AIDS. Biomedical research has a rich history of discovery based on screens of medicinal herbs and traditional medicine practices. Compounds derived from natural products, which repress HIV and those that activate latent HIV, have been reported. It is important to remember the tradition in medical research to derive therapies based on these natural products and to overcome the negative perception of natural products as an "alternative medicine."

In vitro antifungal activity of extracts obtained from Hypericum perforatum adventitious roots cultured in a mist bioreactor against planktonic cells and biofilm of Malassezia furfur.

PubMed

Simonetti, Giovanna; Tocci, Noemi; Valletta, Alessio; Brasili, Elisa; D'Auria, Felicia Diodata; Idoux, Alicia; Pasqua, Gabriella

2016-01-01

Xanthone-rich extracts from Hypericum perforatum root cultures grown in a Mist Bioreactor as antifungal agents against Malassezia furfur. Extracts of Hypericum perforatum roots grown in a bioreactor showed activity against planktonic cells and biofilm of Malassezia furfur. Dried biomass, obtained from roots grown under controlled conditions in a ROOTec mist bioreactor, has been extracted with solvents of increasing polarity (i.e. chloroform, ethyl acetate and methanol). The methanolic fraction was the richest in xanthones (2.86 ± 0.43 mg g(-1) DW) as revealed by HPLC. The minimal inhibitory concentration of the methanol extract against M. furfur planktonic cells was 16 μg mL(-1). The inhibition percentage of biofilm formation, at a concentration of 16 μg mL(-1), ranged from 14% to 39%. The results show that H. perforatum root extracts could be used as new antifungal agents in the treatment of Malassezia infections.

Localization of hypericin-induced fluorescence after Hypericum perforatum polar fraction instillation in normal rat urinary bladder

NASA Astrophysics Data System (ADS)

Stavropoulos, Nikos E.; Skalkos, Dimitris; Tsimaris, Ioannis; Kalogeras, D.; Nseyo, Unyime O.; Batistatou, A.; Agnantis, N. J.

2005-04-01

The photodynamic action of the Hypericum perforatum L. extract, mainly its polar methanolic fraction (PMF) has recently been substantiated by our group. The herb contains a number of naphthodianthrones - photosensitizers mainly hypericin and pseudohypericin. The concentration of hypericins in PMF was found to be 1.37 %. The distribution of hypericins fluorescence in sections of normal rat bladder tissues after the intravesical instillation of the polar methanolic fraction of hypericum (PMF) was studied by the use of fluorescence microscopy. PMF was dissolved in normal saline containing 0.5 μg/ml concentration of hypericins, and was then instilled in rat bladder for 15, 30, 60 and 120 minutes respectively. PMF solutions were withdrawn, bladders were rinsed through the catheter with normal saline and rats were sacrificed. Bladders were then removed, cut open and immediately mounted in medium, and immersed in liquid nitrogen. Two consecutive 3-μm frozen sections were cut with a cryostat. The first section was examined by fluorescence microscopy and the second section was stained with hematoxylin and eosin. For fluorescence imaging the filter set used included a 535/50 nm bandpass excitation filter and a 610/75 nm emission filter. Fluorescence images were acquired and documented using photography. Fluorescene could be detected in bladder samples after only 15 minutes of instillation with the above described solution. The urothelium / muscle fluorescence ratio ranged from 5/1 to 11/1 in various sites of the samples examined. No fluorescence originating from the muscle could be detected. PMF should be further studied towards the direction of its use in photodynamic therapy.

An Overview of Some Natural Products with Two A-Level Science Club Natural Products Experiments

ERIC Educational Resources Information Center

Sosabowski, Michael Hal; Olivier, George W. J.; Jawad, Hala; Maatta, Sieja

2017-01-01

Natural products are ubiquitous in nature but do not form a large proportion of the A-level syllabuses in the UK. In this article we briefly discuss a small selection of natural products, focusing on alcohols, aldehydes and ketones, and alkaloids. We then outline two natural product experiments that are suitable for A-level chemistry clubs or…

Glycosylation and Activities of Natural Products.

PubMed

Huang, Gangliang; Lv, Meijiao; Hu, Jinchuan; Huang, Kunlin; Xu, Hong

2016-01-01

Natural products are widely found in nature, their number and variety are numerous, the structures are complex and diverse. These natural products have many physiological and pharmacological activities. Glycosylation can increase the diversity of structure and function of natural product, it has become the focus of drug research and development. The impacts of glycosylation of natural products to water solubility, pharmacological activities, bioavailability, or others were described in this review, which provides a reference for the development and application of glycosylated natural products.

Elemental fingerprinting of Hypericum perforatum (St John's Wort) herb and preparations using ICP-OES and chemometrics.

PubMed

Owen, Jade D; Kirton, Stewart B; Evans, Sara J; Stair, Jacqueline L

2016-06-05

St. John's wort (SJW) (Hypericum perforatum) is a herbal remedy commonly used to treat mild depression. The elemental profiles of 54 samples (i.e., dry herbs, tablets and capsules) were evaluated by monitoring 25 elements using Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES). The major elemental constituents in the SJW samples were Ca (300-199,000μg/g), Mg (410-3,530μg/g), Al (4.4-900μg/g), Fe (1.154-760μg/g), Mn (2.4-261μg/g), Sr (0.88-83.6μg/g), and Zn (7-64μg/g). For the sixteen elements that could be reliably quantified, principal component analysis (PCA) was used to investigate underlying patterns in the data. PCA models identified 7 key elements (i.e., Ba, Ca, Cd, Mg, Mo, Ni and Y), which described 85% of the variance in the dataset in the first three principal components. The PCA approach resulted in a general delineation between the three different formulations and provides a basis for monitoring product quality in this manner. Copyright © 2016 Elsevier B.V. All rights reserved.

An automated Genomes-to-Natural Products platform (GNP) for the discovery of modular natural products.

PubMed

Johnston, Chad W; Skinnider, Michael A; Wyatt, Morgan A; Li, Xiang; Ranieri, Michael R M; Yang, Lian; Zechel, David L; Ma, Bin; Magarvey, Nathan A

2015-09-28

Bacterial natural products are a diverse and valuable group of small molecules, and genome sequencing indicates that the vast majority remain undiscovered. The prediction of natural product structures from biosynthetic assembly lines can facilitate their discovery, but highly automated, accurate, and integrated systems are required to mine the broad spectrum of sequenced bacterial genomes. Here we present a genome-guided natural products discovery tool to automatically predict, combinatorialize and identify polyketides and nonribosomal peptides from biosynthetic assembly lines using LC-MS/MS data of crude extracts in a high-throughput manner. We detail the directed identification and isolation of six genetically predicted polyketides and nonribosomal peptides using our Genome-to-Natural Products platform. This highly automated, user-friendly programme provides a means of realizing the potential of genetically encoded natural products.

Metabolic Engineering for the Production of Natural Products

PubMed Central

Pickens, Lauren B.; Tang, Yi; Chooi, Yit-Heng

2014-01-01

Natural products and natural product derived compounds play an important role in modern healthcare as frontline treatments for many diseases and as inspiration for chemically synthesized therapeutics. With advances in sequencing and recombinant DNA technology, many of the biosynthetic pathways responsible for the production of these chemically complex and pharmaceutically valuable compounds have been elucidated. With an ever expanding toolkit of biosynthetic components, metabolic engineering is an increasingly powerful method to improve natural product titers and generate novel compounds. Heterologous production platforms have enabled access to pathways from difficult to culture strains; systems biology and metabolic modeling tools have resulted in increasing predictive and analytic capabilities; advances in expression systems and regulation have enabled the fine-tuning of pathways for increased efficiency, and characterization of individual pathway components has facilitated the construction of hybrid pathways for the production of new compounds. These advances in the many aspects of metabolic engineering have not only yielded fascinating scientific discoveries but also make it an increasingly viable approach for the optimization of natural product biosynthesis. PMID:22432617

Xanthone biosynthesis in Hypericum perforatum cells provides antioxidant and antimicrobial protection upon biotic stress.

PubMed

Franklin, Gregory; Conceição, Luis F R; Kombrink, Erich; Dias, Alberto C P

2009-01-01

Xanthone production in Hypericum perforatum (HP) suspension cultures in response to elicitation by Agrobacterium tumefaciens co-cultivation has been studied. RNA blot analyses of HP cells co-cultivated with A. tumefaciens have shown a rapid up-regulation of genes encoding important enzymes of the general phenylpropanoid pathway (PAL, phenylalanine ammonia lyase and 4CL, 4-coumarate:CoA ligase) and xanthone biosynthesis (BPS, benzophenone synthase). Analyses of HPLC chromatograms of methanolic extracts of control and elicited cells (HP cells that were co-cultivated for 24h with A. tumefaciens) have revealed a 12-fold increase in total xanthone concentration and also the emergence of many xanthones after elicitation. Methanolic extract of elicited cells exhibited significantly higher antioxidant and antimicrobial competence than the equivalent extract of control HP cells indicating that these properties have been significantly increased in HP cells after elicitation. Four major de novo synthesized xanthones have been identified as 1,3,6,7-tetrahydroxy-8-prenyl xanthone, 1,3,6,7-tetrahydroxy-2-prenyl xanthone, 1,3,7-trihydroxy-6-methoxy-8-prenyl xanthone and paxanthone. Antioxidant and antimicrobial characterization of these de novo xanthones have revealed that xanthones play dual function in plant cells during biotic stress: (1) as antioxidants to protect the cells from oxidative damage and (2) as phytoalexins to impair the pathogen growth.

NCI Program for Natural Product Discovery: A Publicly-Accessible Library of Natural Product Fractions for High-Throughput Screening.

PubMed

Thornburg, Christopher C; Britt, John R; Evans, Jason R; Akee, Rhone K; Whitt, James A; Trinh, Spencer K; Harris, Matthew J; Thompson, Jerell R; Ewing, Teresa L; Shipley, Suzanne M; Grothaus, Paul G; Newman, David J; Schneider, Joel P; Grkovic, Tanja; O'Keefe, Barry R

2018-06-13

The US National Cancer Institute's (NCI) Natural Product Repository is one of the world's largest, most diverse collections of natural products containing over 230,000 unique extracts derived from plant, marine, and microbial organisms that have been collected from biodiverse regions throughout the world. Importantly, this national resource is available to the research community for the screening of extracts and the isolation of bioactive natural products. However, despite the success of natural products in drug discovery, compatibility issues that make extracts challenging for liquid handling systems, extended timelines that complicate natural product-based drug discovery efforts and the presence of pan-assay interfering compounds have reduced enthusiasm for the high-throughput screening (HTS) of crude natural product extract libraries in targeted assay systems. To address these limitations, the NCI Program for Natural Product Discovery (NPNPD), a newly launched, national program to advance natural product discovery technologies and facilitate the discovery of structurally defined, validated lead molecules ready for translation will create a prefractionated library from over 125,000 natural product extracts with the aim of producing a publicly-accessible, HTS-amenable library of >1,000,000 fractions. This library, representing perhaps the largest accumulation of natural-product based fractions in the world, will be made available free of charge in 384-well plates for screening against all disease states in an effort to reinvigorate natural product-based drug discovery.

Biomimetic syntheses of racemic natural products.

PubMed

Zask, Arie; Ellestad, George

2018-02-01

Racemic natural products are rarely produced in plants and microorganisms and are thought to be the result of nonenzymatic, spontaneous reactions. These compounds are often highly complex with multiple contiguous chiral centers that present a challenge to organic synthesis. Formation of these racemates often occurs by cyclization reactions that can generate multiple stereocenters from achiral precursors. Biomimetic synthesis of these racemic natural products provides support for their proposed nonenzymatic spontaneous biosynthesis. These elegant syntheses also provide scalable and efficient routes to these complex natural products. Although the number of reported racemic natural products is relatively low, an isolated natural product that has a very small optical rotation has been shown to be a true racemate. Thus, the occurrence of racemic natural products could be more common than thought. © 2017 Wiley Periodicals, Inc.

Natural Products as Aromatase Inhibitors

PubMed Central

Balunas, Marcy J.; Su, Bin; Brueggemeier, Robert W.; Kinghorn, A. Douglas

2010-01-01

With the clinical success of several synthetic aromatase inhibitors (AIs) in the treatment of postmenopausal estrogen receptor-positive breast cancer, researchers have also been investigating also the potential of natural products as AIs. Natural products from terrestrial and marine organisms provide a chemically diverse array of compounds not always available through current synthetic chemistry techniques. Natural products that have been used traditionally for nutritional or medicinal purposes (e.g., botanical dietary supplements) may also afford AIs with reduced side effects. A thorough review of the literature regarding natural product extracts and secondary metabolites of plant, microbial, and marine origin that have been shown to exhibit aromatase inhibitory activity is presented herein. PMID:18690828

Hypericum perforatum Reduces Paracetamol-Induced Hepatotoxicity and Lethality in Mice by Modulating Inflammation and Oxidative Stress.

PubMed

Hohmann, Miriam S N; Cardoso, Renato D R; Fattori, Victor; Arakawa, Nilton S; Tomaz, José C; Lopes, Norberto P; Casagrande, Rubia; Verri, Waldiceu A

2015-07-01

Hypericum perforatum is a medicinal plant with anti-inflammatory and antioxidant properties, which is commercially available for therapeutic use in Brazil. Herein the effect of H. perforatum extract on paracetamol (acetaminophen)-induced hepatotoxicity, lethality, inflammation, and oxidative stress in male swiss mice were investigated. HPLC analysis demonstrated the presence of rutin, quercetin, hypericin, pseudohypericin, and hyperforin in H. perforatum extract. Paracetamol (0.15-3.0 g/kg, p.o.) induced dose-dependent mortality. The sub-maximal lethal dose of paracetamol (1.5 g/kg, p.o.) was chosen for the experiments in the study. H. perforatum (30-300 mg/kg, i.p.) dose-dependently reduced paracetamol-induced lethality. Paracetamol-induced increase in plasma aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations, and hepatic myeloperoxidase activity, IL-1β, TNF-α, and IFN-γ concentrations as well as decreased reduced glutathione (GSH) concentrations and capacity to reduce 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonate radical cation; ABTS˙(+) ) were inhibited by H. perforatum (300 mg/kg, i.p.) treatment. Therefore, H. perforatum protects mice against paracetamol-induced lethality and liver damage. This effect seems to be related to the reduction of paracetamol-induced cytokine production, neutrophil recruitment, and oxidative stress. Copyright © 2015 John Wiley & Sons, Ltd.

Management of acute skin toxicity with Hypericum perforatum and neem oil during platinum-based concurrent chemo-radiation in head and neck cancer patients.

PubMed

Franco, Pierfrancesco; Rampino, Monica; Ostellino, Oliviero; Schena, Marina; Pecorari, Giancarlo; Garzino Demo, Paolo; Fasolis, Massimo; Arcadipane, Francesca; Martini, Stefania; Cavallin, Chiara; Airoldi, Mario; Ricardi, Umberto

2017-02-01

Acute skin toxicity is a frequent finding during combined radiotherapy and chemotherapy in head and neck cancer patients. Its timely and appropriate management is crucial for both oncological results and patient's global quality of life. We herein report clinical data on the use of Hypericum perforatum and neem oil in the treatment of acute skin toxicity during concurrent chemo-radiation for head and neck cancer. A consecutive series of 50 head and neck cancer patients undergoing concomitant radio-chemotherapy with weekly cisplatin was analyzed. Treatment with Hypericum perforatum and neem oil was started in case of G2 acute skin toxicity according to the RTOG/EORTC scoring scale and continued during the whole treatment course and thereafter until complete recovery. The maximum detected acute skin toxicity included Grade 2 events in 62% of cases and G3 in 32% during treatment and G2 and G3 scores in 52 and 8%, respectively, at the end of chemo-radiation. Grade 2 toxicity was mainly observed during weeks 4-5, while G3 during weeks 5-6. Median times spent with G2 or G3 toxicity were 23.5 and 14 days. Patients with G3 toxicity were reconverted to a G2 profile in 80% of cases, while those with a G2 score had a decrease to G1 in 58% of cases. Time between maximum acute skin toxicity and complete skin recovery was 30 days. Mean worst pain score evaluated with the Numerical Rating Scale-11 was 6.9 during treatment and 4.5 at the end of chemo-radiotherapy. Hypericum perforatum and neem oil proved to be a safe and effective option in the management of acute skin toxicity in head and neck cancer patients submitted to chemo-radiation with weekly cisplatin. Further studies with a control group and patient-reported outcomes are needed to confirm this hypothesis.

Hypericum perforatum L. subsp. perforatum induces inhibition of free radicals and enhanced phototoxicity in human melanoma cells under ultraviolet light.

PubMed

Menichini, G; Alfano, C; Marrelli, M; Toniolo, C; Provenzano, E; Statti, G A; Nicoletti, M; Menichini, F; Conforti, F

2013-04-01

Our interest continues in discovering phytocomplexes from medicinal plants with phototoxic activity against human melanoma cells; thus the aim of the present study was to assess antioxidant, anti-inflammatory and phototoxic activity of Hypericum perforatum L. subsp. perforatum, and relate these properties to the plant's chemical composition. Components of H. perforatum subsp. perforatum were extracted by hydroalcoholic solution and chemical profiles of preparations (HyTE-3) performed by HPTLC. Linoleic acid peroxidation and DPPH tests were used to assess antioxidant activity, while MTT assay allowed evaluation of anti-proliferative activity with respect to A375 human melanoma cells after irradiation with UVA dose, 1.8 J/cm(2) . Inhibition of nitric oxide production of macrophages was also investigated. HyTE-3 indicated better antioxidant activity with β-carotene bleaching test in comparison to DPPH assay (IC50 = 0.89 μg/ml); significant phototoxicity in A375 cells at 78 μg/ml concentration resulted in cell destruction of 50%. HyTE-3 caused significant dose-related inhibition of nitric oxide production in murine monocytic macrophage cell line RAW 264.7 with IC50 value of 342 μg/ml. The H. perforatum subsp. perforatum-derived product was able to suppress proliferation of human malignant melanoma A375 cells; extract together with UVA irradiation enhanced phototoxicity. This biological activity of antioxidant effects was combined with inhibition of nitric oxide production. © 2013 Blackwell Publishing Ltd.

Natural products used for diabetes.

PubMed

Shapiro, Karen; Gong, William C

2002-01-01

To review the efficacy and safety of natural products commonly used for diabetes. English and Spanish-language journals retrieved through a MEDLINE search of articles published between 1960 and December 2001 using these index terms: Opuntia, karela, gymnema, tecoma, alpha lipoic acid, thioctic acid, ginseng, panaxans, and diabetes. Natural products have long been used in traditional systems of medicine for diabetes. Products in common use include nopal (prickly pear cactus), fenu-greek, karela (bitter melon), gymnema, ginseng, tronadora, chromium, and alpha-lipoic acid. The popularity of these products varies among people of different ethnicities. Nopal is the most commonly used herbal hypoglycemic among persons of Mexican descent. Karela is more commonly used by persons from Asian countries. Some of these agents have gained universal appeal. For a select number of products, studies have revealed single or multiple mechanisms of action. For several of these, high soluble fiber content is a contributing factor. Based on the available evidence, several natural products in common use can lower blood glucose in patients with diabetes. Commonly used natural products often have a long history of traditional use, and pharmacists who have a stronger understanding of these products are better positioned to counsel patients on their appropriate use.

Construction of a 3D-shaped, natural product like fragment library by fragmentation and diversification of natural products.

PubMed

Prescher, Horst; Koch, Guido; Schuhmann, Tim; Ertl, Peter; Bussenault, Alex; Glick, Meir; Dix, Ina; Petersen, Frank; Lizos, Dimitrios E

2017-02-01

A fragment library consisting of 3D-shaped, natural product-like fragments was assembled. Library construction was mainly performed by natural product degradation and natural product diversification reactions and was complemented by the identification of 3D-shaped, natural product like fragments available from commercial sources. In addition, during the course of these studies, novel rearrangements were discovered for Massarigenin C and Cytochalasin E. The obtained fragment library has an excellent 3D-shape and natural product likeness, covering a novel, unexplored and underrepresented chemical space in fragment based drug discovery (FBDD). Copyright © 2016 Elsevier Ltd. All rights reserved.

Alternative Fuels Data Center: Natural Gas Production

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Engineering microbial hosts for production of bacterial natural products.

PubMed

Zhang, Mingzi M; Wang, Yajie; Ang, Ee Lui; Zhao, Huimin

2016-08-27

Covering up to end 2015Microbial fermentation provides an attractive alternative to chemical synthesis for the production of structurally complex natural products. In most cases, however, production titers are low and need to be improved for compound characterization and/or commercial production. Owing to advances in functional genomics and genetic engineering technologies, microbial hosts can be engineered to overproduce a desired natural product, greatly accelerating the traditionally time-consuming strain improvement process. This review covers recent developments and challenges in the engineering of native and heterologous microbial hosts for the production of bacterial natural products, focusing on the genetic tools and strategies for strain improvement. Special emphasis is placed on bioactive secondary metabolites from actinomycetes. The considerations for the choice of host systems will also be discussed in this review.

Photodynamic therapy of nonmelanoma skin cancer with topical hypericum perforatum extract--a pilot study.

PubMed

Kacerovská, Denisa; Pizinger, Karel; Majer, Filip; Smíd, Frantisek

2008-01-01

Hypericin, the photoactive compound of Hypericum perforatum, is probably the most powerful photosensitizer found in nature. This compound has shown high potency in the photodynamic treatment of tumor cells. However, there is only limited knowledge regarding the photodynamic effect of hypericin on nonmelanoma skin cancer cells. The aim of this prospective study was to investigate the efficacy of photodynamic therapy with topical application of an extract of H. perforatum in actinic keratosis, basal cell carcinoma (BCC) and morbus Bowen (carcinoma in situ). The study was carried out on 34 patients--eight with actinic keratoses (AKs), 21 with BCC and five with Bowen's disease. The extract of H. perforatum was applied on the skin lesions under occlusion and that was followed by irradiation with 75 J cm(-2) of red light 2 h later. The treatment was performed weekly for 6 weeks on average. The percentage of complete clinical response was 50% for AKs, 28% in patients with superficial BCC and 40% in patients with Bowen's disease. There was only a partial remission seen in patients with nodular BCCs. A complete disappearance of tumor cells was found in the histologic preparation of 11% of patients with superficial BCCs and 80% in the patients with Bowen's disease. All patients complained of burning and pain sensations during irradiation. Although the results of this first clinical trial could be regarded as disappointing, there are still possibilities for improvement. Better preparation of the lesions, enhancement of hypericin delivery and other types of light exposure procedures could significantly improve the clinical outcomes of this relatively inexpensive treatment modality.

Enantiomeric Natural Products: Occurrence and Biogenesis**

PubMed Central

Finefield, Jennifer M.; Sherman, David H.; Kreitman, Martin; Williams, Robert M.

2012-01-01

In Nature, chiral natural products are usually produced in optically pure form; however, on occasion Nature is known to produce enantiomerically opposite metabolites. These enantiomeric natural products can arise in Nature from a single species, or from different genera and/or species. Extensive research has been carried out over the years in an attempt to understand the biogenesis of naturally occurring enantiomers, however, many fascinating puzzles and stereochemical anomalies still remain. PMID:22555867

Toward the Dark Matter of Natural Products.

PubMed

Wakimoto, Toshiyuki

2017-11-01

Considering the dynamic features of natural products, our access toward exploring the entire diversity of natural products has been quite limited. It is challenging to assess the diversity of natural products by using conventional analytical methods, even with tandem chromatographic techniques, such as LC-MS and GC-MS. This viewpoint is supported by the sequencing analyses of microbial genomes, which have unveiled the potential of secondary metabolite production far exceeding the number of isolated molecules. Recent advancements in metabolomics, in concert with genomics analyses, have further extended the natural product diversity, prompting growing awareness of the existence of reactive or short-lived natural molecules. This personal account introduces some examples of the discoveries of hitherto elusive natural products, due to physico-chemical or biological reasons, and highlights the significance of the dark matter of natural products. © 2017 The Chemical Society of Japan & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Cancer wars: natural products strike back

PubMed Central

Basmadjian, Christine; Zhao, Qian; Bentouhami, Embarek; Djehal, Amel; Nebigil, Canan G.; Johnson, Roger A.; Serova, Maria; de Gramont, Armand; Faivre, Sandrine; Raymond, Eric; Désaubry, Laurent G.

2014-01-01

Natural products have historically been a mainstay source of anticancer drugs, but in the 90's they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many solid tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, 12 novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery. PMID:24822174

In silico polypharmacology of natural products.

PubMed

Fang, Jiansong; Liu, Chuang; Wang, Qi; Lin, Ping; Cheng, Feixiong

2017-04-27

Natural products with polypharmacological profiles have demonstrated promise as novel therapeutics for various complex diseases, including cancer. Currently, many gaps exist in our knowledge of which compounds interact with which targets, and experimentally testing all possible interactions is infeasible. Recent advances and developments of systems pharmacology and computational (in silico) approaches provide powerful tools for exploring the polypharmacological profiles of natural products. In this review, we introduce recent progresses and advances of computational tools and systems pharmacology approaches for identifying drug targets of natural products by focusing on the development of targeted cancer therapy. We survey the polypharmacological and systems immunology profiles of five representative natural products that are being considered as cancer therapies. We summarize various chemoinformatics, bioinformatics and systems biology resources for reconstructing drug-target networks of natural products. We then review currently available computational approaches and tools for prediction of drug-target interactions by focusing on five domains: target-based, ligand-based, chemogenomics-based, network-based and omics-based systems biology approaches. In addition, we describe a practical example of the application of systems pharmacology approaches by integrating the polypharmacology of natural products and large-scale cancer genomics data for the development of precision oncology under the systems biology framework. Finally, we highlight the promise of cancer immunotherapies and combination therapies that target tumor ecosystems (e.g. clones or 'selfish' sub-clones) via exploiting the immunological and inflammatory 'side' effects of natural products in the cancer post-genomics era. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

High impact technologies for natural products screening.

PubMed

Koehn, Frank E

2008-01-01

Natural products have historically been a rich source of lead molecules in drug discovery. However, natural products have been de-emphasized as high throughput screening resources in the recent past, in part because of difficulties in obtaining high quality natural products screening libraries, or in applying modern screening assays to these libraries. In addition, natural products programs based on screening of extract libraries, bioassay-guided isolation, structure elucidation and subsequent production scale-up are challenged to meet the rapid cycle times that are characteristic of the modern HTS approach. Fortunately, new technologies in mass spectrometry, NMR and other spectroscopic techniques can greatly facilitate the first components of the process - namely the efficient creation of high-quality natural products libraries, bimolecular target or cell-based screening, and early hit characterization. The success of any high throughput screening campaign is dependent on the quality of the chemical library. The construction and maintenance of a high quality natural products library, whether based on microbial, plant, marine or other sources is a costly endeavor. The library itself may be composed of samples that are themselves mixtures - such as crude extracts, semi-pure mixtures or single purified natural products. Each of these library designs carries with it distinctive advantages and disadvantages. Crude extract libraries have lower resource requirements for sample preparation, but high requirements for identification of the bioactive constituents. Pre-fractionated libraries can be an effective strategy to alleviate interferences encountered with crude libraries, and may shorten the time needed to identify the active principle. Purified natural product libraries require substantial resources for preparation, but offer the advantage that the hit detection process is reduced to that of synthetic single component libraries. Whether the natural products library

Cancer wars: Natural products strike back

NASA Astrophysics Data System (ADS)

Basmadjian, Christine; Zhao, Qian; Djehal, Amel; Bentouhami, Embarek; Nebigil, Canan; Johnson, Roger; Serova, Maria; De Gramont, Armand; Faivre, Sandrine; Raymond, Eric; Désaubry, Laurent

2014-05-01

Natural products have historically been a mainstay source of anticancer drugs, but in the 90’s they fell out of favor in pharmaceutical companies with the emergence of targeted therapies, which rely on antibodies or small synthetic molecules identified by high throughput screening. Although targeted therapies greatly improved the treatment of a few cancers, the benefit has remained disappointing for many sol¬¬id tumors, which revitalized the interest in natural products. With the approval of rapamycin in 2007, twelve novel natural product derivatives have been brought to market. The present review describes the discovery and development of these new anticancer drugs and highlights the peculiarities of natural product and new trends in this exciting field of drug discovery.

Natural product-based amyloid inhibitors.

PubMed

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R; Xu, Bin

2017-09-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. Copyright © 2017 Elsevier Inc. All rights reserved.

Natural product-based amyloid inhibitors

PubMed Central

Velander, Paul; Wu, Ling; Henderson, Frances; Zhang, Shijun; Bevan, David R.; Xu, Bin

2018-01-01

Many chronic human diseases, including multiple neurodegenerative diseases, are associated with deleterious protein aggregates, also called protein amyloids. One common therapeutic strategy is to develop protein aggregation inhibitors that can slow down, prevent, or remodel toxic amyloids. Natural products are a major class of amyloid inhibitors, and several dozens of natural product-based amyloid inhibitors have been identified and characterized in recent years. These plant- or microorganism-extracted compounds have shown significant therapeutic potential from in vitro studies as well as in vivo animal tests. Despite the technical challenges of intrinsic disordered or partially unfolded amyloid proteins that are less amenable to characterizations by structural biology, a significant amount of research has been performed, yielding biochemical and pharmacological insights into how inhibitors function. This review aims to summarize recent progress in natural product-based amyloid inhibitors and to analyze their mechanisms of inhibition in vitro. Major classes of natural product inhibitors and how they were identified are described. Our analyses comprehensively address the molecular interactions between the inhibitors and relevant amyloidogenic proteins. These interactions are delineated at molecular and atomic levels, which include covalent, non-covalent, and metal-mediated mechanisms. In vivo animal studies and clinical trials have been summarized as an extension. To enhance natural product bioavailability in vivo, emerging work using nanocarriers for delivery has also been described. Finally, issues and challenges as well as future development of such inhibitors are envisioned. PMID:28390938

Alternative Fuels Data Center: Conventional Natural Gas Production

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Synthesis of Polycyclic Natural Products

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nguyen, Tuan Hoang

With the continuous advancements in molecular biology and modern medicine, organic synthesis has become vital to the support and extension of those discoveries. The isolations of new natural products allow for the understanding of their biological activities and therapeutic value. Organic synthesis is employed to aid in the determination of the relationship between structure and function of these natural products. The development of synthetic methodologies in the course of total syntheses is imperative for the expansion of this highly interdisciplinary field of science. In addition to the practical applications of total syntheses, the structural complexity of natural products represents amore » worthwhile challenge in itself. The pursuit of concise and efficient syntheses of complex molecules is both gratifying and enjoyable.« less

De Novo Sequencing of Hypericum perforatum Transcriptome to Identify Potential Genes Involved in the Biosynthesis of Active Metabolites

PubMed Central

He, Miao; Wang, Ying; Hua, Wenping; Zhang, Yuan; Wang, Zhezhi

2012-01-01

Background Hypericum perforatum L. (St. John’s wort) is a medicinal plant with pharmacological properties that are antidepressant, anti-inflammatory, antiviral, anti-cancer, and antibacterial. Its major active metabolites are hypericins, hyperforins, and melatonin. However, little genetic information is available for this species, especially that concerning the biosynthetic pathways for active ingredients. Methodology/Principal Findings Using de novo transcriptome analysis, we obtained 59,184 unigenes covering the entire life cycle of these plants. In all, 40,813 unigenes (68.86%) were annotated and 2,359 were assigned to secondary metabolic pathways. Among them, 260 unigenes are involved in the production of hypericin, hyperforin, and melatonin. Another 2,291 unigenes are classified as potential Type III polyketide synthase. Our BlastX search against the AGRIS database reveals 1,772 unigenes that are homologous to 47 known Arabidopsis transcription factor families. Further analysis shows that 10.61% (6,277) of these unigenes contain 7,643 SSRs. Conclusion We have identified a set of putative genes involved in several secondary metabolism pathways, especially those related to the synthesis of its active ingredients. Our results will serve as an important platform for public information about gene expression, genomics, and functional genomics in H. perforatum. PMID:22860059

Bioactive Oligosaccharide Natural Products

PubMed Central

McCranie, Emilianne K.; Bachmann, Brian O.

2016-01-01

Oligosaccharide natural products target a wide spectrum of biological processes including disruption of cell wall biosynthesis, interference of bacterial translation, and inhibition of human α-amylase. Correspondingly, oligosaccharides possess potential for development as treatments of such diverse diseases as bacterial infections and type II diabetes. Despite their potent and selective activities and potential clinical relevance, isolated bioactive secondary metabolic oligosaccharides are less prevalent than other classes of natural products and their biosynthesis has received comparatively less attention. This review highlights the unique modes of action and biosynthesis of four classes of bioactive oligosaccharides: the orthosomycins, moenomycins, saccharomicins, and acarviostatins. PMID:24883430

Natural Products as a Foundation for Drug Discovery

PubMed Central

Beutler, John A.

2009-01-01

Natural products have contributed to the development of many drugs for diverse indications. While most U.S. pharmaceutical companies have reduced or eliminated their in-house natural product groups, new paradigms and new enterprises have evolved to carry on a role for natural products in the pharmaceutical industry. Many of the reasons for the decline in popularity of natural products are being addressed by the development of new techniques for screening and production. This overview aims to inform pharmacologists of current strategies and techniques that make natural products a viable strategic choice for inclusion in drug discovery programs. PMID:20161632

Evaluation of the cytotoxicity, mutagenicity and antimutagenicity of a natural antidepressant, Hypericum perforatum L. (St. John’s wort), on vegetal and animal test systems

PubMed Central

2013-01-01

Background St. John’s wort (Hypericum perforatum L.) is an herbaceous plant that is native to Europe, West Asia and North Africa and that is recognized and used worldwide for the treatment of mild and moderate depression. It also has been shown to be therapeutic for the treatment of burns, bruises and swelling and can be used for its wound healing, antiviral, antimicrobial, antioxidant, analgesic, hepato-protective and anxiolytic properties. The aim of this study was to evaluate the potential cytotoxic, mutagenic and antimutagenic action of H. Perforatum. Methods Meristematic cells were used as the test system for Allium cepa L., and bone marrow cells from Rattus norvegicus, ex vivo, were used to calculate the mitotic index and the percentage of chromosomal aberration. Statistical analysis was performed using the chi-square test. Results This medicinal plant had no cytotoxic potential in the vegetal test system evaluated. In the animal test system, none of the acute treatments, including intraperitoneal gavage and subchronic gavage, were cytotoxic or mutagenic. Moreover, this plant presented antimutagenic activity against the clastogenic action of cyclophosphamide, as confirmed in pre-treatment (76% reduction in damage), simultaneous treatment (95%) and post-treatment (97%). Conclusions Thus, the results of this study suggest that the administration of H. perforatum, especially by gavage similar to oral consumption used by humans, is safe and with beneficial antimutagenic potential. PMID:23647762

Underexplored Opportunities for Natural Products in Drug Discovery.

PubMed

DeCorte, Bart L

2016-10-27

The importance of natural products in the treatment of human disease is well documented. While natural products continue to have a profound impact on human health, chemists have succeeded in generating semisynthetic analogues that sometimes overshadow the original natural product in terms of clinical significance. Synthetic efforts based on natural products have primarily focused on improving their drug-like features while targeting utility in the same biological space. A less documented phenomenon is that natural products can serve as powerful starting materials to generate drug substances with novel therapeutic utility that is unrelated to the biological space of the natural product starting material. In this Perspective, examples of natural product derived marketed drugs with therapeutic utility in clinical space that is different from the biological profile of the starting material are presented, demonstrating that this is not merely a theoretical concept but both a clinical reality and an underexplored opportunity.

Effect of eluent pH on the HPLC-UV analysis of hyperforin from St. John's Wort (Hypericum perforatum L.).

PubMed

Fourneron, Jean-Dominique; Naït-Si, Youssef

2006-01-01

The effect of the pH of the mobile phase in HPLC analysis of hyperforin was investigated. Working with an extract of St. John's Wort (Hypericum perforatum L.) that is rich in hyperforin, significant differences were observed in conventional chromatograms depending on whether the mobile phase was acidic or alkaline. Chromatogram changes were paralleled by changes in the UV spectrum of the hyperforin peak. The structural changes in hyperforin occur in the chromatographic column itself, as has been confirmed by UV spectroscopy performed on a sample of purified hyperforin, which showed that the UV spectrum is indeed dependent on the pH of its environment.

Bioactive natural products from novel microbial sources.

PubMed

Challinor, Victoria L; Bode, Helge B

2015-09-01

Despite the importance of microbial natural products for human health, only a few bacterial genera have been mined for the new natural products needed to overcome the urgent threat of antibiotic resistance. This is surprising, given that genome sequencing projects have revealed that the capability to produce natural products is not a rare feature among bacteria. Even the bacteria occurring in the human microbiome produce potent antibiotics, and thus potentially are an untapped resource for novel compounds, potentially with new activities. This review highlights examples of bacteria that should be considered new sources of natural products, including anaerobes, pathogens, and symbionts of humans, insects, and nematodes. Exploitation of these producer strains, combined with advances in modern natural product research methodology, has the potential to open the way for a new golden age of microbial therapeutics. © 2015 New York Academy of Sciences.

Hypericum perforatum as a cognitive enhancer in rodents: A meta-analysis

PubMed Central

Ben-Eliezer, Daniel; Yechiam, Eldad

2016-01-01

Considered an antidepressant and anti-anxiety agent, Hypericum perforatum affects multiple neurotransmitters in a non-competitive synergistic manner, and may have nootropic potential. We quantitatively reviewed the pre-clinical literature to examine if there is a cognitive-enhancing effect of H. perforatum in healthy rodents. Additionally, within these studies, we compared the effects observed in intact rodents versus those whose performance has been impaired, mostly through stress manipulations. The meta-analysis incorporated studies that examined the effect of H. perforatum versus placebo on memory indices of task performance. All analyses were based on weighting different studies according to their inverse variance. Thirteen independent studies (published 2000–2014) involving 20 experimental comparisons met our inclusion criteria. The results showed a large positive effect of H. perforatum on cognitive performance for intact, healthy rodents (d = 1.11), though a larger effect emerged for stress-impaired rodents (d = 3.10 for restraint stress). The positive effect on intact rodents was observed in tasks assessing reference memory as well as working memory, and was not moderated by the type of memory or motivation (appetitive versus aversive). Thus, while primarily considered as a medication for depression, H. perforatum shows considerable nootropic potential in rodents. PMID:27762349

Natural Health Products and Community Pharmacy-Remove the Mysticism Not the Product.

PubMed

Blackburn, David F; Gill, Munpreet; Krol, Ed; Taylor, Jeff

2017-12-01

The allure of natural products has captivated humans for centuries. Although they can be compatible with evidence-based care, attitudes surrounding natural products can seem almost mystical and may even be accompanied by contempt toward Western medicine. Considering the high volumes of natural products sold in community pharmacies, pharmacists can inject balanced information to minimize the mysticism and help patients make informed decisions. The aim of this article is to argue for standardized guidelines pertaining to the management of natural products in community pharmacy practice.

Sources for Leads: Natural Products and Libraries.

PubMed

van Herwerden, Eric F; Süssmuth, Roderich D

2016-01-01

Natural products have traditionally been a major source of leads in the drug discovery process. However, the development of high-throughput screening led to an increased interest in synthetic methods that enabled the rapid construction of large libraries of molecules. This resulted in the termination or downscaling of many natural product research programs, but the chemical libraries did not necessarily produce a larger amount of drug leads. On one hand, this chapter explores the current state of natural product research within the drug discovery process. On the other hand it evaluates the efforts made to increase the amount of leads generated from chemical libraries and considers what role natural products could play here.

Natural products as a foundation for drug discovery.

PubMed

Beutler, John A

2009-09-01

Natural products have provided chemical leads for the development of many drugs for diverse indications. While most U.S. pharmaceutical firms have reduced or eliminated their in-house natural product groups, there is a renewed interest in this source of new chemical entities. Many of the reasons for the past decline in popularity of natural products are being addressed by the development of new techniques for screening and production. The aim of this unit is to review current strategies and techniques that increase the value of natural products as a source for novel drug candidates.

Targeting Nuclear Receptors with Marine Natural Products

PubMed Central

Yang, Chunyan; Li, Qianrong; Li, Yong

2014-01-01

Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators. PMID:24473166

Factors affecting polyphenol biosynthesis in wild and field grown St. John's Wort (Hypericum perforatum L. Hypericaceae/Guttiferae).

PubMed

Bruni, Renato; Sacchetti, Gianni

2009-02-11

The increasing diffusion of herbal products is posing new questions: why are products so often different in their composition and efficacy? Which approach is more suitable to increase the biochemical productivity of medicinal plants with large-scale, low-cost solutions? Can the phytochemical profile of a medicinal plant be modulated in order to increase the accumulation of its most valuable constituents? Will polyphenol-rich medicinal crops ever be traded as commodities? Providing a proactive answer to such questions is an extremely hard task, due to the large number of variables involved: intraspecific chemodiversity, plant breeding, ontogenetic stage, post-harvest handling, biotic and abiotic factors, to name but a few. An ideal path in this direction should include the definition of optimum pre-harvesting and post-harvesting conditions and the availability of specific Good Agricultural Practices centered on secondary metabolism enhancement. The first steps to be taken are undoubtedly the evaluation and the organization of scattered data regarding the diverse factors involved in the optimization of medicinal plant cultivation, in order to provide an interdisciplinary overview of main possibilities, weaknesses and drawbacks. This review is intended to be a synopsis of the knowledge on this regard focused on Hypericum perforatum L. (Hypericaceae/Guttiferae) secondary metabolites of phenolic origin, with the aim to provide a reference and suggest an evolution towards the maximization of St. John's Wort bioactive constituents. Factors considered emerged not only from in-field agronomic results, but also from physiological, genetical, biotic, abiotic and phytochemical data that could be scaled up to the application level. To increase quality for final beneficiaries, growers' profits and ultimately transform phenolic-rich medicinal crops into commodities, the emerging trend suggests an integrated and synergic approach. Agronomy and genetics will need to develop their

Natural products and combinatorial chemistry: back to the future.

PubMed

Ortholand, Jean-Yves; Ganesan, A

2004-06-01

The introduction of high-throughput synthesis and combinatorial chemistry has precipitated a global decline in the screening of natural products by the pharmaceutical industry. Some companies terminated their natural products program, despite the unproven success of the new technologies. This was a premature decision, as natural products have a long history of providing important medicinal agents. Furthermore, they occupy a complementary region of chemical space compared with the typical synthetic compound library. For these reasons, the interest in natural products has been rekindled. Various approaches have evolved that combine the power of natural products and organic chemistry, ranging from the combinatorial total synthesis of analogues to the exploration of natural product scaffolds and the design of completely unnatural molecules that resemble natural products in their molecular characteristics.

Antioxidant, anticancer and anticholinesterase activities of flower, fruit and seed extracts of Hypericum amblysepalum HOCHST.

PubMed

Keskin, Cumali

2015-01-01

Cancer is an unnatural type of tissue growth in which the cells exhibit unrestrained division, leading to a progressive increase in the number of dividing cells. It is now the second largest cause of death in the world. The present study concerned antioxidant, anticancer and anticholinesterase activities and protocatechuic, catechin, caffeic acid, syringic acid, p-coumaric acid and o-coumaric concentrations in methanol extracts of flowers, fruits and seeds of Hypericum amblysepalum. Antioxidant properties including free radical scavenging activity and reducing power, and amounts of total phenolic compounds were evaluated using different tests. Protocatechuic, catechin, caffeic acid, syringic acid, p-coumaric acid and o-coumaric concentrations in extracts were determined by HPLC. Cytotoxic effects were determined using the MTT test with human cervix cancer (HeLa) and rat kidney epithelium cell (NRK-52E) lines. Acetyl and butyrylcholinesterase inhibitory activities were measured by by Ellman method. Total phenolic content of H. amblysepalum seeds was found to be higher than in fruit and flower extracts. DPPH free radical scavenging activity of the obtained extracts gave satisfactory results versus butylated hydroxyanisole and butylated hydroxytoluene as controls. Reducing power activity was linearly proportional to the studied concentration range: 10-500 μg/ mL LC50 values for H. amblysepalum seeds were 11.7 and 2.86 respectively for HeLa and NRK-52E cell lines. Butyryl-cholinesterase inhibitory activity was 76.9±0.41 for seed extract and higher than with other extracts. The present results suggested that H. amblysepalum could be a potential candidate anti-cancer drug for the treatment of human cervical cancer, and good source of natural antioxidants.

Arbuscular mycorrhizal fungi altered the hypericin, pseudohypericin, and hyperforin content in flowers of Hypericum perforatum grown under contrasting P availability in a highly organic substrate.

PubMed

Lazzara, Silvia; Militello, Marcello; Carrubba, Alessandra; Napoli, Edoardo; Saia, Sergio

2017-05-01

St. John's Wort (Hypericum perforatum) is a perennial herb able to produce water-soluble active ingredients (a.i.), mostly in flowers, with a wide range of medicinal and biotechnological uses. However, information about the ability of arbuscular mycorrhizal fungi (AMF) to affect its biomass accumulation, flower production, and concentration of a.i. under contrasting nutrient availability is still scarce. In the present experiment, we evaluated the role of AMF on growth, flower production, and concentration of bioactive secondary metabolites (hypericin, pseudohypericin, and hyperforin) of H. perforatum under contrasting P availability. AMF stimulated the production of aboveground biomass under low P conditions and increased the production of root biomass. AMF almost halved the number of flowers per plant by means of a reduction of the number of flower-bearing stems per plant under high P availability and through a lower number of flowers per stem in the low-P treatment. Flower hyperforin concentration was 17.5% lower in mycorrhizal than in non-mycorrhizal plants. On the contrary, pseudohypericin and hypericin concentrations increased by 166.8 and 279.2%, respectively, with AMF under low P availability, whereas no effect of AMF was found under high P availability. These results have implications for modulating the secondary metabolite production of H. perforatum. However, further studies are needed to evaluate the competition for photosynthates between AMF and flowers at different nutrient availabilities for both plant and AM fungus.

Polar extracts from the berry-like fruits of Hypericum androsaemum L. as a promising ingredient in skin care formulations.

PubMed

Antognoni, Fabiana; Lianza, Mariacaterina; Poli, Ferruccio; Buccioni, Michela; Santinelli, Claudia; Caprioli, Giovanni; Iannarelli, Romilde; Lupidi, Giulio; Damiani, Elisabetta; Beghelli, Daniela; Alunno, Alessia; Maggi, Filippo

2017-01-04

The top flowering aerial parts of the Hypericum species are traditionally used to prepare ointments to heal cuts and burns. Sometimes even the fruits are used for these purposes. Hypericum androsaemum L., commonly known as tutsan or shrubby St. John's Wort, is a Mediterranean medicinal plant which has been traditionally used to prepare an ointment for treating cuts and wounds. To evaluate the extracts obtained from H. androsaemum red berries as functional ingredients for skin care formulations. The methanolic extract was obtained by Soxhlet extraction while the aqueous extract was prepared by decoction; their composition was determined by HPLC analysis. Their biological activities were measured in terms of proliferation and migration of human fibroblasts, inhibition of collagenase activity, and immunomodulatory effects on human peripheral blood mononuclear cells (PBMCs). In addition, we evaluated their photostability by UV spectroscopy and their protective effects against APPH-induced hemolysis in red blood cells (RBC). The polar extracts contained significant amounts of shikimic (108,143.7-115,901.3mg/kg) and chlorogenic acids (45,781.1-57,002.7mg/kg). The main components of these extracts made an important contribution to a significant increase in human fibroblast migration. Both extracts were also active as collagenase inhibitors, with the aqueous one showing a greater inhibitory capacity (IC 50 value of 88.1µg/mL), similar to that of chlorogenic acid. The kinetic parameters determined for the enzymatic reaction revealed for both aqueous extract and chlorogenic acid an uncompetitive mechanism of inhibition. The methanolic extract showed important effects on PBMCs by modulating IL-6. Both extracts proved to be photostable in the UVA/B range and protected RBC against peroxidation at low concentrations. H. androsaemum red berries were proven to contain phytochemicals that improve skin regeneration, hence potentially employable in skin care formulations. Copyright

Differences of response of human bladder cancer cells to photodynamic therapy (PDT) with Hypericum perforantum L extract and Photofrin

NASA Astrophysics Data System (ADS)

Nseyo, Unyime; Kim, Albert; Stavropoulos, Nikos E.; Skalkos, Dimitris; Nseyo, Unwana U.; Chung, Theodore D.

2005-04-01

Refractory carcinoma in situ and resistant multifocal transitional cell carcinoma (TCC) of the human urinary bladder respond modestly to PHOTOFRIN (PII) PDT. Hypericum perforatum L., (St. John"s wort /Epirus" Vasalmo, Greece), a medicinal plant used for many human ailments, is under investigation as a new photosensitizer. We have reported on the antiproliferative activity of the lipophilic extract of the Hypericum perforatum L. (HP) against cultured T-24, and NBT-11 bladder cancer cells. We investigated response of the polar methanolic fraction (PMF) of the HP extract versus PHOTOFRIN in photodynamic therapy (PDT) of human bladder cancer cells, RT-4 and T-24.The PMF was extracted from the dry herb with methanol, followed by liquid extraction with petroleum ether. RT-4/T-24, were plated (105 cells/well) and placed in the incubator (370 C, 5%CO) for 24 hours prior to addition of drugs. PII 2ug/ml, or PMF 60ug /ml was added and incubation continued. After 24 hours, the cells were treated with laser light (630nm) with 0,1,2,4 and 8 Joules. The cells were then washed and reincubated for another 24 hours. After this incubation cell survival was assessed by the MTT assay. PMF-PDT induced percent cell kill of 0%, 0%, 0%, 29% and 75%, in RT-4 cells (primary noninvasive urinary bladder TCC) versus 5%, 9%, 13%, 69% and 86%, in T-24 cells(metastatic TTC) at 0,1,2,4 and 8 Joules respectively. PII-PDT induced cell kill of 0 %, 0% ,0%,0% and 9 %, in RT-4 cells versus 0%,10%,0%,21% and 77%, in T-24 cells at 0,1,2,4 and 8 Joules respectively.RT-24 cells were relatively more resistant than T-24 cells to PMF and PII-PDT. Understanding mechanisms of such differential responses might prove useful

The quality of information on websites selling St. John's wort.

PubMed

Thakor, Vijeta; Leach, Matthew J; Gillham, David; Esterman, Adrian

2011-06-01

Health consumers are increasingly using the Internet to access information about health care, to self-diagnose, and to purchase medication. The use of the Internet to purchase herbal products is of particular interest because of the high level of consumer expenditure on herbal medicines, and the misperception by some consumers that herbal products are natural, and thus absent of any contraindications, drug interactions and adverse effects. It is possible that consumers may purchase herbal medicines via the Internet without consulting health professionals and therefore, use these medicines in an unsafe manner. To examine the quality of e-commerce websites that sell herbal products; specifically, websites where St. John's wort (Hypericum perforatum) can be purchased. Cross-sectional survey of 54 selected websites, including online pharmacies, online health food stores and manufacturers of herbal medicines. A modified version of the DISCERN instrument was used to assess the quality of websites. The majority of websites rated poorly with a concerning lack of information about the interaction between hypericum and warfarin, anti-depressants and oral contraceptives. Most sites also failed to provide sufficient information about the contraindications and adverse effects of hypericum treatment. The results of this study strongly support the need for improved consumer education about herbal medicine, as well as the application of more stringent standards to websites that sell medications. Copyright © 2011 Elsevier Ltd. All rights reserved.

(±)-Japonones A and B, two pairs of new enantiomers with anti-KSHV activities from Hypericum japonicum

NASA Astrophysics Data System (ADS)

Hu, Linzhen; Zhu, Hucheng; Li, Lei; Huang, Jinfeng; Sun, Weiguang; Liu, Junjun; Li, Hua; Luo, Zengwei; Wang, Jianping; Xue, Yongbo; Zhang, Yu; Zhang, Yonghui

2016-06-01

Two pairs of new enantiomers with unusual 5,5-spiroketal cores, termed (±)-japonones A and B [(±)-1 and (±)-2], were obtained from Hypericum japonicum Thunb. The absolute configurations of (±)-1 and (±)-2 were characterized by extensive analyses of spectroscopic data and calculated electronic circular dichroism (ECD) spectra, the application of modified Mosher’s methods, and the assistance of quantum chemical predictions (QCP) of 13C NMR chemical shifts. Among these metabolites, (+)-1 exhibited some inhibitory activity on Kaposi’s sarcoma associated herpesvirus (KSHV). Virtual screening of (±)-1 and (±)-2 were conducted using the Surflex-Dock module in the Sybyl software, and (+)-1 exhibited ability to bind with ERK to form key interactions with residues Lys52, Pro56, Ile101, Asp165, Gly167 and Val99.

Novel Natural Products from Extremophilic Fungi.

PubMed

Zhang, Xuan; Li, Shou-Jie; Li, Jin-Jie; Liang, Zi-Zhen; Zhao, Chang-Qi

2018-06-04

Extremophilic fungi have been found to develop unique defences to survive extremes of pressure, temperature, salinity, desiccation, and pH, leading to the biosynthesis of novel natural products with diverse biological activities. The present review focuses on new extremophilic fungal natural products published from 2005 to 2017, highlighting the chemical structures and their biological potential.

Natural Products for Cancer Prevention: Clinical Update 2016.

PubMed

Sanders, Kathleen; Moran, Zelda; Shi, Zaixing; Paul, Rachel; Greenlee, Heather

2016-08-01

To present a clinical update of natural products for cancer prevention and provide oncology nurses with an evidence-based review of natural products for patient counseling and education. Clinical trials published in PubMed. In the past 4 years since the publication of the original review there have been minimal changes in the conclusions of the published literature on the use of natural products for cancer prevention. To date, clinical trials have not demonstrated conclusive benefit of using natural products for cancer prevention, and current guidelines do not recommend their use. This review provides an update on published and ongoing trials and can serve as an updated resource for nurses. Evidence-based natural products databases can help nurses stay current with the scientific literature and be effective educators and health coaches for their patients, who can be influenced by marketing of unregulated products. Patients often discuss the use of natural products with nurses. Nurses have an opportunity to educate and coach patients in effective preventive lifestyle practices. Copyright © 2016 Elsevier Inc. All rights reserved.

[Status of libraries and databases for natural products at abroad].

PubMed

Zhao, Li-Mei; Tan, Ning-Hua

2015-01-01

For natural products are one of the important sources for drug discovery, libraries and databases of natural products are significant for the development and research of natural products. At present, most of compound libraries at abroad are synthetic or combinatorial synthetic molecules, resulting to access natural products difficult; for information of natural products are scattered with different standards, it is difficult to construct convenient, comprehensive and large-scale databases for natural products. This paper reviewed the status of current accessing libraries and databases for natural products at abroad and provided some important information for the development of libraries and database for natural products.

Synthetic Biological Approaches to Natural Product Biosynthesis

PubMed Central

Winter, Jaclyn M; Tang, Yi

2012-01-01

Small molecules produced in Nature continue to be an inspiration for the development of new therapeutic agents. These natural products possess exquisite chemical diversity, which gives rise to their wide range of biological activities. In their host organism, natural products are assembled and modified by dedicated biosynthetic pathways that Nature has meticulously developed. Often times, the complex structures or chemical modifications instated by these pathways are difficult to replicate using traditional synthetic methods. An alternative approach for creating or enhancing the structural variation of natural products is through combinatorial biosynthesis. By rationally reprogramming and manipulating the biosynthetic machinery responsible for their production, unnatural metabolites that were otherwise inaccessible can be obtained. Additionally, new chemical structures can be synthesized or derivatized by developing the enzymes that carry out these complicated chemical reactions into biocatalysts. In this review, we will discuss a variety of combinatorial biosynthetic strategies, their technical challenges, and highlight some recent (since 2007) examples of rationally designed unnatural metabolites, as well as platforms that have been established for the production and modification of clinically important pharmaceutical compounds. PMID:22221832

Anti-proliferative and anti-migration effects of Polish propolis combined with Hypericum perforatum L. on glioblastoma multiforme cell line U87MG.

PubMed

Borawska, Maria H; Naliwajko, Sylwia K; Moskwa, Justyna; Markiewicz-Żukowska, Renata; Puścion-Jakubik, Anna; Soroczyńska, Jolanta

2016-09-20

Propolis and Hypericum perforatum L. are natural products which contain many active compounds and have numerous beneficial effects, including an antitumor effect. Gliobmastoma multiforme (GBM) is a common primary brain tumor with poor prognosis and limited treatment options. In this study, the effect of propolis (EEP) combined with H. perforatum L. (HPE) on glioblastoma cell line U87MG was investigated for the first time. Anti-proliferative activity of EEP, HPE and their combination (EEP + HPE) was determined by a cytotoxicity test, DNA binding by [(3)H]-thymidine incorporation and cell migration assay. Anti-metastatic properties in U87MG treated with EEP, HPE and EEP + HPE were estimated on cells migration test (scratch assay) and metalloproteinases (MMP2 and MMP9) secretion (gelatin zymography). Combination of HPE and EEP extracts was found to have a time- and dose-dependent inhibitory effect on the viability of U87MG cells. This effect was significantly higher (p < 0.05) when compared to these two extracts applied separately, which was confirmed by the significant reduction of DNA synthesis and significantly higher mitochondrial membrane permeabilization. A significant decreasing in migration cells and in pro-MMP9 and pro-MMP2 secretion in U87MG cells were demonstrated after exposure to combination of EEP (30 μg/ml) with HPE (6.25 μg/ml). In this study, the combination of ethanolic extract from propolis and ethanolic extract of fresh-cut H. perforatum L. was proved the ability to reduce invasiveness of glioma cells through the inhibition of MMP2 and MMP9 secretion and suppression of cell migration. It has a more potent anti-proliferative effect on U87MG glioma cell line compared to using propolis and H. perforatum L. separately. Further studies are required to verify whether the examined extracts can activate apoptotic pathways.

Biosynthesis of therapeutic natural products using synthetic biology.

PubMed

Awan, Ali R; Shaw, William M; Ellis, Tom

2016-10-01

Natural products are a group of bioactive structurally diverse chemicals produced by microorganisms and plants. These molecules and their derivatives have contributed to over a third of the therapeutic drugs produced in the last century. However, over the last few decades traditional drug discovery pipelines from natural products have become far less productive and far more expensive. One recent development with promise to combat this trend is the application of synthetic biology to therapeutic natural product biosynthesis. Synthetic biology is a young discipline with roots in systems biology, genetic engineering, and metabolic engineering. In this review, we discuss the use of synthetic biology to engineer improved yields of existing therapeutic natural products. We further describe the use of synthetic biology to combine and express natural product biosynthetic genes in unprecedented ways, and how this holds promise for opening up completely new avenues for drug discovery and production. Copyright © 2016 Elsevier B.V. All rights reserved.

Natural Products for Antithrombosis

PubMed Central

Chen, Cen; Zhang, Qian; Wang, Feng-Qin; Hu, Yuan-Jia; Xia, Zhi-Ning

2015-01-01

Thrombosis is considered to be closely related to several diseases such as atherosclerosis, ischemic heart disease and stroke, as well as rheumatoid arthritis, hyperuricemia, and various inflammatory conditions. More and more studies have been focused on understanding the mechanism of molecular and cellular basis of thrombus formation as well as preventing thrombosis for the treatment of thrombotic diseases. In reality, there is considerable interest in the role of natural products and their bioactive components in the prevention and treatment of thrombosis related disorders. This paper briefly describes the mechanisms of thrombus formation on three aspects, including coagulation system, platelet activation, and aggregation, and change of blood flow conditions. Furthermore, the natural products for antithrombosis by anticoagulation, antiplatelet aggregation, and fibrinolysis were summarized, respectively. PMID:26075003

Strategies for target identification of antimicrobial natural products.

PubMed

Farha, Maya A; Brown, Eric D

2016-05-04

Covering: 2000 to 2015Despite a pervasive decline in natural product research at many pharmaceutical companies over the last two decades, natural products have undeniably been a prolific and unsurpassed source for new lead antibacterial compounds. Due to their inherent complexity, natural extracts face several hurdles in high-throughout discovery programs, including target identification. Target identification and validation is a crucial process for advancing hits through the discovery pipeline, but has remained a major bottleneck. In the case of natural products, extremely low yields and limited compound supply further impede the process. Here, we review the wealth of target identification strategies that have been proposed and implemented for the characterization of novel antibacterials. Traditionally, these have included genomic and biochemical-based approaches, which, in recent years, have been improved with modern-day technology and better honed for natural product discovery. Further, we discuss the more recent innovative approaches for uncovering the target of new antibacterial natural products, which have resulted from modern advances in chemical biology tools. Finally, we present unique screening platforms implemented to streamline the process of target identification. The different innovative methods to respond to the challenge of characterizing the mode of action for antibacterial natural products have cumulatively built useful frameworks that may advocate a renovated interest in natural product drug discovery programs.

Natural products as sources for new pesticides.

PubMed

Cantrell, Charles L; Dayan, Franck E; Duke, Stephen O

2012-06-22

Natural products as pesticides have been reviewed from several perspectives in the past, but no prior treatment has examined the impact of natural product and natural product-based pesticides on the U.S. market, as a function of new active ingredient registrations with the Environmental Protection Agency (EPA). Thus, EPA registration details of new active ingredients for all conventional pesticide registrations and biopesticide registrations were compiled from the years 1997-2010. Conventional pesticide registrations and biopesticide registrations were examined both collectively and independently for all 277 new active ingredients (NAI) and subsequently categorized and sorted into four types: biological (B), natural product (NP), synthetic (S), and synthetic natural derived (SND). When examining conventional pesticides alone, the S category accounted for the majority of NAI registrations, with 78.0%, followed by SND with 14.7%, NP with 6.4%, and B with 0.9%. Biopesticides alone were dominated by NPs with 54.8%, followed by B with 44.6%, SND with 0.6%, and 0% for S. When examining conventional pesticides and biopesticides combined, NPs accounted for the majority of NAI registrations, with 35.7%, followed by S with 30.7%, B with 27.4%, and SND with 6.1%. Despite the common perception that natural products may not be the best sources for NAI as pesticides, when both conventional and biopesticides are examined collectively, and considering that NP, SND, and B all have origins from natural product research, it can be argued that their combined impact with the EPA from 1997 to 2010 accounted for 69.3% of all NAI registrations.

Natural product synthesis at the interface of chemistry and biology

PubMed Central

2014-01-01

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. PMID:25043880

Natural product synthesis at the interface of chemistry and biology.

PubMed

Hong, Jiyong

2014-08-11

Nature has evolved to produce unique and diverse natural products that possess high target affinity and specificity. Natural products have been the richest sources for novel modulators of biomolecular function. Since the chemical synthesis of urea by Wöhler, organic chemists have been intrigued by natural products, leading to the evolution of the field of natural product synthesis over the past two centuries. Natural product synthesis has enabled natural products to play an essential role in drug discovery and chemical biology. With the introduction of novel, innovative concepts and strategies for synthetic efficiency, natural product synthesis in the 21st century is well poised to address the challenges and complexities faced by natural product chemistry and will remain essential to progress in biomedical sciences. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Hypericum perforatum incorporated chitosan films as potential bioactive wound dressing material.

PubMed

Güneş, Seda; Tıhmınlıoğlu, Funda

2017-09-01

Recent studies in wound dressing applications offer new therapies and promote wound healing process. The aim of this study was to develop Hypericum perforatum (St John's Wort) oil incorporated chitosan films for wound dressing applications. H. perforatum oil as a potential therapeutic agent was encapsulated in chitosan film to achieve a better wound dressing material. Oil incorporated chitosan films were successfully prepared by solvent casting method in different oil concentrations (0.25-1.5%v/v). Water vapor permeability (WVP), mechanical test, swelling behavior and surface hydrophobicity were performed in order to characterize the prepared films. Antimicrobial test was performed by disc diffusion method and the growth inhibition effects of the films including different amount of H. perforatum oil were investigated on Escherichia coli and Staphylococcus aureus. WVP increased with oil incorporation and the highest value was obtained for 0.25% oil concentration.The highest strain value was obtained in 0.25% oil content films although tensile stress decreased with increasing oil content. H. perforatum oil incorporated films had antimicrobial effect on both microorganisms. Chitosan based films had no cytotoxic effects on NIH3T3fibroblast cells and provided a good surface for cell attachment and proliferation. The results showed that the H. perforatum incorporated chitosan films seems to be a potential and novel biomaterial for wound healing applications. Copyright © 2017 Elsevier B.V. All rights reserved.

Effect of Hypericum perforatum on different models of movement disorders in rats.

PubMed

Reis, Elizete M; Röpke, Jivago; Busanello, Alcindo; Reckziegel, Patrícia; Leal, Caroline Q; Wagner, Caroline; Boligon, Aline A; Athayde, Margareth L; Fachinetto, Roselei

2013-10-01

The effects of Hypericum perforatum, a plant with antidepressant action, were evaluated in models of abnormal movements in rats, brought about by administration of fluphenazine or reserpine. The number of vacuous chewing movements (VCMs) and locomotor activity (the number of crossings and rears in the open field test) were measured. In experiment 1, rats received a single administration of fluphenazine enanthate (25 mg/kg, intramuscular) and/or daily treatment with H. perforatum (300 mg/kg, in place of drinking water) for 7 days. Fluphenazine increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the locomotor activity. In experiment 2, rats received reserpine every 2 days for 6 days (0.5 mg/kg, subcutaneous) and/or H. perforatum (300 mg/kg, in place of drinking water) daily for 16 days beginning 10 days before the first administration of reserpine. Reserpine treatment increased VCMs and decreased locomotor activity. H. perforatum had no effect on either the number of VCMs or the number of rears but did prevent the effect of reserpine on the number of crossings. In conclusion, H. perforatum failed to protect against orofacial movements induced by fluphenazine or reserpine in rats.

Hypericum perforatum L. treatment restored bone mass changes in swimming stressed rats.

PubMed

Seferos, Nikos; Petrokokkinos, Loukas; Kotsiou, Antonia; Rallis, George; Tesseromatis, Christine

2016-01-01

Stress, via corticosteroids release, influences bone mass density. Hypericum perforatum (Hp) a traditional remedy possess antidepressive activity (serotonin reuptake inhibitor) and wound healing properties. Hp preparation contains mainly hypericin, hyperforin, hyperoside and flavonoids exerting oestrogen-mimetic effect. Cold swimming represents an experimental model of stress associating mental strain and corporal exhaustion. This study investigates the Hp effect on femur and mandible bone mass changes in rats under cold forced swimming procedure. 30 male Wistar rats were randomized into three groups. Group A was treated with Methanolic extract of Hp (Jarsin®) via gastroesophageal catheter, and was submitted to cold swimming stress for 10 min/daily. Group B was submitted to cold stress, since group C served as control. Experiment duration was 10 days. Haematocrite and serum free fatty acids (FFA) were estimated. Furthermore volume and specific weight of each bone as well as bone mass density via dual energy X-Ray absorptiometry (DEXA) were measured. Statistic analysis by t-test. Hp treatment restores the stress injuries. Adrenals and bone mass density regain their normal values. Injuries occurring by forced swimming stress in the rats are significantly improved by Hp treatment. Estrogen-like effects of Hp flavonoids eventually may act favorable in bone remodeling.

How EIA Estimates Natural Gas Production

EIA Publications

2004-01-01

The Energy Information Administration (EIA) publishes estimates monthly and annually of the production of natural gas in the United States. The estimates are based on data EIA collects from gas producing states and data collected by the U. S. Minerals Management Service (MMS) in the Department of Interior. The states and MMS collect this information from producers of natural gas for various reasons, most often for revenue purposes. Because the information is not sufficiently complete or timely for inclusion in EIA's Natural Gas Monthly (NGM), EIA has developed estimation methodologies to generate monthly production estimates that are described in this document.

The neurocognitive effects of Hypericum perforatum Special Extract (Ze 117) during smoking cessation.

PubMed

Camfield, D A; Scholey, A B; Pipingas, A; Silberstein, R B; Kure, C; Zangara, A; Kras, M; Stough, C

2013-11-01

The efficacy and tolerability of current treatments for smoking cessation are relatively poor. More research is required to address the biological mechanisms underpinning nicotine withdrawal and drug treatments for smoking cessation. We assessed the neurocognitive effects of Remotiv® (Hypericum perforatum Special Extract - Ze 117), Nicabate CQ Nicotine Replacement therapy (NRT) and combined NRT/HP during conditions of smoking abstinence in 20 regular smokers aged between 18 and 60 years over a period of 10 weeks during smoking cessation. A Spatial Working Memory (SWM) task was completed at baseline, 4 weeks prior to quitting, as well as at the completion of the study, following the 10 weeks of treatment. Brain activity was recorded during the completion of the SWM task using Steady-State Probe Topography. Reaction time and accuracy on the SWM task were not found to be significantly different between treatment groups at retest. Differences in SSVEP treatment profiles at retest are discussed, including stronger SSVEP Amplitude increase in posterior-parietal regions for the HP and NRT groups and greater fronto-central SSVEP Phase Advance in the HP group. Copyright © 2012 John Wiley & Sons, Ltd.

A new chromanone derivative isolated from Hypericum lissophloeus (Hypericaceae) potentiates GABAA receptor currents in a subunit specific fashion.

PubMed

Crockett, Sara; Baur, Roland; Kunert, Olaf; Belaj, Ferdinand; Sigel, Erwin

2016-02-15

A phytochemical investigation of the lipophilic extract of Hypericum lissophloeus (smoothbark St. John's wort, Hypericaceae) was conducted, resulting in the isolation and identification of a new chromanone derivative: 5,7-dihydroxy-2,3-dimethyl-6-(3-methyl-but-2-enyl)-chroman-4-one (1). This compound was demonstrated to act as a potent stimulator of currents elicited by GABA in recombinant α1β2γ2 GABAA receptors, with a half-maximal potentiation observed at a concentration of about 4μM and a maximal potentiation of >4000%. Significant potentiation was already evident at a concentration as low as 0.1μM. Extent of potentiation strongly depends on the type of α subunit, the type of β subunit and the presence of the γ subunit. Copyright © 2016 Elsevier Ltd. All rights reserved.

Natural products and the athlete: facts and folklore.

PubMed

Barron, R L; Vanscoy, G J

1993-05-01

To contrast scientific facts with suggested manufacturers' claims regarding food supplements (natural products) marketed for enhanced athletic prowess. A MEDLINE search was performed to obtain documentation supporting the claims of natural-product manufacturers. In addition, several references pertaining to pharmacognosy, natural products, herbs, pharmacy practice, and sports medicine were reviewed. Claims were obtained from promotional advertisements in bodybuilding magazines, product labels, and fact sheets for sales representatives in nutrition and health-food stores. We reviewed all of the clinical trials, published between 1966 and 1992, relative to the manufacturers' claims regarding these products. Pertinent human and/or animal studies supporting each natural product were compared with the manufacturers' claims. We found that there was no published scientific evidence to support the promotional claims for a large proportion of the products (8/19, 42 percent). Only 4 of 19 products (21 percent) were associated with any documented human clinical trials supporting their promotional claims. Six of 19 agents (32 percent) had some scientific documentation to support their promotional claims; however, these products were judged to be marketed in a misleading manner.

Bioengineering natural product biosynthetic pathways for therapeutic applications.

PubMed

Wu, Ming-Cheng; Law, Brian; Wilkinson, Barrie; Micklefield, Jason

2012-12-01

With the advent of next-generation DNA sequencing technologies, the number of microbial genome sequences has increased dramatically, revealing a vast array of new biosynthetic gene clusters. Genomics data provide a tremendous opportunity to discover new natural products, and also to guide the bioengineering of new and existing natural product scaffolds for therapeutic applications. Notably, it is apparent that the vast majority of biosynthetic gene clusters are either silent or produce very low quantities of the corresponding natural products. It is imperative therefore to devise methods for activating unproductive biosynthetic pathways to provide the quantities of natural products needed for further development. Moreover, on the basis of our expanding mechanistic and structural knowledge of biosynthetic assembly-line enzymes, new strategies for re-programming biosynthetic pathways have emerged, resulting in focused libraries of modified products with potentially improved biological properties. In this review we will focus on the latest bioengineering approaches that have been utilised to optimise yields and increase the structural diversity of natural product scaffolds for future clinical applications. Copyright © 2012 Elsevier Ltd. All rights reserved.

Editorial for Special Issue on Herbal Medicines and Natural Products.

PubMed

Zhou, Zhi-Wei; Zhou, Shu-Feng

2015-11-16

Herbal medicines and natural products have been the most productive source of drug development and there is a large line of evidence on the applications of herbal medicines and natural products for the management of body function and the treatment of aliments. The multiple bioactive components in herbal medicines and natural products can explain the multiple targets effect in their medical applications. The increasing usage of state-of-art computational, molecular biological, and analytical chemistry techniques will promote the exploration of the pharmacological effect of previously inaccessible sources of herbal medicines and natural products. Notably, with the increasing reports on the safety issues regarding the medical use of herbal medicines and natural products, the awareness of pharmacovigilance in herbal medicines and natural products needs to be strengthened. To prevent the adverse drug reactions related to herbal medicines and natural products, physicians need to be aware of potential risks and alert patients in the use of herbal medicines and natural products.

Protein Engineering Towards Natural Product Synthesis and Diversification

PubMed Central

Zabala, Angelica O.; Cacho, Ralph A.; Tang, Yi

2014-01-01

A dazzling array of enzymes is used by nature in making structurally complex natural products. These enzymes constitute a molecular toolbox that may be used in the construction and fine-tuning of pharmaceutically active molecules. Aided by technological advancements in protein engineering, it is now possible to tailor the activities and specificities of these enzymes as biocatalysts in the production of both natural products and their unnatural derivatives. These efforts are crucial in drug discovery and development, where there is a continuous quest for more potent agents. Both rational and random evolution techniques have been utilized in engineering these enzymes. This review will highlight some examples from several large families of natural products. PMID:22006344

Bacterial symbionts and natural products

PubMed Central

Crawford, Jason M.; Clardy, Jon

2011-01-01

The study of bacterial symbionts of eukaryotic hosts has become a powerful discovery engine for chemistry. This highlight looks at four case studies that exemplify the range of chemistry and biology involved in these symbioses: a bacterial symbiont of a fungus and a marine invertebrate that produce compounds with significant anticancer activity, and bacterial symbionts of insects and nematodes that produce compounds that regulate multilateral symbioses. In the last ten years, a series of shocking revelations – the molecular equivalents of a reality TV show’s uncovering the true parents of a well known individual or a deeply hidden family secret – altered the study of genetically encoded small molecules, natural products for short. These revelations all involved natural products produced by bacterial symbionts, and while details differed, two main plot lines emerged: parentage, in which the real producers of well known natural products with medical potential were not the organisms from which they were originally discovered, and hidden relationships, in which bacterially produced small molecules turned out to be the unsuspected regulators of complex interactions. For chemists, these studies led to new molecules, new biosynthetic pathways, and an understanding of the biological functions these molecules fulfill. PMID:21594283

Natural product discovery: past, present, and future.

PubMed

Katz, Leonard; Baltz, Richard H

2016-03-01

Microorganisms have provided abundant sources of natural products which have been developed as commercial products for human medicine, animal health, and plant crop protection. In the early years of natural product discovery from microorganisms (The Golden Age), new antibiotics were found with relative ease from low-throughput fermentation and whole cell screening methods. Later, molecular genetic and medicinal chemistry approaches were applied to modify and improve the activities of important chemical scaffolds, and more sophisticated screening methods were directed at target disease states. In the 1990s, the pharmaceutical industry moved to high-throughput screening of synthetic chemical libraries against many potential therapeutic targets, including new targets identified from the human genome sequencing project, largely to the exclusion of natural products, and discovery rates dropped dramatically. Nonetheless, natural products continued to provide key scaffolds for drug development. In the current millennium, it was discovered from genome sequencing that microbes with large genomes have the capacity to produce about ten times as many secondary metabolites as was previously recognized. Indeed, the most gifted actinomycetes have the capacity to produce around 30-50 secondary metabolites. With the precipitous drop in cost for genome sequencing, it is now feasible to sequence thousands of actinomycete genomes to identify the "biosynthetic dark matter" as sources for the discovery of new and novel secondary metabolites. Advances in bioinformatics, mass spectrometry, proteomics, transcriptomics, metabolomics and gene expression are driving the new field of microbial genome mining for applications in natural product discovery and development.

Forest Products Laboratory natural finish

Treesearch

J. M. Black; D. F. Laughnan; E. A. Mraz

1979-01-01

A simple and durable exterior natural finish developed at the Forest Products Laboratory is described. The finish is classified as a semi-transparent oil-base penetrating stain that effectively retains much of the natural grain and texture of wood when exposed to the weather. The directions for preparation are included as are the recommendations for application to both...

Natural Products in the Discovery of Agrochemicals.

PubMed

Loiseleur, Olivier

2017-12-01

Natural products have a long history of being used as, or serving as inspiration for, novel crop protection agents. Many of the discoveries in agrochemical research in the last decades have their origin in a wide range of natural products from a variety of sources. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, new agricultural practices and evolving regulatory requirements, the needs for new agrochemical tools remains as critical as ever. In that respect, nature continues to be an important source for novel chemical structures and biological mechanisms to be applied for the development of pest control agents. Here we review several of the natural products and their derivatives which contributed to shape crop protection research in past and present.

Natural products from filamentous fungi and production by heterologous expression.

PubMed

Alberti, Fabrizio; Foster, Gary D; Bailey, Andy M

2017-01-01

Filamentous fungi represent an incredibly rich and rather overlooked reservoir of natural products, which often show potent bioactivity and find applications in different fields. Increasing the naturally low yields of bioactive metabolites within their host producers can be problematic, and yield improvement is further hampered by such fungi often being genetic intractable or having demanding culturing conditions. Additionally, total synthesis does not always represent a cost-effective approach for producing bioactive fungal-inspired metabolites, especially when pursuing assembly of compounds with complex chemistry. This review aims at providing insights into heterologous production of secondary metabolites from filamentous fungi, which has been established as a potent system for the biosynthesis of bioactive compounds. Numerous advantages are associated with this technique, such as the availability of tools that allow enhanced production yields and directing biosynthesis towards analogues of the naturally occurring metabolite. Furthermore, a choice of hosts is available for heterologous expression, going from model unicellular organisms to well-characterised filamentous fungi, which has also been shown to allow the study of biosynthesis of complex secondary metabolites. Looking to the future, fungi are likely to continue to play a substantial role as sources of new pharmaceuticals and agrochemicals-either as producers of novel natural products or indeed as platforms to generate new compounds through synthetic biology.

Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product-based combinatorial libraries.

PubMed

Lee, M L; Schneider, G

2001-01-01

Natural products were analyzed to determine whether they contain appealing novel scaffold architectures for potential use in combinatorial chemistry. Ring systems were extracted and clustered on the basis of structural similarity. Several such potential scaffolds for combinatorial chemistry were identified that are not present in current trade drugs. For one of these scaffolds a virtual combinatorial library was generated. Pharmacophoric properties of natural products, trade drugs, and the virtual combinatorial library were assessed using a self-organizing map. Obviously, current trade drugs and natural products have several topological pharmacophore patterns in common. These features can be systematically explored with selected combinatorial libraries based on a combination of natural product-derived and synthetic molecular building blocks.

Natural product-based nanomedicine: recent advances and issues

PubMed Central

Watkins, Rebekah; Wu, Ling; Zhang, Chenming; Davis, Richey M; Xu, Bin

2015-01-01

Natural products have been used in medicine for many years. Many top-selling pharmaceuticals are natural compounds or their derivatives. These plant- or microorganism-derived compounds have shown potential as therapeutic agents against cancer, microbial infection, inflammation, and other disease conditions. However, their success in clinical trials has been less impressive, partly due to the compounds’ low bioavailability. The incorporation of nanoparticles into a delivery system for natural products would be a major advance in the efforts to increase their therapeutic effects. Recently, advances have been made showing that nanoparticles can significantly increase the bioavailability of natural products both in vitro and in vivo. Nanotechnology has demonstrated its capability to manipulate particles in order to target specific areas of the body and control the release of drugs. Although there are many benefits to applying nanotechnology for better delivery of natural products, it is not without issues. Drug targeting remains a challenge and potential nanoparticle toxicity needs to be further investigated, especially if these systems are to be used to treat chronic human diseases. This review aims to summarize recent progress in several key areas relevant to natural products in nanoparticle delivery systems for biomedical applications. PMID:26451111

Natural product mode of action (MOA) studies: a link between natural and synthetic worlds.

PubMed

La Clair, James J

2010-07-01

In our understanding of matter, natural products deliver plots that would stun even the best productions of the legendary filmmaker, Sergio Leone. While every decade heralds a new genre of film (as well as avenues of small-molecule discovery), natural products and their "untamed prehistoric" plots continue to dazzle the fields of biotechnology, drug discovery, fragrances, food additives and agrochemistry. This review provides an abridged synopsis of the modes of natural product action discovered within the last decade and the tools and methods used in their discovery. Their stories are united in a common theme that unveils one of the more vital aspects of chemical biological research:understanding the global activity of Nature's arsenal of secondary metabolites.

Marinopyrroles: Unique Drug Discoveries Based on Marine Natural Products.

PubMed

Li, Rongshi

2016-01-01

Natural products provide a successful supply of new chemical entities (NCEs) for drug discovery to treat human diseases. Approximately half of the NCEs are based on natural products and their derivatives. Notably, marine natural products, a largely untapped resource, have contributed to drug discovery and development with eight drugs or cosmeceuticals approved by the U.S. Food and Drug Administration and European Medicines Agency, and ten candidates undergoing clinical trials. Collaborative efforts from drug developers, biologists, organic, medicinal, and natural product chemists have elevated drug discoveries to new levels. These efforts are expected to continue to improve the efficiency of natural product-based drugs. Marinopyrroles are examined here as a case study for potential anticancer and antibiotic agents. © 2015 Wiley Periodicals, Inc.

Natural Products from Mangrove Actinomycetes

PubMed Central

Xu, Dong-Bo; Ye, Wan-Wan; Han, Ying; Deng, Zi-Xin; Hong, Kui

2014-01-01

Mangroves are woody plants located in tropical and subtropical intertidal coastal regions. The mangrove ecosystem is becoming a hot spot for natural product discovery and bioactivity survey. Diverse mangrove actinomycetes as promising and productive sources are worth being explored and uncovered. At the time of writing, we report 73 novel compounds and 49 known compounds isolated from mangrove actinomycetes including alkaloids, benzene derivatives, cyclopentenone derivatives, dilactones, macrolides, 2-pyranones and sesquiterpenes. Attractive structures such as salinosporamides, xiamycins and novel indolocarbazoles are highlighted. Many exciting compounds have been proven as potential new antibiotics, antitumor and antiviral agents, anti-fibrotic agents and antioxidants. Furthermore, some of their biosynthetic pathways have also been revealed. This review is an attempt to consolidate and summarize the past and the latest studies on mangrove actinomycetes natural product discovery and to draw attention to their immense potential as novel and bioactive compounds for marine drugs discovery. PMID:24798926

Natural products from the genus tephrosia.

PubMed

Chen, Yinning; Yan, Tao; Gao, Chenghai; Cao, Wenhao; Huang, Riming

2014-01-27

The genus Tephrosia, belonging to the Leguminosae family, is a large pantropical genus of more than 350 species, many of which have important traditional uses in agriculture. This review not only outlines the source, chemistry and biological evaluations of natural products from the genus Tephrosia worldwide that have appeared in literature from 1910 to December 2013, but also covers work related to proposed biosynthetic pathways and synthesis of some natural products from the genus Tephrosia, with 105 citations and 168 new compounds.

Antibiotics: natural products essential to human health.

PubMed

Demain, Arnold L

2009-11-01

For more than 50 years, natural products have served us well in combating infectious bacteria and fungi. Microbial and plant secondary metabolites helped to double our life span during the 20th century, reduced pain and suffering, and revolutionized medicine. Most antibiotics are either (i) natural products of microorganisms, (ii) semi-synthetically produced from natural products, or (iii) chemically synthesized based on the structure of the natural products. Production of antibiotics began with penicillin in the late 1940s and proceeded with great success until the 1970-1980s when it became harder and harder to discover new and useful products. Furthermore, resistance development in pathogens became a major problem, which is still with us today. In addition, new pathogens are continually emerging and there are still bacteria that are not eliminated by any antibiotic, e.g., Pseudomonas aeruginosa. In addition to these problems, many of the major pharmaceutical companies have abandoned the antibiotic field, leaving much of the discovery efforts to small companies, new companies, and the biotechnology industries. Despite these problems, development of new antibiotics has continued, albeit at a much lower pace than in the last century. We have seen the (i) appearance of newly discovered antibiotics (e.g., candins), (ii) development of old but unutilized antibiotics (e.g., daptomycin), (iii) production of new semi-synthetic versions of old antibiotics (e.g., glycylcyclines, streptogrammins), as well as the (iv) very useful application of old but underutilized antibiotics (e.g., teicoplanin).

Methodological aspects of biologically active compounds quantification in the genus Hypericum.

PubMed

Dresler, Sławomir; Kováčik, Jozef; Strzemski, Maciej; Sowa, Ireneusz; Wójciak-Kosior, Magdalena

2018-06-05

Accumulation of selected secondary metabolites in two Hypericum species (H. perforatum and H. annulatum) was compared in their vegetative parts (stems and leaves) and in terms of the extraction solvent (80% aq. methanol or 60% aq. ethanol). The presence of chlorogenic acid and quercitrin was not detected in stem of both species. Almost all metabolites were more accumulated in the leaves than in the stems (rutin, hyperoside, quercetin and hypericin) but epicatechin showed the opposite in both species and hyperforin in H. annulatum. Extraction solvents showed rather species-specific differences with EtOH being more suitable for the extraction of hypericin, quercetin, quercitrin, and hyperoside (on average, for both the leaves and stems, extraction increased by approximately 130, 30, 25, and 15%, respectively) while MeOH for the extraction of epicatechin, rutin, and hyperforin (increased extraction by approximately 50, 40, and 35%, respectively). On the other hand, content of total soluble phenols did not differ in relation to solvent in any organ or species. Various ages of H. annulatum plants did not show dramatic impact on the amount of metabolites. Subsequently, the usefulness of capillary electrophoresis (CE) as an alternative to HPLC for the quantification of metabolites in H. perforatum was tested and results showed non-significant differences between CE and HPLC with the methods we developed (the difference did not exceed 10%). Copyright © 2018 Elsevier B.V. All rights reserved.

Natural Products Version 2.0: Connecting Genes to Molecules

PubMed Central

Walsh, Christopher T.; Fischbach, Michael A.

2009-01-01

Natural products have played a prominent role in the history of organic chemistry, and they continue to be important as drugs, biological probes, and targets of study for synthetic and analytical chemists. In this perspective, we explore how connecting Nature’s small molecules to the genes that encode them has sparked a renaissance in natural product research, focusing primarily on the biosynthesis of polyketides and nonribosomal peptides. We survey monomer biogenesis, coupling chemistries from templated and non-templated pathways, and the broad set of tailoring reactions and hybrid pathways that give rise to the diverse scaffolds and functionalization patterns of natural products. We conclude by considering two questions: What would it take to find all natural product scaffolds? What kind of scientists will be studying natural products in the future? PMID:20121095

Fungi as a source of natural coumarins production.

PubMed

Costa, Tania Maria; Tavares, Lorena Benathar Ballod; de Oliveira, Débora

2016-08-01

Natural coumarins and derivatives are compounds that occur naturally in several organisms (plant, bacteria, and fungi) consisting of fused benzene and α-pyrone rings. These compounds show high technological potential applications in agrochemical, food, pharmaceuticals, and cosmetics industries. Therefore, the need for bulk production of coumarins and the advancement of the chemical and pharmaceutical industries led to the development of synthetic coumarin. However, biotransformation process, synthetic bioengineering, metabolic engineering, and bioinformatics have proven effective in the production of natural products. Today, these biological systems are recognized as green chemistry innovation and business strategy. This review article aims to report the potential of fungi for synthesis of coumarin. These microorganisms are described as a source of natural products capable of synthesizing many bioactive metabolites. The features, classification, properties, and industrial applications of natural coumarins as well as new molecules obtained by basidiomycetes and ascomycetes fungi are reported in order to explore a topic not yet discussed in the scientific literature.

Direct Capture Technologies for Genomics-Guided Discovery of Natural Products.

PubMed

Chan, Andrew N; Santa Maria, Kevin C; Li, Bo

2016-01-01

Microbes are important producers of natural products, which have played key roles in understanding biology and treating disease. However, the full potential of microbes to produce natural products has yet to be realized; the overwhelming majority of natural product gene clusters encoded in microbial genomes remain "cryptic", and have not been expressed or characterized. In contrast to the fast-growing number of genomic sequences and bioinformatic tools, methods to connect these genes to natural product molecules are still limited, creating a bottleneck in genome-mining efforts to discover novel natural products. Here we review developing technologies that leverage the power of homologous recombination to directly capture natural product gene clusters and express them in model hosts for isolation and structural characterization. Although direct capture is still in its early stages of development, it has been successfully utilized in several different classes of natural products. These early successes will be reviewed, and the methods will be compared and contrasted with existing traditional technologies. Lastly, we will discuss the opportunities for the development of direct capture in other organisms, and possibilities to integrate direct capture with emerging genome-editing techniques to accelerate future study of natural products.

Hypericum perforatum: pharmacokinetic, mechanism of action, tolerability, and clinical drug-drug interactions.

PubMed

Russo, Emilio; Scicchitano, Francesca; Whalley, Benjamin J; Mazzitello, Carmela; Ciriaco, Miriam; Esposito, Stefania; Patanè, Marinella; Upton, Roy; Pugliese, Michela; Chimirri, Serafina; Mammì, Maria; Palleria, Caterina; De Sarro, Giovambattista

2014-05-01

Hypericum perforatum (HP) belongs to the Hypericaceae family and is one of the oldest used and most extensively investigated medicinal herbs. The medicinal form comprises the leaves and flowering tops of which the primary ingredients of interest are naphthodianthrones, xanthones, flavonoids, phloroglucinols (e.g. hyperforin), and hypericin. Although several constituents elicit pharmacological effects that are consistent with HP's antidepressant activity, no single mechanism of action underlying these effects has thus far been found. Various clinical trials have shown that HP has a comparable antidepressant efficacy as some currently used antidepressant drugs in the treatment of mild/moderate depression. Interestingly, low-hyperforin-content preparations are effective in the treatment of depression. Moreover, HP is also used to treat certain forms of anxiety. However, HP can induce various cytochrome P450s isozymes and/or P-glycoprotein, of which many drugs are substrates and which are the main origin of HP-drug interactions. Here, we analyse the existing evidence describing the clinical consequence of HP-drug interactions. Although some of the reported interactions are based on findings from in vitro studies, the clinical importance of which remain to be demonstrated, others are based on case reports where causality can, in some cases, be determined to reveal clinically significant interactions that suggest caution, consideration, and disclosure of potential interactions prior to informed use of HP. Copyright © 2013 John Wiley & Sons, Ltd.

Bioactive activities of natural products against herpesvirus infection.

PubMed

Son, Myoungki; Lee, Minjung; Sung, Gi-Ho; Lee, Taeho; Shin, Yu Su; Cho, Hyosun; Lieberman, Paul M; Kang, Hyojeung

2013-10-01

More than 90% of adults have been infected with at least one human herpesvirus, which establish long-term latent infection for the life of the host. While anti-viral drugs exist that limit herpesvirus replication, many of these are ineffective against latent infection. Moreover, drug-resistant strains of herpesvirus emerge following chemotherapeutic treatment. For example, resistance to acyclovir and related nucleoside analogues can occur when mutations arise in either HSV thymidine kinase or DNA polymerases. Thus, there exists an unmet medical need to develop new anti-herpesvirus agents with different mechanisms of action. In this Review, we discuss the promise of anti-herpetic substances derived from natural products including extracts and pure compounds from potential herbal medicines. One example is Glycyrrhizic acid isolated from licorice that shows promising antiviral activity towards human gammaherpesviruses. Secondly, we discuss anti-herpetic mechanisms utilized by several natural products in molecular level. While nucleoside analogues inhibit replicating herpesviruses in lytic replication, some natural products can disrupt the herpesvirus latent infection in the host cell. In addition, natural products can stimulate immune responses against herpesviral infection. These findings suggest that natural products could be one of the best choices for development of new treatments for latent herpesvirus infection, and may provide synergistic anti-viral activity when supplemented with nucleoside analogues. Therefore, it is important to identify which natural products are more efficacious anti-herpetic agents, and to understand the molecular mechanism in detail for further advance in the anti-viral therapies.

Rediscovering natural products as a source of new drugs.

PubMed

Koehn, Frank E; Carter, Guy T

2005-04-01

Extract: Since the very beginnings of human medicine, physicians have relied on chemical compounds produced by animals, plants and microorganisms, so-called natural products, to treat diseases. Natural products are directly or indirectly responsible for roughly one-half of all drugs currently in use. Of the 877 small-molecule new drug molecules introduced between 1981 and 2002, 49% were natural products or natural product analogs. Despite the great success of the 70s and 80s, the pharmaceutical industry de-emphasized natural products research during the following decade. In this article, we examine the underlying reasons for the decline, and assess future prospects for natural products research in drug discovery. In the 1990s, major pharmaceutical companies moved to a lead-finding strategy based on High Throughput Screening (HTS) of very large collections (libraries) of synthetic compounds. The move arose from the belief that techniques such as combinatorial chemistry could produce larger, more cost-effective libraries with improved hit rates and quality. Additionally, advances in molecular biology, cellular biology and genomics dramatically increased the number of molecular targets, prompting shorter drug discovery timelines. In today's drug discovery environment, rapid screening and identification of potential drug molecules is essential for success. This puts traditional natural products-based programs, with their reliance on the lengthy processes of the screening of extracts library, bioassay-guided isolation of the active components, structure elucidation and subsequent production scale-up, at a competitive disadvantage.

Plants as natural antioxidants for meat products

NASA Astrophysics Data System (ADS)

Tomović, V.; Jokanović, M.; Šojić, B.; Škaljac, S.; Ivić, M.

2017-09-01

The meat industry is demanding antioxidants from natural sources to replace synthetic antioxidants because of the negative health consequences or beliefs regarding some synthetic ones. Plants materials provide good alternatives. Spices and herbs, generally used for their flavouring characteristics, can be added to meat products in various forms: whole, ground, or as isolates from their extracts. These natural antioxidants contain some active compounds, which exert antioxidative potential in meat products. This antioxidant activity is most often due to phenolic acids, phenolic diterpenes, flavonoids and volatile oils. Each of these compounds often has strong H-donating activity, thus making them extremely effective antioxidants; some compounds can chelate metals and donate H to oxygen radicals, thus slowing oxidation via two mechanisms. Numerous studies have demonstrated the efficacy of natural antioxidants when used in meat products. Based on this literature review, it can be concluded that natural antioxidants are added to fresh and processed meat and meat products to delay, retard, or prevent lipid oxidation, retard development of off-flavours (rancidity), improve colour stability, improve microbiological quality and extend shelf-life, without any damage to the sensory or nutritional properties.

Environmental Impact of Natural Gas Hydrate Production

NASA Astrophysics Data System (ADS)

Max, M. D.; Johnson, A. H.

2017-12-01

Unmet conventional energy demand is encouraging a number of deep energy importing nations closer to production of their potentially very large Natural Gas Hydrate (NGH) resources. As methane and other natural gases are potent greenhouse gases, concerns exist about the possible environmental risks associated NGH development. Accidental of natural gas would have environmental consequences. However, the special characteristics of NGH and production models indicate a very low environmental risk from the reservoir to the deepwater wellhead that is much lower than for conventional deepwater gas. NGH is naturally stable in its solid form in the reservoir and shutting in the gas can be achieved by stopping NGH conversion and gas production in the reservoir. Rapid shut down results in re-crystallization of gas and stabilization of the reservoir through NGH reformation. In addition, new options for innovative technologies have the potential to allow safe development of NGH at a fraction of the current estimated cost. Gas produced from NGH is about the same as processed conventional gas, although almost certainly more pure. Leakage of gas during transport is not a production issue. Gas transport leakage is a matter for best practices regulation that is rigorously enforced.

Data Resources for the Computer-Guided Discovery of Bioactive Natural Products.

PubMed

Chen, Ya; de Bruyn Kops, Christina; Kirchmair, Johannes

2017-09-25

Natural products from plants, animals, marine life, fungi, bacteria, and other organisms are an important resource for modern drug discovery. Their biological relevance and structural diversity make natural products good starting points for drug design. Natural product-based drug discovery can benefit greatly from computational approaches, which are a valuable precursor or supplementary method to in vitro testing. We present an overview of 25 virtual and 31 physical natural product libraries that are useful for applications in cheminformatics, in particular virtual screening. The overview includes detailed information about each library, the extent of its structural information, and the overlap between different sources of natural products. In terms of chemical structures, there is a large overlap between freely available and commercial virtual natural product libraries. Of particular interest for drug discovery is that at least ten percent of known natural products are readily purchasable and many more natural products and derivatives are available through on-demand sourcing, extraction and synthesis services. Many of the readily purchasable natural products are of small size and hence of relevance to fragment-based drug discovery. There are also an increasing number of macrocyclic natural products and derivatives becoming available for screening.

Discovery of Repellents from Natural Products

USDA-ARS?s Scientific Manuscript database

Natural products are an ideal source of chemicals for topical application to human skin, and can be a means of personal protection from the bites of mosquitoes and other arthropods. This report covers a diverse array of natural compounds, and includes descriptions of observed correlations between ch...

Natural products in modern life science.

PubMed

Bohlin, Lars; Göransson, Ulf; Alsmark, Cecilia; Wedén, Christina; Backlund, Anders

2010-06-01

With a realistic threat against biodiversity in rain forests and in the sea, a sustainable use of natural products is becoming more and more important. Basic research directed against different organisms in Nature could reveal unexpected insights into fundamental biological mechanisms but also new pharmaceutical or biotechnological possibilities of more immediate use. Many different strategies have been used prospecting the biodiversity of Earth in the search for novel structure-activity relationships, which has resulted in important discoveries in drug development. However, we believe that the development of multidisciplinary incentives will be necessary for a future successful exploration of Nature. With this aim, one way would be a modernization and renewal of a venerable proven interdisciplinary science, Pharmacognosy, which represents an integrated way of studying biological systems. This has been demonstrated based on an explanatory model where the different parts of the model are explained by our ongoing research. Anti-inflammatory natural products have been discovered based on ethnopharmacological observations, marine sponges in cold water have resulted in substances with ecological impact, combinatory strategy of ecology and chemistry has revealed new insights into the biodiversity of fungi, in depth studies of cyclic peptides (cyclotides) has created new possibilities for engineering of bioactive peptides, development of new strategies using phylogeny and chemography has resulted in new possibilities for navigating chemical and biological space, and using bioinformatic tools for understanding of lateral gene transfer could provide potential drug targets. A multidisciplinary subject like Pharmacognosy, one of several scientific disciplines bridging biology and chemistry with medicine, has a strategic position for studies of complex scientific questions based on observations in Nature. Furthermore, natural product research based on intriguing scientific

Impact of natural products in modern drug development.

PubMed

Dev, Sukh

2010-03-01

Usage of natural substances as therapeutic agents in modern medicine has sharply declined from the predominant position held in the early decades of last century, but search for bioactive molecules from nature (plants, animals, microflora) continues to play an important role in fashioning new medicinal agents. With the advent of modern techniques, instrumentation and automation in isolation and structural characterisation, we have on hand an enormous repository of natural compounds. In parallel to this, biology has also made tremendous progress in expanding its frontiers of knowledge. An interplay of these two disciplines constitutes the modern thrust in research in the realm of compounds elaborated by nature. The purpose of this article is to underline how natural products research continues to make significant contributions in the domain of discovery and development of new medicinal products. It is proposed to present the material under several heads, each of which has made natural products research relevant in the search for new and better medication.

Hypericum perforatum: a 'modern' herbal antidepressant: pharmacokinetics of active ingredients.

PubMed

Wurglics, Mario; Schubert-Zsilavecz, Manfred

2006-01-01

Hypericum perforatum (St John's Wort [SJW]) counts among the most favourite herbal drugs, and is the only herbal alternative to classic synthetic antidepressants in the therapy of mild to moderate depression. Several clinical studies have been conducted to verify the effectiveness of ethanolic or methanolic extracts of SJW. Alcoholic SJW extracts are a mixture of substances with widely varying physical and chemical properties and activities. Hyperforin, a phloroglucinol derivative, is the main source of pharmacological effects caused by the consumption of alcoholic extracts of SJW in the therapy of depression. However, several studies indicate that flavone derivatives, e.g. rutin, and also the naphthodianthrones hypericin and pseudohypericin, take part in the antidepressant efficacy. In contrast to the amount of documentation concerning clinical efficacy, oral bioavailability and pharmacokinetic data about the active components are rather scarce. The hyperforin plasma concentration in humans was investigated in a small number of studies. The results of these studies indicate a relevant plasma concentration, comparable with that used in in vitro tests. Furthermore, hyperforin is the only ingredient of H. perforatum that could be determined in the brain of rodents after oral administration of alcoholic extracts. The plasma concentrations of the hypericins were, compared with hyperforin, only one-tenth and, until now, the hypericins could not be found in the brain after oral administration of alcoholic H. perforatum extracts or pure hypericin. Until now, the pharmacokinetic profile of the flavonoids in humans after oral administration of an alcoholic H. perforatum extract has been investigated in only one study. More data are available for rutin and the aglycone quercetin after administration of pure substances or other flavonoid sources.

Collective synthesis of natural products by means of organocascade catalysis

PubMed Central

Jones, Spencer B.; Simmons, Bryon; Mastracchio, Anthony; MacMillan, David W. C.

2012-01-01

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. PMID:21753848

[The recent research progress of chemistry of marine natural products].

PubMed

Shi, Qing-wen; Li, Li-geng; Wang, Yu-fang; Huo, Chang-hong; Zhang, Man-li

2010-10-01

Ocean is a unique and excellent resource that provides a diverse array of intriguing natural products. Marine natural products have demonstrated significant and extremely potent biological activities and have captured the attention of natural products chemists in the past few decades. It is increasingly recognized that a wealth of fascinating natural products and novel chemical entities will play a dominant role in the discovery of useful leads for the development of pharmaceutical agents and provide useful probes to lead to breakthroughs in a variety of life-science fields. This article focused on the research progress of chemistry of marine natural products in recent five years.

Natural Product Biosynthetic Diversity and Comparative Genomics of the Cyanobacteria.

PubMed

Dittmann, Elke; Gugger, Muriel; Sivonen, Kaarina; Fewer, David P

2015-10-01

Cyanobacteria are an ancient lineage of slow-growing photosynthetic bacteria and a prolific source of natural products with intricate chemical structures and potent biological activities. The bulk of these natural products are known from just a handful of genera. Recent efforts have elucidated the mechanisms underpinning the biosynthesis of a diverse array of natural products from cyanobacteria. Many of the biosynthetic mechanisms are unique to cyanobacteria or rarely described from other organisms. Advances in genome sequence technology have precipitated a deluge of genome sequences for cyanobacteria. This makes it possible to link known natural products to biosynthetic gene clusters but also accelerates the discovery of new natural products through genome mining. These studies demonstrate that cyanobacteria encode a huge variety of cryptic gene clusters for the production of natural products, and the known chemical diversity is likely to be just a fraction of the true biosynthetic capabilities of this fascinating and ancient group of organisms. Copyright © 2015. Published by Elsevier Ltd.

Effective use of heterologous hosts for characterization of biosynthetic enzymes allows production of natural products and promotes new natural product discovery.

PubMed

Watanabe, Kenji

2014-01-01

In the past few years, there has been impressive progress in elucidating the mechanism of biosynthesis of various natural products accomplished through the use of genetic, molecular biological and biochemical techniques. Here, we present a comprehensive overview of the current results from our studies on fungal natural product biosynthetic enzymes, including nonribosomal peptide synthetase and polyketide synthase-nonribosomal peptide synthetase hybrid synthetase, as well as auxiliary enzymes, such as methyltransferases and oxygenases. Specifically, biosynthesis of the following compounds is described in detail: (i) Sch210972, potentially involving a Diels-Alder reaction that may be catalyzed by CghA, a functionally unknown protein identified by targeted gene disruption in the wild type fungus; (ii) chaetoglobosin A, formed via multi-step oxidations catalyzed by three redox enzymes, one flavin-containing monooxygenase and two cytochrome P450 oxygenases as characterized by in vivo biotransformation of relevant intermediates in our engineered Saccharomyces cerevisiae; (iii) (-)-ditryptophenaline, formed by a cytochrome P450, revealing the dimerization mechanism for the biosynthesis of diketopiperazine alkaloids; (iv) pseurotins, whose variations in the C- and O-methylations and the degree of oxidation are introduced combinatorially by multiple redox enzymes; and (v) spirotryprostatins, whose spiro-carbon moiety is formed by a flavin-containing monooxygenase or a cytochrome P450 as determined by heterologous de novo production of the biosynthetic intermediates and final products in Aspergillus niger. We close our discussion by summarizing some of the key techniques that have facilitated the discovery of new natural products, production of their analogs and identification of biosynthetic mechanisms in our study.

Monthly Crude Oil and Natural Gas Production Report

EIA Publications

2017-01-01

Crude oil production (including lease condensate) and natural gas production (gross withdrawals) from data collected on Form EIA-914 (Monthly Crude Oil, Lease Condensate, and Natural Gas Production Report) for Federal Offshore Gulf of Mexico, Texas, Louisiana, New Mexico, Oklahoma, Texas, Wyoming, other states and lower 48 states. Alaska data are from the Alaska state government and included to obtain a U.S. total.

Techniques for extraction and isolation of natural products: a comprehensive review.

PubMed

Zhang, Qing-Wen; Lin, Li-Gen; Ye, Wen-Cai

2018-01-01

Natural medicines were the only option for the prevention and treatment of human diseases for thousands of years. Natural products are important sources for drug development. The amounts of bioactive natural products in natural medicines are always fairly low. Today, it is very crucial to develop effective and selective methods for the extraction and isolation of those bioactive natural products. This paper intends to provide a comprehensive view of a variety of methods used in the extraction and isolation of natural products. This paper also presents the advantage, disadvantage and practical examples of conventional and modern techniques involved in natural products research.

Collective synthesis of natural products by means of organocascade catalysis.

PubMed

Jones, Spencer B; Simmons, Bryon; Mastracchio, Anthony; MacMillan, David W C

2011-07-13

Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine. ©2011 Macmillan Publishers Limited. All rights reserved

Antiviral Natural Products and Herbal Medicines

PubMed Central

Lin, Liang-Tzung; Hsu, Wen-Chan; Lin, Chun-Ching

2014-01-01

Viral infections play an important role in human diseases, and recent outbreaks in the advent of globalization and ease of travel have underscored their prevention as a critical issue in safeguarding public health. Despite the progress made in immunization and drug development, many viruses lack preventive vaccines and efficient antiviral therapies, which are often beset by the generation of viral escape mutants. Thus, identifying novel antiviral drugs is of critical importance and natural products are an excellent source for such discoveries. In this mini-review, we summarize the antiviral effects reported for several natural products and herbal medicines. PMID:24872930

Natural Product-Derived Drugs for the Treatment of Inflammatory Bowel Diseases

PubMed Central

2014-01-01

Natural products have been used as drugs for millennia, and the therapeutic potential of natural products has been studied for more than a century. Since the mid-1880s, approximately 60% of drugs have originated from natural products. Recently, the importance of using natural products has increased, as has interest in discovering efficient new drugs. Natural drugs are desirable for the treatment of inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease. This review discusses the discovery and development of drugs derived from natural products for the treatment of inflammatory bowel diseases. PMID:25349576

Natural production of biological optical systems

NASA Astrophysics Data System (ADS)

Choi, Seung Ho; Kim, Young L.

2015-03-01

Synthesis and production in nature often provide ideas to design and fabricate advanced biomimetic photonic materials and structures, leading to excellent physical properties and enhanced performance. In addition, the recognition and utilization of natural or biological substances have been typical routes to develop biocompatible and biodegradable materials for medical applications. In this respect, biological lasers utilizing such biomaterials and biostructures have been received considerable attention, given a variety of implications and potentials for bioimaging, biosensing, implantation, and therapy. However, without relying on industrial facilities, eco-friendly massive production of such optical components or systems has not yet been investigated. We show examples of bioproduction of biological lasers using agriculture and fisheries. We anticipate that such approaches will open new possibilities for scalable eco-friendly `green' production of biological photonics components and systems.

Dearomatization Strategies in the Synthesis of Complex Natural Products

PubMed Central

Roche, Stéphane P.; Porco, John A.

2014-01-01

Evolution in the field of the total synthesis of natural products has led to exciting developments over the last decade. Numerous chemo-selective and enantioselective methodologies have emerged from total syntheses, resulting in efficient access to many important natural product targets. This Review highlights recent developments concerning dearomatization, a powerful strategy for the total synthesis of architecturally complex natural products wherein planar, aromatic scaffolds are converted to three-dimensional molecular architectures. PMID:21506209

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489.

PubMed

Geddis, Stephen M; Carro, Laura; Hodgkinson, James T; Spring, David R

2016-12-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald-Hartwig amination and a final acid-catalysed 1,3-allylic-alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported.

Divergent Synthesis of Quinolone Natural Products from Pseudonocardia sp. CL38489

PubMed Central

Geddis, Stephen M.; Carro, Laura; Hodgkinson, James T.

2016-01-01

Two divergent synthetic routes are reported offering access to four quinolone natural products from Pseudonocardia sp. CL38489. Key steps to the natural products involved a regioselective epoxidation, an intramolecular Buchwald–Hartwig amination and a final acid‐catalysed 1,3‐allylic‐alcohol rearrangement to give two of the natural products in one step. This study completes the synthesis of all eight antibacterial quinolone natural products reported in the family. In addition, this modular strategy enables an improved synthesis towards two natural products previously reported. PMID:28111524

The Natural Product Phyllanthusmin C Enhances IFN-γ Production by Human Natural Killer Cells through Upregulation of TLR-Mediated NF-κB Signaling

PubMed Central

Deng, Youcai; Chu, Jianhong; Ren, Yulin; Fan, Zhijin; Ji, Xiaotian; Mundy, Bethany; Yuan, Shunzong; Hughes, Tiffany; Zhang, Jianying; Cheema, Baljash; Camardo, Andrew T.; Xia, Yong; Wu, Lai-Chu; Wang, Li-Shu; He, Xiaoming; Kinghorn, A. Douglas; Li, Xiaohui; Caligiuri, Michael A; Yu, Jianhua

2014-01-01

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer initiating cells, and clear viral infections. However, few reports describe a natural product that selectively stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 mg/ml, and stimulated IFN-γ production in both human CD56bright and CD56dim NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C’s activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12/IL-15 receptors and their related STAT signaling pathways were not significantly modulated by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively activate human NK cell IFN-γ. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted. PMID:25122922

Natural products as reservoirs of novel therapeutic agents.

PubMed

Mushtaq, Sadaf; Abbasi, Bilal Haider; Uzair, Bushra; Abbasi, Rashda

2018-01-01

Since ancient times, natural products from plants, animals, microbial and marine sources have been exploited for treatment of several diseases. The knowledge of our ancestors is the base of modern drug discovery process. However, due to the presence of extensive biodiversity in natural sources, the percentage of secondary metabolites screened for bioactivity is low. This review aims to provide a brief overview of historically significant natural therapeutic agents along with some current potential drug candidates. It will also provide an insight into pros and cons of natural product discovery and how development of recent approaches has answered the challenges associated with it.

Antifungal potential of marine natural products.

PubMed

El-Hossary, Ebaa M; Cheng, Cheng; Hamed, Mostafa M; El-Sayed Hamed, Ashraf Nageeb; Ohlsen, Knut; Hentschel, Ute; Abdelmohsen, Usama Ramadan

2017-01-27

Fungal diseases represent an increasing threat to human health worldwide which in some cases might be associated with substantial morbidity and mortality. However, only few antifungal drugs are currently available for the treatment of life-threatening fungal infections. Furthermore, plant diseases caused by fungal pathogens represent a worldwide economic problem for the agriculture industry. The marine environment continues to provide structurally diverse and biologically active secondary metabolites, several of which have inspired the development of new classes of therapeutic agents. Among these secondary metabolites, several compounds with noteworthy antifungal activities have been isolated from marine microorganisms, invertebrates, and algae. During the last fifteen years, around 65% of marine natural products possessing antifungal activities have been isolated from sponges and bacteria. This review gives an overview of natural products from diverse marine organisms that have shown in vitro and/or in vivo potential as antifungal agents, with their mechanism of action whenever applicable. The natural products literature is covered from January 2000 until June 2015, and we are reporting the chemical structures together with their biological activities, as well as the isolation source. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

An analysis of FDA-approved drugs: natural products and their derivatives.

PubMed

Patridge, Eric; Gareiss, Peter; Kinch, Michael S; Hoyer, Denton

2016-02-01

Natural products contribute greatly to the history and landscape of new molecular entities (NMEs). An assessment of all FDA-approved NMEs reveals that natural products and their derivatives represent over one-third of all NMEs. Nearly one-half of these are derived from mammals, one-quarter from microbes and one-quarter from plants. Since the 1930s, the total fraction of natural products has diminished, whereas semisynthetic and synthetic natural product derivatives have increased. Over time, this fraction has also become enriched with microbial natural products, which represent a significant portion of approved antibiotics, including more than two-thirds of all antibacterial NMEs. In recent years, the declining focus on natural products has impacted the pipeline of NMEs from specific classes, and this trend is likely to continue without specific investment in the pursuit of natural products. Copyright © 2015 Elsevier Ltd. All rights reserved.

Informatic analysis reveals Legionella as a source of novel natural products.

PubMed

Johnston, Chad W; Plumb, Jonathan; Li, Xiang; Grinstein, Sergio; Magarvey, Nathan A

2016-06-01

Microbial natural products are a crucial source of bioactive molecules and unique chemical scaffolds. Despite their importance, rediscovery of known natural products from established productive microbes has led to declining interest, even while emergent genomic data suggest that the majority of microbial natural products remain to be discovered. Now, new sources of microbial natural products must be defined in order to provide chemical scaffolds for the next generation of small molecules for therapeutic, agricultural, and industrial purposes. In this work, we use specialized bioinformatic programs, genetic knockouts, and comparative metabolomics to define the genus Legionella as a new source of novel natural products. We show that Legionella spp. hold a diverse collection of biosynthetic gene clusters for the production of polyketide and nonribosomal peptide natural products. To confirm this bioinformatic survey, we create targeted mutants of L. pneumophila and use comparative metabolomics to identify a novel polyketide surfactant. Using spectroscopic techniques, we show that this polyketide possesses a new chemical scaffold, and firmly demonstrate that this unexplored genus is a source for novel natural products.

The Traditional Medicine and Modern Medicine from Natural Products.

PubMed

Yuan, Haidan; Ma, Qianqian; Ye, Li; Piao, Guangchun

2016-04-29

Natural products and traditional medicines are of great importance. Such forms of medicine as traditional Chinese medicine, Ayurveda, Kampo, traditional Korean medicine, and Unani have been practiced in some areas of the world and have blossomed into orderly-regulated systems of medicine. This study aims to review the literature on the relationship among natural products, traditional medicines, and modern medicine, and to explore the possible concepts and methodologies from natural products and traditional medicines to further develop drug discovery. The unique characteristics of theory, application, current role or status, and modern research of eight kinds of traditional medicine systems are summarized in this study. Although only a tiny fraction of the existing plant species have been scientifically researched for bioactivities since 1805, when the first pharmacologically-active compound morphine was isolated from opium, natural products and traditional medicines have already made fruitful contributions for modern medicine. When used to develop new drugs, natural products and traditional medicines have their incomparable advantages, such as abundant clinical experiences, and their unique diversity of chemical structures and biological activities.

Countercurrent Separation of Natural Products: An Update

PubMed Central

2015-01-01

This work assesses the current instrumentation, method development, and applications in countercurrent chromatography (CCC) and centrifugal partition chromatography (CPC), collectively referred to as countercurrent separation (CCS). The article provides a critical review of the CCS literature from 2007 since our last review (J. Nat. Prod.2008, 71, 1489–1508), with a special emphasis on the applications of CCS in natural products research. The current state of CCS is reviewed in regard to three continuing topics (instrumentation, solvent system development, theory) and three new topics (optimization of parameters, workflow, bioactivity applications). The goals of this review are to deliver the necessary background with references for an up-to-date perspective of CCS, to point out its potential for the natural product scientist, and thereby to induce new applications in natural product chemistry, metabolome, and drug discovery research involving organisms from terrestrial and marine sources. PMID:26177360

Reduction in hypericin-induced phototoxicity by Hypericum perforatum extracts and pure compounds

PubMed Central

Schmitt, Laura A.; Liu, Yi; Murphy, Patricia A.; Petrich, Jacob W.; Dixon, Philip M.; Birt, Diane F.

2006-01-01

Clinical evidence suggests that administration of Hypericum perforatum (Hp) extracts containing the photo-activated hypericin compounds may cause fewer skin photosensitization reactions than administration of pure hypericin. This study was conducted to determine whether the phototoxicity of hypericin in HaCaT keratinocytes could be attenuated by H. perforatum extracts and constituents. Two extracts, when supplemented with 20 μM hypericin: (1) an ethanol re-extraction of residue following a chloroform extraction (denoted ethanol(-chloroform)) (3.35 μM hypericin and 124.0 μM total flavonoids); and (2) a chloroform extract (hypericin and flavonoids not detected), showed 25% and 50% (p < 0.0001) less phototoxicity than 20 μM hypericin alone. Two H. perforatum constituents, when supplemented with 20 μM hypericin: (1) 10 μM chlorogenic acid; and (2) 0.25 μM pyropheophorbide, exhibited 24% (p < 0.05) and 40% (p < 0.05) less phototoxicity than 20 μM hypericin alone. The peroxidation of arachidonic acid was assessed as a measure of oxidative damage by photo-activated hypericin, but this parameter of lipid peroxidation was not influenced by the extracts or constituents. However α-tocopherol, a known antioxidant also did not influence the amount of lipid peroxidation induced in this system. These observations indicate that hypericin combined with H. perforatum extracts or constituents may exert less phototoxicity than pure hypericin, but possibly not through a reduction in arachidonic acid peroxidation. PMID:16859921

Does species diversity limit productivity in natural grassland communities?

USGS Publications Warehouse

Grace, J.B.; Anderson, T.M.; Smith, M.D.; Seabloom, E.; Andelman, S.J.; Meche, G.; Weiher, E.; Allain, L.K.; Jutila, H.; Sankaran, M.; Knops, J.; Ritchie, M.; Willig, M.R.

2007-01-01

Theoretical analyses and experimental studies of synthesized assemblages indicate that under particular circumstances species diversity can enhance community productivity through niche complementarity. It remains unclear whether this process has important effects in mature natural ecosystems where competitive feedbacks and complex environmental influences affect diversity-productivity relationships. In this study, we evaluated diversity-productivity relationships while statistically controlling for environmental influences in 12 natural grassland ecosystems. Because diversity-productivity relationships are conspicuously nonlinear, we developed a nonlinear structural equation modeling (SEM) methodology to separate the effects of diversity on productivity from the effects of productivity on diversity. Meta-analysis was used to summarize the SEM findings across studies. While competitive effects were readily detected, enhancement of production by diversity was not. These results suggest that the influence of small-scale diversity on productivity in mature natural systems is a weak force, both in absolute terms and relative to the effects of other controls on productivity. ?? 2007 Blackwell Publishing Ltd/CNRS.

Marine actinobacteria: an important source of bioactive natural products.

PubMed

Manivasagan, Panchanathan; Kang, Kyong-Hwa; Sivakumar, Kannan; Li-Chan, Eunice C Y; Oh, Hyun-Myung; Kim, Se-Kwon

2014-07-01

Marine environment is largely an untapped source for deriving actinobacteria, having potential to produce novel, bioactive natural products. Actinobacteria are the prolific producers of pharmaceutically active secondary metabolites, accounting for about 70% of the naturally derived compounds that are currently in clinical use. Among the various actinobacterial genera, Actinomadura, Actinoplanes, Amycolatopsis, Marinispora, Micromonospora, Nocardiopsis, Saccharopolyspora, Salinispora, Streptomyces and Verrucosispora are the major potential producers of commercially important bioactive natural products. In this respect, Streptomyces ranks first with a large number of bioactive natural products. Marine actinobacteria are unique enhancing quite different biological properties including antimicrobial, anticancer, antiviral, insecticidal and enzyme inhibitory activities. They have attracted global in the last ten years for their ability to produce pharmaceutically active compounds. In this review, we have focused attention on the bioactive natural products isolated from marine actinobacteria, possessing unique chemical structures that may form the basis for synthesis of novel drugs that could be used to combat resistant pathogenic microorganisms. Copyright © 2014 Elsevier B.V. All rights reserved.

The effect of hypericum perforatum on kidney ischemia/reperfusion damage.

PubMed

Cakir, Murat; Duzova, Halil; Baysal, Işil; Gül, Cemile Ceren; Kuşcu, Gülbahar; Kutluk, Fatma; Çakin, Hilal; Şeker, Şifanur; İlbeği, Esranur; Uslu, Seda; Avci, Umut; Demir, Samet; Akinci, Cihan; Atli, Sercan

2017-11-01

It has been revealed in recent studies that Hypericum Perforatum (HP) is influential on cancer, inflammatory diseases, bacterial and viral diseases, and has neuroprotective and antioxidant properties. In this study, we investigated the effect of HP, which is known to have antioxidant and anti-inflammatory effects, on kidney I/R damage. Male Sprague-Dawley rats were divided into three groups, and each of the groups had eight rats: The Control Group; the Ischemia/Reperfusion (I/R) Group; and the IR + HP Group which was treated with 50 mg/kg of HP. The right kidneys of the rats were removed, and the left kidney developed ischemia during the 45th min, and reperfusion occurred in the following 3rd h. The histopathological findings and also the level of Malondialdehyde (MDA), Glutathione (GSH) and superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX) enzyme activations in the renal tissues were measured. Blood Urea Nitrogen (BUN), Creatinin (Cre) from serum samples were determined. The levels of BUN, Cre, and kidney tissue MDA increased at a significant level, and the SOD, CAT, and GSH-PX enzyme activity decreased at a significant level in the I/R group, compared with the Control Group (p < 0.05). In the I/R + HP group, the levels of MDA decreased at a significant level compared to the I/R group, while the SOD, CAT, and GSH-PX activity increased (p < 0.05). In histopathological examinations, it was observed that the tubular dilatation and epithelial desquamation regressed in the IR + HP Group when compared with the I/R Group. It has been shown with the histological and biochemical results in this study that HP is protective against acute renal I/R.

Natural products as reservoirs of novel therapeutic agents

PubMed Central

Mushtaq, Sadaf; Abbasi, Bilal Haider; Uzair, Bushra; Abbasi, Rashda

2018-01-01

Since ancient times, natural products from plants, animals, microbial and marine sources have been exploited for treatment of several diseases. The knowledge of our ancestors is the base of modern drug discovery process. However, due to the presence of extensive biodiversity in natural sources, the percentage of secondary metabolites screened for bioactivity is low. This review aims to provide a brief overview of historically significant natural therapeutic agents along with some current potential drug candidates. It will also provide an insight into pros and cons of natural product discovery and how development of recent approaches has answered the challenges associated with it. PMID:29805348

Culture-independent discovery of natural products from soil metagenomes.

PubMed

Katz, Micah; Hover, Bradley M; Brady, Sean F

2016-03-01

Bacterial natural products have proven to be invaluable starting points in the development of many currently used therapeutic agents. Unfortunately, traditional culture-based methods for natural product discovery have been deemphasized by pharmaceutical companies due in large part to high rediscovery rates. Culture-independent, or "metagenomic," methods, which rely on the heterologous expression of DNA extracted directly from environmental samples (eDNA), have the potential to provide access to metabolites encoded by a large fraction of the earth's microbial biosynthetic diversity. As soil is both ubiquitous and rich in bacterial diversity, it is an appealing starting point for culture-independent natural product discovery efforts. This review provides an overview of the history of soil metagenome-driven natural product discovery studies and elaborates on the recent development of new tools for sequence-based, high-throughput profiling of environmental samples used in discovering novel natural product biosynthetic gene clusters. We conclude with several examples of these new tools being employed to facilitate the recovery of novel secondary metabolite encoding gene clusters from soil metagenomes and the subsequent heterologous expression of these clusters to produce bioactive small molecules.

EIA's Natural Gas Production Data

EIA Publications

2009-01-01

This special report examines the stages of natural gas processing from the wellhead to the pipeline network through which the raw product becomes ready for transportation and eventual consumption, and how this sequence is reflected in the data published by the Energy Information Administration (EIA).

Utilization of natural products for treatment of blood diseases.

PubMed

Miles, D H; Nguyen, C L; Miles, D H

1998-12-01

This chapter presents an introduction to several diseases of the blood including infectious mononucleosis, leukemia, thrombosis and coagulation, bone marrow disorders, malaria, and anemia. In addition a survey of the recent literature is presented relative to natural products that have been utilized for the treatment of these diseases. The natural products that are reported represent a wide range of structural types and present interesting mechanisms of action. Thus the possibility exists that new drugs may be developed from these natural products which are more effective than those currently on the market.

Natural personal care products-analysis of ingredient lists and legal situation.

PubMed

Klaschka, Ursula

2016-01-01

Many natural substances are classified as dangerous substances according to the European regulation on classification and labelling. Are they used in natural personal care products today? One hundred ingredient lists were analyzed to find this out. All products with natural substances contained dangerous natural substances or they contained natural substances, for which the information about their classification as dangerous substances is not available. 54 natural substances quoted in the ingredient lists were found to be classified, with 37 substances being classified due to hazardous effects for skin and eyes. However, the most frequently used natural substances are not classified as dangerous. Natural substances are multi-constituent compounds, leading to two main problems in personal care products: the potential interactions of a multitude of substances and the fact that dangerous constituents are not disclosed in the ingredient lists. For example, the fragrance allergens citral, farnesol, limonene, and linalool are frequent components of the natural substances employed. In addition, 82 products listed allergenic fragrance ingredients as single substances in their ingredient lists. Recommendations for sensitive skin in a product's name do not imply that the '26 fragrance allergens' are omitted. Furthermore, 80 products listed 'parfum'/'aroma', and 50 products listed ethanol. The data show that the loopholes for natural substances and for personal care products in the present European chemical legislation (e.g. the exception for classification and labelling of cosmetic products and the exception for information transfer in the supply chain) are not in line with an adequate consumer and environmental protection.

Molecular scaffold analysis of natural products databases in the public domain.

PubMed

Yongye, Austin B; Waddell, Jacob; Medina-Franco, José L

2012-11-01

Natural products represent important sources of bioactive compounds in drug discovery efforts. In this work, we compiled five natural products databases available in the public domain and performed a comprehensive chemoinformatic analysis focused on the content and diversity of the scaffolds with an overview of the diversity based on molecular fingerprints. The natural products databases were compared with each other and with a set of molecules obtained from in-house combinatorial libraries, and with a general screening commercial library. It was found that publicly available natural products databases have different scaffold diversity. In contrast to the common concept that larger libraries have the largest scaffold diversity, the largest natural products collection analyzed in this work was not the most diverse. The general screening library showed, overall, the highest scaffold diversity. However, considering the most frequent scaffolds, the general reference library was the least diverse. In general, natural products databases in the public domain showed low molecule overlap. In addition to benzene and acyclic compounds, flavones, coumarins, and flavanones were identified as the most frequent molecular scaffolds across the different natural products collections. The results of this work have direct implications in the computational and experimental screening of natural product databases for drug discovery. © 2012 John Wiley & Sons A/S.

Cheminformatic comparison of approved drugs from natural product versus synthetic origins.

PubMed

Stratton, Christopher F; Newman, David J; Tan, Derek S

2015-11-01

Despite the recent decline of natural product discovery programs in the pharmaceutical industry, approximately half of all new drug approvals still trace their structural origins to a natural product. Herein, we use principal component analysis to compare the structural and physicochemical features of drugs from natural product-based versus completely synthetic origins that were approved between 1981 and 2010. Drugs based on natural product structures display greater chemical diversity and occupy larger regions of chemical space than drugs from completely synthetic origins. Notably, synthetic drugs based on natural product pharmacophores also exhibit lower hydrophobicity and greater stereochemical content than drugs from completely synthetic origins. These results illustrate that structural features found in natural products can be successfully incorporated into synthetic drugs, thereby increasing the chemical diversity available for small-molecule drug discovery. Copyright © 2015 Elsevier Ltd. All rights reserved.

Antimicrobial activity of natural products against Clostridium difficile in vitro.

PubMed

Roshan, N; Riley, T V; Hammer, K A

2017-05-10

To investigate the antimicrobial activity of various natural products against Clostridium difficile in vitro. The antibacterial activity of 20 natural products was determined by the agar well diffusion and broth microdilution assays against four C. difficile strains, three comparator organisms and four gastrointestinal commensal organisms. Of the raw natural products, garlic juice had the highest activity. The most active processed products were peppermint oil and the four pure compounds trans-cinnamaldehyde, allicin, menthol and zingerone. Furthermore, Bacteroides species had similar susceptibility to C. difficile to most natural products; however, Lactobacillus casei was less susceptible. The combined effect of natural products with vancomycin or metronidazole was determined using the conventional checkerboard titration method and the fractional inhibitory concentration index was calculated. The results showed a possible synergism between trans-cinnamaldehyde and vancomycin and partial synergy between trans-cinnamaldehyde and metronidazole. The study indicates a range of antimicrobial activity of natural products against C. difficile and suggests that they may be useful as alternative or complementary treatments for C. difficile infection (CDI), particularly as most are able to be given orally. This study encourages further investigation of natural products for treatment of CDI. © 2017 The Society for Applied Microbiology.

Applications of Nonenzymatic Catalysts to the Alteration of Natural Products.

PubMed

Shugrue, Christopher R; Miller, Scott J

2017-09-27

The application of small molecules as catalysts for the diversification of natural product scaffolds is reviewed. Specifically, principles that relate to the selectivity challenges intrinsic to complex molecular scaffolds are summarized. The synthesis of analogues of natural products by this approach is then described as a quintessential "late-stage functionalization" exercise wherein natural products serve as the lead scaffolds. Given the historical application of enzymatic catalysts to the site-selective alteration of complex molecules, the focus of this Review is on the recent studies of nonenzymatic catalysts. Reactions involving hydroxyl group derivatization with a variety of electrophilic reagents are discussed. C-H bond functionalizations that lead to oxidations, aminations, and halogenations are also presented. Several examples of site-selective olefin functionalizations and C-C bond formations are also included. Numerous classes of natural products have been subjected to these studies of site-selective alteration including polyketides, glycopeptides, terpenoids, macrolides, alkaloids, carbohydrates, and others. What emerges is a platform for chemical remodeling of naturally occurring scaffolds that targets virtually all known chemical functionalities and microenvironments. However, challenges for the design of very broad classes of catalysts, with even broader selectivity demands (e.g., stereoselectivity, functional group selectivity, and site-selectivity) persist. Yet, a significant spectrum of powerful, catalytic alterations of complex natural products now exists such that expansion of scope seems inevitable. Several instances of biological activity assays of remodeled natural product derivatives are also presented. These reports may foreshadow further interdisciplinary impacts for catalytic remodeling of natural products, including contributions to SAR development, mode of action studies, and eventually medicinal chemistry.

Docking of Natural Products against Neurodegenerative Diseases: General Concepts.

PubMed

Ribeiro, Frederico F; Mendonca Junior, Francisco J B; Ghasemi, Jahan B; Ishiki, Hamilton M; Scotti, Marcus T; Scotti, Luciana

2018-01-01

Since antiquity, humanity has used medicinal plant preparations to cure its ills, and, as research has progressed, new technologies have enabled more investigations on natural compounds which originate from plants, fungi, and marine species. The health benefits that these natural products provide have become a motive for treatment studies of various diseases. Among them, the neurodegenerative diseases like Alzheimer's and Parkinson's, a major age-related neurodegenerative disorder. Studies with natural products for neurodegenerative diseases (particularly through molecular docking) search for, and then focus on those ligands which offer effective inhibition of the enzymes monoamine oxidase and acetylcholinesterase. This review introduces the main concepts involved in docking studies with natural products: and also in our group, which has conducted a docking study of natural products isolated from Tetrapterys mucronata for inhibition of acetylcholinesterase. We observed that compounds 4 and 5 formed more interactions than the theoretical ligand, but that ligands with greater activity also interacted with residues HIS 381 and GLN 527. We have reported on our docking study performed with AChE and alkaloids isolated from the plant Tetrapterys mucronata. Our docking results corroborate the experiments conducted, and emphasize the positive contribution that these theoretical studies involving natural products bring to the fight against neurodegenerative diseases. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Marine Natural Products as Models to Circumvent Multidrug Resistance.

PubMed

Long, Solida; Sousa, Emília; Kijjoa, Anake; Pinto, Madalena M M

2016-07-08

Multidrug resistance (MDR) to anticancer drugs is a serious health problem that in many cases leads to cancer treatment failure. The ATP binding cassette (ABC) transporter P-glycoprotein (P-gp), which leads to premature efflux of drugs from cancer cells, is often responsible for MDR. On the other hand, a strategy to search for modulators from natural products to overcome MDR had been in place during the last decades. However, Nature limits the amount of some natural products, which has led to the development of synthetic strategies to increase their availability. This review summarizes the research findings on marine natural products and derivatives, mainly alkaloids, polyoxygenated sterols, polyketides, terpenoids, diketopiperazines, and peptides, with P-gp inhibitory activity highlighting the established structure-activity relationships. The synthetic pathways for the total synthesis of the most promising members and analogs are also presented. It is expected that the data gathered during the last decades concerning their synthesis and MDR-inhibiting activities will help medicinal chemists develop potential drug candidates using marine natural products as models which can deliver new ABC transporter inhibitor scaffolds.

Natural product-like virtual libraries: recursive atom-based enumeration.

PubMed

Yu, Melvin J

2011-03-28

A new molecular enumerator is described that allows chemically and architecturally diverse sets of natural product-like and drug-like structures to be generated from a core structure as simple as a single carbon atom or as complex as a polycyclic ring system. Integrated with a rudimentary machine-learning algorithm, the enumerator has the ability to assemble biased virtual libraries enriched in compounds predicted to meet target criteria. The ability to dynamically generate relatively small focused libraries in a recursive manner could reduce the computational time and infrastructure necessary to construct and manage extremely large static libraries. Depending on enumeration conditions, natural product-like structures can be produced with a wide range of heterocyclic and alicyclic ring assemblies. Because natural products represent a proven source of validated structures for identifying and designing new drug candidates, mimicking the structural and topological diversity found in nature with a dynamic set of virtual natural product-like compounds may facilitate the creation of new ideas for novel, biologically relevant lead structures in areas of uncharted chemical space.

Retrospective analysis of natural products provides insights for future discovery trends.

PubMed

Pye, Cameron R; Bertin, Matthew J; Lokey, R Scott; Gerwick, William H; Linington, Roger G

2017-05-30

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties.

Retrospective analysis of natural products provides insights for future discovery trends

PubMed Central

Pye, Cameron R.; Bertin, Matthew J.; Lokey, R. Scott; Gerwick, William H.

2017-01-01

Understanding of the capacity of the natural world to produce secondary metabolites is important to a broad range of fields, including drug discovery, ecology, biosynthesis, and chemical biology, among others. Both the absolute number and the rate of discovery of natural products have increased significantly in recent years. However, there is a perception and concern that the fundamental novelty of these discoveries is decreasing relative to previously known natural products. This study presents a quantitative examination of the field from the perspective of both number of compounds and compound novelty using a dataset of all published microbial and marine-derived natural products. This analysis aimed to explore a number of key questions, such as how the rate of discovery of new natural products has changed over the past decades, how the average natural product structural novelty has changed as a function of time, whether exploring novel taxonomic space affords an advantage in terms of novel compound discovery, and whether it is possible to estimate how close we are to having described all of the chemical space covered by natural products. Our analyses demonstrate that most natural products being published today bear structural similarity to previously published compounds, and that the range of scaffolds readily accessible from nature is limited. However, the analysis also shows that the field continues to discover appreciable numbers of natural products with no structural precedent. Together, these results suggest that the development of innovative discovery methods will continue to yield compounds with unique structural and biological properties. PMID:28461474

Capturing Biological Activity in Natural Product Fragments by Chemical Synthesis

PubMed Central

Crane, Erika A.

2016-01-01

Abstract Natural products have had an immense influence on science and have directly led to the introduction of many drugs. Organic chemistry, and its unique ability to tailor natural products through synthesis, provides an extraordinary approach to unlock the full potential of natural products. In this Review, an approach based on natural product derived fragments is presented that can successfully address some of the current challenges in drug discovery. These fragments often display significantly reduced molecular weights, reduced structural complexity, a reduced number of synthetic steps, while retaining or even improving key biological parameters such as potency or selectivity. Examples from various stages of the drug development process up to the clinic are presented. In addition, this process can be leveraged by recent developments such as genome mining, antibody–drug conjugates, and computational approaches. All these concepts have the potential to identify the next generation of drug candidates inspired by natural products. PMID:26833854

Bluegenics: Bioactive Natural Products of Medicinal Relevance and Approaches to Their Diversification.

PubMed

Zarins-Tutt, Joseph S; Abraham, Emily R; Bailey, Christopher S; Goss, Rebecca J M

Nature provides a valuable resource of medicinally relevant compounds, with many antimicrobial and antitumor agents entering clinical trials being derived from natural products. The generation of analogues of these bioactive natural products is important in order to gain a greater understanding of structure activity relationships; probing the mechanism of action, as well as to optimise the natural product's bioactivity and bioavailability. This chapter critically examines different approaches to generating natural products and their analogues, exploring the way in which synthetic and biosynthetic approaches may be blended together to enable expeditious access to new designer natural products.

Neurotrophic Natural Products: Chemistry and Biology

PubMed Central

Xu, Jing; Lacoske, Michelle H.

2014-01-01

Neurodegenerative diseases and spinal cord injury affect approximately 50 million people worldwide, bringing the total healthcare cost to over 600 billion dollars per year. Nervous system growth factors, that is, neurotrophins, are a potential solution to these disorders, since they could promote nerve regeneration. An average of 500 publications per year attests to the significance of neurotrophins in biomedical sciences and underlines their potential for therapeutic applications. Nonetheless, the poor pharmacokinetic profile of neurotrophins severely restricts their clinical use. On the other hand, small molecules that modulate neurotrophic activity offer a promising therapeutic approach against neurological disorders. Nature has provided an impressive array of natural products that have potent neurotrophic activities. This Review highlights the current synthetic strategies toward these compounds and summarizes their ability to induce neuronal growth and rehabilitation. It is anticipated that neurotrophic natural products could be used not only as starting points in drug design but also as tools to study the next frontier in biomedical sciences: the brain activity map project. PMID:24353244

Cyclooxygenase inhibitory natural products: current status.

PubMed

Jachak, Sanjay M

2006-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are of huge therapeutic benefit in the treatment of rheumatoid arthritis and various types of inflammatory conditions. The target for these drugs is cyclooxygenase (COX), a rate-limiting enzyme involved in the conversion of arachidonic acid into inflammatory prostaglandins. COX-2 selective inhibitors are believed to have the same anti-inflammatory, anti-pyretic and analgesic activities as that of nonselective inhibitor NSAIDs with little or none of the gastrointestinal side effects. Thus, in the last 6-7 years several selective COX-2 inhibitors including coxibs were discovered and introduced into clinic. Recent reports evidence that selective COX-2 inhibitor such as rofecoxib, can lead to thrombotic cardiovascular events through inhibition of prostacyclin formation in the infracted heart. This has resulted in withdrawal of rofecoxib from the clinic in September 2004. Moreover, the COX-2/COX-1 selectivity ratio is vital in the design of COX-2 inhibitory drugs, as it is clear from rofecoxib, which is more than 50-fold COX-2 selective. After looking at all above mentioned facts, natural product-based compounds seem better as these compounds are generally supposed to be devoid of severe side effects. The literature indicates that natural product-based compounds are mainly COX-1 selective. Through minor semi-synthetic changes in the structures, their selectivity towards COX-2 can be increased. The present review article addresses natural product COX inhibitors of plant and marine origin, reported during last ten years and their advantages, possible leads for further development and current status. In addition we describe our experience in the characterization, design and synthesis of potential natural COX inhibitors.

Opportunities for natural products in 21st century antibiotic discovery.

PubMed

Wright, Gerard D

2017-07-01

Natural products and their derivatives are mainstays of our antibiotic drugs, but they are increasingly in peril. The combination of widespread multidrug resistance in once susceptible bacterial pathogens, disenchantment with natural products as sources of new drugs, lack of success using synthetic compounds and target-based discovery methods, along with shifting economic and regulatory issues, conspire to move investment in research and development away from the antibiotics arena. The result is a growing crisis in antibiotic drug discovery that threatens modern medicine. 21 st century natural product research is perfectly positioned to fill the antibiotic discovery gap and bring new drug candidates to the clinic. Innovations in genomics and techniques to explore new sources of antimicrobial chemical matter are revealing new chemistry. Increasing appreciation of the value of narrow-spectrum drugs and re-examination of once discarded chemical scaffolds coupled with synthetic biology methods to generate new compounds and improve yields offer new strategies to revitalize once moribund natural product programs. The increasing awareness that the combination of antibiotics with adjuvants, non-antibiotic compounds that overcome resistance and enhance drug activity, can rescue older chemical scaffolds, and concepts such as blocking pathogen virulence present orthogonal strategies to traditional antibiotics. In all these areas, natural products offer chemical matter, shaped by natural selection, that is privileged in this therapeutic area. Natural product research is poised to regain prominence in delivering new drugs to solve the antibiotic crisis.

The impact of natural products upon modern drug discovery.

PubMed

Ganesan, A

2008-06-01

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules. We believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more likely than purely synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.

Regulation of natural health products in Canada.

PubMed

Smith, Alysyn; Jogalekar, Sumedha; Gibson, Adam

2014-12-02

In Canada, all natural health products (NHPs) are regulated by Health Canada (HC) under the Food and Drugs Act and the Natural Health Product Regulations. All authorized products undergo pre-market assessment for safety, efficacy and quality and the degree of pre-market oversight varies depending on the risk of the product. In Canada, over 70,000 products have been authorized for sale and over 2000 sites have been licensed to produce NHPs. In the management of NHPs on the Canadian market, HC employs a number of active and collaborative methods to address the most common issues such as contamination, adulteration and deceptive or misleading advertising practices. HC is currently evolving its approaches to NHPs to recognize them as part of the larger group of health products available without a prescription. As such, the regulatory responsibility for all over-the-counter (OTC) drugs, including non-prescription drugs and NHPs, has been transferred to a single federal division. As a result of this transition a number of benefits are being realized with respect to government efficiency, clarity for industry, support for new innovations and consolidated government interactions with the Canadian market. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Use of Natural Products as Chemical Library for Drug Discovery and Network Pharmacology

PubMed Central

Gu, Jiangyong; Gui, Yuanshen; Chen, Lirong; Yuan, Gu; Lu, Hui-Zhe; Xu, Xiaojie

2013-01-01

Background Natural products have been an important source of lead compounds for drug discovery. How to find and evaluate bioactive natural products is critical to the achievement of drug/lead discovery from natural products. Methodology We collected 19,7201 natural products structures, reported biological activities and virtual screening results. Principal component analysis was employed to explore the chemical space, and we found that there was a large portion of overlap between natural products and FDA-approved drugs in the chemical space, which indicated that natural products had large quantity of potential lead compounds. We also explored the network properties of natural product-target networks and found that polypharmacology was greatly enriched to those compounds with large degree and high betweenness centrality. In order to make up for a lack of experimental data, high throughput virtual screening was employed. All natural products were docked to 332 target proteins of FDA-approved drugs. The most potential natural products for drug discovery and their indications were predicted based on a docking score-weighted prediction model. Conclusions Analysis of molecular descriptors, distribution in chemical space and biological activities of natural products was conducted in this article. Natural products have vast chemical diversity, good drug-like properties and can interact with multiple cellular target proteins. PMID:23638153

Introducing N-glycans into natural products through a chemoenzymatic approach.

PubMed

Huang, Wei; Ochiai, Hirofumi; Zhang, Xinyu; Wang, Lai-Xi

2008-11-24

The present study describes an efficient chemoenzymatic method for introducing a core N-glycan of glycoprotein origin into various lipophilic natural products. It was found that the endo-beta-N-acetylglucosaminidase from Arthrobactor protophormiae (Endo-A) had broad substrate specificity and can accommodate a wide range of glucose (Glc)- or N-acetylglucosamine (GlcNAc)-containing natural products as acceptors for transglycosylation, when an N-glycan oxazoline was used as a donor substrate. Using lithocholic acid as a model compound, we have shown that introduction of an N-glycan could be achieved by a two-step approach: chemical glycosylation to introduce a monosaccharide (Glc or GlcNAc) as a handle, and then Endo-A catalyzed transglycosylation to accomplish the site-specific N-glycan attachment. For those natural products that already carry terminal Glc or GlcNAc residues, direct enzymatic transglycosylation using sugar oxazoline as the donor substrate was achievable to introduce an N-glycan. It was also demonstrated that simultaneous double glycosylation could be fulfilled when the natural product contains two Glc residues. This chemoenzymatic method is concise, site-specific, and highly convergent. Because N-glycans of glycoprotein origin can serve as ligands for diverse lectins and cell-surface receptors, introduction of a defined N-glycan into biologically significant natural products may bestow novel properties onto these natural products for drug discovery and development.

HPLC-UV-ESI-MS analysis of phenolic compounds and antioxidant properties of Hypericum undulatum shoot cultures and wild-growing plants.

PubMed

Rainha, Nuno; Koci, Kamila; Coelho, Ana Varela; Lima, Elisabete; Baptista, José; Fernandes-Ferreira, Manuel

2013-02-01

LC-UV and LC-MS analysis were used to study the phenolic composition of water extracts of Hypericum undulatum (HU) shoot cultures and wild-growing (WG) plants. Total phenolic content (TPC), determined using the Folin-Ciocalteu assay, and the antioxidant activity measured by two complementary methods were also performed for each sample. Mass spectrometry revealed several phenolics acids with quinic acid moieties, flavonols, mostly quercetin, luteolin and apigenin glycosides, flavan-3-ols (catechin and epicatechin) and the xanthonoid mangiferin. Differences in phenolic composition profile and TPC were found between the samples. The major phenolic in HU culture-growing (CG) samples is chlorogenic acid, followed by epicatechin, quercitrin and isoquercitrin. The WG plants presents hyperoside as the main phenolic, followed by isoquercitrin, chlorogenic acid and quercetin. The TPC and antioxidant activity were higher in samples from WG plants. Copyright © 2012 Elsevier Ltd. All rights reserved.

Hypericum perforatum with Vitex agnus-castus in menopausal symptoms: a randomized, controlled trial.

PubMed

van Die, M Diana; Burger, Henry G; Bone, Kerry M; Cohen, Marc M; Teede, Helena J

2009-01-01

To evaluate the effectiveness of a phytotherapeutic intervention comprising a combination of Hypericum perforatum (St. John's wort) and Vitex agnus-castus (Chaste tree/berry) in the management of menopausal symptoms. A double-blind, randomized, placebo-controlled, parallel trial was performed over 16 weeks in 100 eligible late-perimenopausal or postmenopausal women experiencing hot flushes and other menopausal symptoms. Herbal combination therapy or placebo tablets were administered twice daily. The primary endpoint was hot flush episodes. Secondary endpoints included Greene Climacteric Scale scores, Hamilton Depression Inventory scores, and Utian Quality of Life Scale scores. Ninety-three women completed the study. Data analysis on an intent-to-treat basis found no significant differences between the two groups for any of the endpoints. Analyses performed at interim data time points revealed no significant differences at week 4, 8, or 12 for daily weighted flushes or scores on the Greene Climacteric Scale or Hamilton Depression Inventory. However, significant improvements across the treatment phase were observed in both the placebo and active treatment groups for these endpoints. No significant change was found for either group on quality of life. The herbal combination of H. perforatum and V. agnus-castus was not found to be superior to placebo for the treatment of menopausal symptoms. The herbal combination was well tolerated with no significant adverse events noted in the short term. Robust findings from quality studies such as this are important for informing the community, healthcare providers, and regulatory authorities.

Human contact imagined during the production process increases food naturalness perceptions.

PubMed

Abouab, Nathalie; Gomez, Pierrick

2015-08-01

It is well established that food processing and naturalness are not good friends, but is food processing always detrimental to naturalness? Building on the contagion principle, this research examines how production mode (handmade vs. machine-made) influences naturalness perceptions. In a pilot study (n = 69) and an experiment (n = 133), we found that compared with both a baseline condition and a condition in which the mode of production process was portrayed as machine-made, a handmade production mode increases naturalness ratings of a grape juice. A mediation analysis demonstrates that these effects result from higher perceived human contact suggesting that the production process may preserve food naturalness when humanized. Copyright © 2015 Elsevier Ltd. All rights reserved.

Natural products discovery from micro-organisms in the post-genome era.

PubMed

Ikeda, Haruo

2017-01-01

With the decision to award the Nobel Prize in Physiology or Medicine to Drs. S. Ōmura, W.C. Campbell, and Y. Tu, the importance and usefulness of natural drug discovery and development have been revalidated. Since the end of the twentieth century, many genome analyses of organisms have been conducted, and accordingly, numerous microbial genomes have been decoded. In particular, genomic studies of actinomycetes, micro-organisms that readily produce natural products, led to the discovery of biosynthetic gene clusters responsible for producing natural products. New explorations for natural products through a comprehensive approach combining genomic information with conventional methods show great promise for the discovery of new natural products and even systematic generation of unnaturally occurring compounds.

Breaking the silence: new strategies for discovering novel natural products.

PubMed

Ren, Hengqian; Wang, Bin; Zhao, Huimin

2017-12-01

Natural products have been a prolific source of antibacterial and anticancer drugs for decades. One of the major challenges in natural product discovery is that the vast majority of natural product biosynthetic gene clusters (BGCs) have not been characterized, partially due to the fact that they are either transcriptionally silent or expressed at very low levels under standard laboratory conditions. Here we describe the strategies developed in recent years (mostly between 2014-2016) for activating silent BGCs. These strategies can be broadly divided into two categories: approaches in native hosts and approaches in heterologous hosts. In addition, we briefly discuss recent advances in developing new computational tools for identification and characterization of BGCs and high-throughput methods for detection of natural products. Copyright © 2017 Elsevier Ltd. All rights reserved.

Natural products in soil microbe interactions and evolution.

PubMed

Traxler, Matthew F; Kolter, Roberto

2015-07-01

In recent years, bacterial interspecies interactions mediated by small molecule natural products have been found to give rise to a surprising array of phenotypes in soil-dwelling bacteria, especially among Streptomyces and Bacillus species. This review examines these interspecies interactions, and the natural products involved, as they have been presented in literature stemming from four disciplines: soil science, interspecies microbiology, ecology, and evolutionary biology. We also consider how these interactions fit into accepted paradigms of signaling, cueing, and coercion.

Flavin-catalyzed redox tailoring reactions in natural product biosynthesis.

PubMed

Teufel, Robin

2017-10-15

Natural products are distinct and often highly complex organic molecules that constitute not only an important drug source, but have also pushed the field of organic chemistry by providing intricate targets for total synthesis. How the astonishing structural diversity of natural products is enzymatically generated in biosynthetic pathways remains a challenging research area, which requires detailed and sophisticated approaches to elucidate the underlying catalytic mechanisms. Commonly, the diversification of precursor molecules into distinct natural products relies on the action of pathway-specific tailoring enzymes that catalyze, e.g., acylations, glycosylations, or redox reactions. This review highlights a selection of tailoring enzymes that employ riboflavin (vitamin B2)-derived cofactors (FAD and FMN) to facilitate unusual redox catalysis and steer the formation of complex natural product pharmacophores. Remarkably, several such recently reported flavin-dependent tailoring enzymes expand the classical paradigms of flavin biochemistry leading, e.g., to the discovery of the flavin-N5-oxide - a novel flavin redox state and oxygenating species. Copyright © 2017 Elsevier Inc. All rights reserved.

α-Haloaldehydes: versatile building blocks for natural product synthesis.

PubMed

Britton, Robert; Kang, Baldip

2013-02-01

The diastereoselective addition of organometallic reagents to α-chloroaldehydes was first reported in 1959 and occupies a historically significant role as the prototypical reaction for Cornforth's model of stereoinduction. Despite clear synthetic potential for these reagents, difficulties associated with producing enantiomerically enriched α-haloaldehydes limited their use in natural product synthesis through the latter half of the 20th century. In recent years, however, a variety of robust, organocatalytic processes have been reported that now provide direct access to optically enriched α-haloaldehydes and have motivated renewed interest in their use as building blocks for natural product synthesis. This Highlight summarizes the methods available for the enantioselective preparation of α-haloaldehydes and their stereoselective conversion into natural products.

Impact of natural resources and research on cancer treatment and prevention: A perspective from Cameroon.

PubMed

Orang-Ojong, Barnabas Bessem; Munyangaju, Jose Edward; Wei, Ma Shang; Lin, Miao; Wei, Fan Guan; Foukunang, Charles; Zhu, Yan

2013-07-01

Cancer is a significant public health concern and treatment poses a problem and is frequently unsuccessful. As such, continuous efforts in the search for new agents and therapies to improve survival are required. A considerable number of plant extracts and isolated compounds possess significant anti-proliferative or pro-apoptotic effects. The majority of biologically active compounds belong to terpenoids, phenolics and alkaloids. Terpenoid plants such as Hypericum lanceolatum and a few alkaloid plants have been found to be potent anti-parasitic agents but have exhibited poor antimicrobial effects. The screening of medicinal plants for anticancer drugs has provided modern medicine with effective cytotoxic pharmaceuticals. Numerous medicinal plants have traditionally been used for the treatment of various ailments. However, a number of these medicinal plants have not been standardized and their mechanisms of actions are generally unknown. Active drug discovery research using local medicinal plants is ongoing. Some of these plant-derived compounds, including 3,39-dimethoxy-49- O -β-d-xylopyronosylellagic acid, have been tested for their potential use as anticancer agents. This review discussed the scope and possibility of natural products as anticancer remedy.

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes

PubMed Central

Skinnider, Michael A.; Merwin, Nishanth J.; Johnston, Chad W.

2017-01-01

Abstract Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/. PMID:28460067

The value of nature's natural product library for the discovery of New Chemical Entities: the discovery of ingenol mebutate.

PubMed

Ogbourne, Steven M; Parsons, Peter G

2014-10-01

In recent decades, 'Big Pharma' has invested billions of dollars into ingenious and innovative strategies designed to develop drugs using high throughput screening of small molecule libraries generated on the laboratory bench. Within the same time frame, screening of natural products by pharmaceutical companies has suffered an equally significant reduction. This is despite the fact that the complexity, functional diversity and druggability of nature's natural product library are considered by many to be superior to any library any team of scientists can prepare. It is therefore no coincidence that the number of New Chemical Entities reaching the market has also suffered a substantial decrease, leading to a productivity crisis within the pharmaceutical sector. In fact, the current dearth of New Chemical Entities reaching the market in recent decades might be a direct consequence of the strategic decision to move away from screening of natural products. Nearly 700 novel drugs derived from natural product New Chemical Entities were approved between 1981 and 2010; more than 60% of all approved drugs over the same time. In this review, we use the example of ingenol mebutate, a natural product identified from Euphorbia peplus and later approved as a therapy for actinic keratosis, as why nature's natural product library remains the most valuable library for discovery of New Chemical Entities and of novel drug candidates. Copyright © 2014 Elsevier B.V. All rights reserved.

The water extract of tutsan (Hypericum androsaemum L.) red berries exerts antidepressive-like effects and in vivo antioxidant activity in a mouse model of post-stroke depression.

PubMed

Nabavi, Seyed Mohammad; Nabavi, Seyed Fazel; Sureda, Antoni; Caprioli, Giovanni; Iannarelli, Romilde; Sokeng, Arold Jorel Tsetegho; Braidy, Nady; Khanjani, Sedigheh; Moghaddam, Akbar Hajizadeh; Atanasov, Atanas G; Daglia, Maria; Maggi, Filippo

2018-03-01

Hypericum androsaemum L., commonly known as 'tutsan' or 'shrubby St. John's Wort', is a member of the Hypericum genus found growing spontaneously in the Mediterranean area and is cultivated extensively as an ornamental plant due to the showy color variation in its fresh berry-like capsules, which turn from red to shiny black as they ripen. Tutsan has also been used in Portuguese and Spanish folk medicine to treat depression. In this study, we assessed the beneficial role of the water extract of H. androsaemum red berries (WE) in an experimental animal model of post-stroke depression. WE was obtained by decoction of H. androsaemum red berries, and its content of ten bioactive compounds was determined through HPLC-DAD analysis. Behavioral tests were carried out using a mouse model of post stroke depression to examine the antidepressive-like activity of WE at two doses (15 and 30 mg/kg bw). In addition, the in vivo antioxidant activity in the mouse brain was evaluated by measuring CAT, GSH, and SOD activity and TBARS levels. WE contained significant amounts of shikimic acid (110.0 g/kg), chlorogenic acid (56.9 g/kg), catechin (5.8 g/kg) and hyperoside (2.7 g/kg). Overall, the highest dosage of WE was found to significantly reduce the symptoms of depression, restoring normal behaviour and reducing levels of oxidative stress by increasing endogenous antioxidant defenses. The protective effects of WE in post-stroke depression in a mouse model were demonstrated in vivo for the first time, and correlated with the antioxidant capacity of its bioactive constituents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders

PubMed Central

Šmejkal, Karel; Heiss, Elke H.; Atanasov, Atanas G.

2016-01-01

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an “opening” of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease. PMID:27338339

Natural Products to Counteract the Epidemic of Cardiovascular and Metabolic Disorders.

PubMed

Waltenberger, Birgit; Mocan, Andrei; Šmejkal, Karel; Heiss, Elke H; Atanasov, Atanas G

2016-06-22

Natural products have always been exploited to promote health and served as a valuable source for the discovery of new drugs. In this review, the great potential of natural compounds and medicinal plants for the treatment or prevention of cardiovascular and metabolic disorders, global health problems with rising prevalence, is addressed. Special emphasis is laid on natural products for which efficacy and safety have already been proven and which are in clinical trials, as well as on plants used in traditional medicine. Potential benefits from certain dietary habits and dietary constituents, as well as common molecular targets of natural products, are also briefly discussed. A glimpse at the history of statins and biguanides, two prominent representatives of natural products (or their derivatives) in the fight against metabolic disease, is also included. The present review aims to serve as an "opening" of this special issue of Molecules, presenting key historical developments, recent advances, and future perspectives outlining the potential of natural products for prevention or therapy of cardiovascular and metabolic disease.

Bioactive natural products from Chinese marine flora and fauna.

PubMed

Zhou, Zhen-Fang; Guo, Yue-Wei

2012-09-01

In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail.

Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity.

PubMed

Aswad, Miran; Rayan, Mahmoud; Abu-Lafi, Saleh; Falah, Mizied; Raiyn, Jamal; Abdallah, Ziyad; Rayan, Anwar

2018-01-01

The aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs. A set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes. The model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules. By applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab. The proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

PRISM 3: expanded prediction of natural product chemical structures from microbial genomes.

PubMed

Skinnider, Michael A; Merwin, Nishanth J; Johnston, Chad W; Magarvey, Nathan A

2017-07-03

Microbial natural products represent a rich resource of pharmaceutically and industrially important compounds. Genome sequencing has revealed that the majority of natural products remain undiscovered, and computational methods to connect biosynthetic gene clusters to their corresponding natural products therefore have the potential to revitalize natural product discovery. Previously, we described PRediction Informatics for Secondary Metabolomes (PRISM), a combinatorial approach to chemical structure prediction for genetically encoded nonribosomal peptides and type I and II polyketides. Here, we present a ground-up rewrite of the PRISM structure prediction algorithm to derive prediction of natural products arising from non-modular biosynthetic paradigms. Within this new version, PRISM 3, natural product scaffolds are modeled as chemical graphs, permitting structure prediction for aminocoumarins, antimetabolites, bisindoles and phosphonate natural products, and building upon the addition of ribosomally synthesized and post-translationally modified peptides. Further, with the addition of cluster detection for 11 new cluster types, PRISM 3 expands to detect 22 distinct natural product cluster types. Other major modifications to PRISM include improved sequence input and ORF detection, user-friendliness and output. Distribution of PRISM 3 over a 300-core server grid improves the speed and capacity of the web application. PRISM 3 is available at http://magarveylab.ca/prism/. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Metabolic engineering of microorganisms for the synthesis of plant natural products.

PubMed

Marienhagen, Jan; Bott, Michael

2013-01-20

Of more than 200,000 plant natural products known to date, many demonstrate important pharmacological activities or are of biotechnological significance. However, isolation from natural sources is usually limited by low abundance and environmental, seasonal as well as regional variation, whereas total chemical synthesis is typically commercially unfeasible considering the complex structures of most plant natural products. With advances in DNA sequencing and recombinant DNA technology many of the biosynthetic pathways responsible for the production of these valuable compounds have been elucidated, offering the opportunity of a functional integration of biosynthetic pathways in suitable microorganisms. This approach offers promise to provide sufficient quantities of the desired plant natural products from inexpensive renewable resources. This review covers recent advancements in the metabolic engineering of microorganisms for the production of plant natural products such as isoprenoids, phenylpropanoids and alkaloids, and highlights general approaches and strategies to gain access to the rich biochemical diversity of plants by employing the biosynthetic power of microorganisms. Copyright © 2012 Elsevier B.V. All rights reserved.

Something old, something new: revisiting natural products in antibiotic drug discovery.

PubMed

Wright, Gerard D

2014-03-01

Antibiotic discovery is in crisis. Despite a growing need for new drugs resulting from the increasing number of multi-antibiotic-resistant pathogens, there have been only a handful of new antibiotics approved for clinical use in the past 2 decades. Faced with scientific, economic, and regulatory challenges, the pharmaceutical sector seems unable to respond to what has been called an "apocalyptic" threat. Natural products produced by bacteria and fungi are genetically encoded products of natural selection that have been the mainstay sources of the antibiotics in current clinical use. The pharmaceutical industry has largely abandoned these compounds in favor of large libraries of synthetic molecules because of difficulties in identifying new natural product antibiotics scaffolds. Advances in next-generation genome sequencing, bioinformatics, and analytical chemistry are combining to overcome barriers to natural products. Coupled with new strategies in antibiotic discovery, including inhibition of resistance, novel drug combinations, and new targets, natural products are poised for a renaissance to address what is a pressing health care crisis.

Natural health product use in Canada.

PubMed

Troppmann, Leticia; Johns, Timothy; Gray-Donald, Katherine

2002-01-01

To quantify patterns of Natural Health Product (NHP) use in Canada. The Food Habits of Canadians surveyed 1,543 Canadian adults using a 24-hour recall to record dietary supplements. Prevalence of use by user profile was examined. Forty-six percent of women and 33% of men reported taking at least one Natural Health Product with a mean of 2.3 among users. The highest prevalence of supplement use, 57%, occurred among women aged 50-65. Supplement users were older, less likely to smoke and perceived their health as better than non-users. Among supplement users, men had higher rates of use of garlic and vitamin C while women used iron, calcium, B complex, evening primrose oil and glucosamine sulfate. Supplement use by Canadians, at 38% for nutrients and 15% for herbal products, was similar to the rate of uses in the U.S., although differences in the reporting of types of supplements underline aspects of consumer behaviour as well as methodological issues specific to NHPs. Investigation of the use of NHPs in the healthcare setting is important given the widespread use and the potential health care consequences associated with supplement use.

Natural and Heterologous Production of Bacteriocins

NASA Astrophysics Data System (ADS)

Cintas, Luis M.; Herranz, Carmen; Hernández, Pablo E.

Bacteriocins are ribosomally synthesized antimicrobial peptides produced by bacteria, and their use as natural and nontoxic food preservatives has been the source of considerable interest for the research community. In addition, bacteriocins have been investigated for their potential use in human and veterinary applications and in the animal production field. In the native bacterial strain, most bacteriocins are synthesized as biologically inactive precursors, with N-terminal extensions, that are cleaved concomitantly during export of the bacteriocin by dedicated ABC transporters, or the general secretory pathway (GSP) or Sec-dependent pathway. However, a few bacteriocins are synthesized without an N-terminal extension, and others are circularized through a head-to-tail peptide bond, complicating the elucidation of their processing and transport across the cytoplasmic membrane. The high cost of synthetic bacteriocin synthesis and their low yields from many natural producers recommends the exploration of recombinant microbial systems for the heterologous production of bacteriocins. Other advantages of such systems include production of bacteriocins in safer hosts, increased bacteriocin production, control of bacteriocin gene expression, production of food ingredients with antimicrobial activity, construction of multibacteriocinogenic strains with a wider antagonistic spectrum, a better adaptation of the selected hosts to food environments, and providing antagonistic properties to lactic acid bacteria (LAB) used as starter, protective, or probiotic cultures. The recombinant production of bacteriocins mostly relies on the use of expression vectors that replicate in Gram-negative bacteria, Gram-positive bacteria, and yeasts, whereas the production of bacteriocins in heterologous LAB hosts may be essentially based on the expression of native biosynthetic genes, by exchanging or replacing leader peptides and/or dedicated processing and secretion systems (ABC transporters

Natural Products as Sources of New Drugs from 1981 to 2014.

PubMed

Newman, David J; Cragg, Gordon M

2016-03-25

This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a "natural product mimic", or "NM", to join the original primary divisions and the designation "natural product botanical", or "NB", to cover those botanical "defined mixtures" now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over the time frame from around the 1940s to the end of 2014, of the 175 small molecules approved, 131, or 75%, are other than "S" (synthetic), with 85, or 49%, actually being either natural products or directly derived therefrom. In other areas, the influence of natural product structures is quite marked, with, as expected from prior information, the anti-infective area being dependent on natural products and their structures. We wish to draw the attention of readers to the rapidly evolving recognition that a significant number of natural product drugs/leads are actually produced by microbes and/or microbial interactions with the "host from whence it was isolated", and therefore it is considered that this area of natural product research should be expanded significantly.

[Strategies of elucidation of biosynthetic pathways of natural products].

PubMed

Zou, Li-Qiu; Kuang, Xue-Jun; Sun, Chao; Chen, Shi-Lin

2016-11-01

Elucidation of the biosynthetic pathways of natural products is not only the major goal of herb genomics, but also the solid foundation of synthetic biology of natural products. Here, this paper reviewed recent advance in this field and put forward strategies to elucidate the biosynthetic pathway of natural products. Firstly, a proposed biosynthetic pathway should be set up based on well-known knowledge about chemical reactions and information on the identified compounds, as well as studies with isotope tracer. Secondly, candidate genes possibly involved in the biosynthetic pathway were screened out by co-expression analysis and/or gene cluster mining. Lastly, all the candidate genes were heterologously expressed in the host and then the enzyme involved in the biosynthetic pathway was characterized by activity assay. Sometimes, the function of the enzyme in the original plant could be further studied by RNAi or VIGS technology. Understanding the biosynthetic pathways of natural products will contribute to supply of new leading compounds by synthetic biology and provide "functional marker" for herbal molecular breeding, thus but boosting the development of traditional Chinese medicine agriculture. Copyright© by the Chinese Pharmaceutical Association.

[Elaboration of Pseudo-natural Products Using Artificial In Vitro Biosynthesis Systems].

PubMed

Goto, Yuki

2018-01-01

 Peptidic natural products often consist of not only proteinogenic building blocks but also unique non-proteinogenic structures such as macrocyclic scaffolds and N-methylated backbones. Since such non-proteinogenic structures are important structural motifs that contribute to diverse bioactivity, we have proposed that peptides with non-proteinogenic structures should be attractive candidates as artificial bioactive peptides mimicking natural products, or so-called pseudo-natural products. We previously devised an engineered translation system for pseudo-natural peptides, referred to as the flexible in vitro translation (FIT) system. This system enabled "one-pot" synthesis of highly diverse pseudo-natural peptide libraries, which can be rapidly screened by mRNA display technology for the discovery of pseudo-natural peptides with diverse bioactivities.

The re-emergence of natural products for drug discovery in the genomics era.

PubMed

Harvey, Alan L; Edrada-Ebel, RuAngelie; Quinn, Ronald J

2015-02-01

Natural products have been a rich source of compounds for drug discovery. However, their use has diminished in the past two decades, in part because of technical barriers to screening natural products in high-throughput assays against molecular targets. Here, we review strategies for natural product screening that harness the recent technical advances that have reduced these barriers. We also assess the use of genomic and metabolomic approaches to augment traditional methods of studying natural products, and highlight recent examples of natural products in antimicrobial drug discovery and as inhibitors of protein-protein interactions. The growing appreciation of functional assays and phenotypic screens may further contribute to a revival of interest in natural products for drug discovery.

Synthesis and Biological Investigation of Antioxidant Pyrrolomorpholine Spiroketal Natural Products

NASA Astrophysics Data System (ADS)

Verano, Alyssa Leigh

The pyrrolomorpholine spiroketal natural product family is comprised of epimeric furanose and pyranose isomers. These compounds were isolated from diverse plant species, all of which are used as traditional Chinese medicines for the treatment of a variety of diseases. Notably, the spiroketal natural products acortatarins A and B exhibit antioxidant activity in a diabetic renal cell model, significantly attenuating hyperglycemia-induced production of reactive oxygen species (ROS), a hallmark of diabetic nephropathy. The xylapyrrosides, additional members of the family, also inhibit t-butyl hydroperoxide-induced cytotoxicity in rat vascular smooth muscle cells. Accordingly, these natural products have therapeutic potential for the treatment of oxidative stress-related pathologies, and synthetic access would provide an exciting opportunity to investigate bioactivity and mechanism of action. Herein, we report the stereoselective synthesis of acortatarins A and B, furanose members of the pyrrolomorpholine spiroketal family. Our synthetic route was expanded to synthesize the pyranose congeners, thus completing entire D-enantiomeric family of natural products. Efficient access towards these scaffolds enabled systematic analogue synthesis, investigation of mechanism-of-action, and the discovery of novel antioxidants.

Novel Artificial Natural Products Against Breast Cancer Through Combinatorial Biosynthesis

DTIC Science & Technology

2002-07-01

compounds normally produced by a certain strain. Our investigations on the discovery of novel natural metabolites using type II polyketide synthase ...limitations, shall be included on any reproduction hereof which includes any part of the portions subject to such limitations. THIS TECHNICAL REPORT HAS... polyketides remain the central group of natural products in this research area, since this class of natural products form one of the largest and most

Flow chemistry syntheses of natural products.

PubMed

Pastre, Julio C; Browne, Duncan L; Ley, Steven V

2013-12-07

The development and application of continuous flow chemistry methods for synthesis is a rapidly growing area of research. In particular, natural products provide demanding challenges to this developing technology. This review highlights successes in the area with an emphasis on new opportunities and technological advances.

Bioactive Natural Products Prioritization Using Massive Multi-informational Molecular Networks.

PubMed

Olivon, Florent; Allard, Pierre-Marie; Koval, Alexey; Righi, Davide; Genta-Jouve, Gregory; Neyts, Johan; Apel, Cécile; Pannecouque, Christophe; Nothias, Louis-Félix; Cachet, Xavier; Marcourt, Laurence; Roussi, Fanny; Katanaev, Vladimir L; Touboul, David; Wolfender, Jean-Luc; Litaudon, Marc

2017-10-20

Natural products represent an inexhaustible source of novel therapeutic agents. Their complex and constrained three-dimensional structures endow these molecules with exceptional biological properties, thereby giving them a major role in drug discovery programs. However, the search for new bioactive metabolites is hampered by the chemical complexity of the biological matrices in which they are found. The purification of single constituents from such matrices requires such a significant amount of work that it should be ideally performed only on molecules of high potential value (i.e., chemical novelty and biological activity). Recent bioinformatics approaches based on mass spectrometry metabolite profiling methods are beginning to address the complex task of compound identification within complex mixtures. However, in parallel to these developments, methods providing information on the bioactivity potential of natural products prior to their isolation are still lacking and are of key interest to target the isolation of valuable natural products only. In the present investigation, we propose an integrated analysis strategy for bioactive natural products prioritization. Our approach uses massive molecular networks embedding various informational layers (bioactivity and taxonomical data) to highlight potentially bioactive scaffolds within the chemical diversity of crude extracts collections. We exemplify this workflow by targeting the isolation of predicted active and nonactive metabolites from two botanical sources (Bocquillonia nervosa and Neoguillauminia cleopatra) against two biological targets (Wnt signaling pathway and chikungunya virus replication). Eventually, the detection and isolation processes of a daphnane diterpene orthoester and four 12-deoxyphorbols inhibiting the Wnt signaling pathway and exhibiting potent antiviral activities against the CHIKV virus are detailed. Combined with efficient metabolite annotation tools, this bioactive natural products

Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases.

PubMed

Zha, Weibin

2018-04-01

The growing use of natural products in cardiovascular (CV) patients has been greatly raising the concerns about potential natural product-CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product-CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product-drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins) have been identified to be substrates and inhibitors of the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients) are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product-CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product-CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product-CV drug interactions and help public and physicians understand these type of interactions. Copyright © 2017. Published by Elsevier B.V.

Bioactive natural products from Chinese marine flora and fauna

PubMed Central

Zhou, Zhen-fang; Guo, Yue-wei

2012-01-01

In recent decades, the pharmaceutical application potential of marine natural products has attracted much interest from both natural product chemists and pharmacologists. Our group has long been engaged in the search for bioactive natural products from Chinese marine flora (such as mangroves and algae) and fauna (including sponges, soft corals, and mollusks), resulting in the isolation and characterization of numerous novel secondary metabolites spanning a wide range of structural classes and various biosynthetic origins. Of particular interest is the fact that many of these compounds show promising biological activities, including cytotoxic, antibacterial, and enzyme inhibitory effects. By describing representative studies, this review presents a comprehensive summary regarding the achievements and progress made by our group in the past decade. Several interesting examples are discussed in detail. PMID:22941288

Fishing for Nature's Hits: Establishment of the Zebrafish as a Model for Screening Antidiabetic Natural Products.

PubMed

Tabassum, Nadia; Tai, Hongmei; Jung, Da-Woon; Williams, Darren R

2015-01-01

Diabetes mellitus affects millions of people worldwide and significantly impacts their quality of life. Moreover, life threatening diseases, such as myocardial infarction, blindness, and renal disorders, increase the morbidity rate associated with diabetes. Various natural products from medicinal plants have shown potential as antidiabetes agents in cell-based screening systems. However, many of these potential "hits" fail in mammalian tests, due to issues such as poor pharmacokinetics and/or toxic side effects. To address this problem, the zebrafish (Danio rerio) model has been developed as a "bridge" to provide an experimentally convenient animal-based screening system to identify drug candidates that are active in vivo. In this review, we discuss the application of zebrafish to drug screening technologies for diabetes research. Specifically, the discovery of natural product-based antidiabetes compounds using zebrafish will be described. For example, it has recently been demonstrated that antidiabetic natural compounds can be identified in zebrafish using activity guided fractionation of crude plant extracts. Moreover, the development of fluorescent-tagged glucose bioprobes has allowed the screening of natural product-based modulators of glucose homeostasis in zebrafish. We hope that the discussion of these advances will illustrate the value and simplicity of establishing zebrafish-based assays for antidiabetic compounds in natural products-based laboratories.

Natural Products as a Source for Novel Antibiotics.

PubMed

Moloney, Mark G

2016-08-01

Natural products have historically been of crucial importance in the identification and development of antibacterial agents. Interest in these systems has waned in recent years, but the rapid emergence of resistant bacterial strains has forced their re-evaluation as a route to identify novel chemical skeletons with antibacterial activity for elaboration in drug development. This overview examines the current situation, highlights new natural product systems which have been found, together with re-examination of some old ones, and new technologies for their identification. While natural products certainly have the potential to re-emerge as a key start-point in antibacterial drug discovery, reports of new or reinvestigated structures need to be supported with sufficient quality chemical (solubility, stability), biochemical (including toxicity in particular, along with target information) and microbiological [minimum inhibitory concentration (MIC) and resistance frequency] validation data to assist in the identification of promising hit structures and to avoid wasted effort from trawling over already cultivated territory. This is particularly important in a resource-limited research environment. Copyright © 2016 Elsevier Ltd. All rights reserved.

Genome mining for ribosomally synthesized natural products.

PubMed

Velásquez, Juan E; van der Donk, Wilfred A

2011-02-01

In recent years, the number of known peptide natural products that are synthesized via the ribosomal pathway has rapidly grown. Taking advantage of sequence homology among genes encoding precursor peptides or biosynthetic proteins, in silico mining of genomes combined with molecular biology approaches has guided the discovery of a large number of new ribosomal natural products, including lantipeptides, cyanobactins, linear thiazole/oxazole-containing peptides, microviridins, lasso peptides, amatoxins, cyclotides, and conopeptides. In this review, we describe the strategies used for the identification of these ribosomally synthesized and posttranslationally modified peptides (RiPPs) and the structures of newly identified compounds. The increasing number of chemical entities and their remarkable structural and functional diversity may lead to novel pharmaceutical applications. Copyright © 2010 Elsevier Ltd. All rights reserved.

Genome Mining for Ribosomally Synthesized Natural Products

PubMed Central

Velásquez, Juan E.; van der Donk, Wilfred

2011-01-01

In recent years, the number of known peptide natural products that are synthesized via the ribosomal pathway has rapidly grown. Taking advantage of sequence homology among genes encoding precursor peptides or biosynthetic proteins, in silico mining of genomes combined with molecular biology approaches has guided the discovery of a large number of new ribosomal natural products, including lantipeptides, cyanobactins, linear thiazole/oxazole-containing peptides, microviridins, lasso peptides, amatoxins, cyclotides, and conopeptides. In this review, we describe the strategies used for the identification of these ribosomally-synthesized and posttranslationally modified peptides (RiPPs) and the structures of newly identified compounds. The increasing number of chemical entities and their remarkable structural and functional diversity may lead to novel pharmaceutical applications. PMID:21095156

Collective Syntheses of Icetexane Natural Products Based on Biogenetic Hypotheses.

PubMed

Thommen, Christophe; Neuburger, Markus; Gademann, Karl

2017-01-01

A divergent synthesis of 10 icetexane natural products based on a proposed biogenetic cationic ring expansion of a reduced carnosic acid derivative is described. Of these icetexanes, (+)-salvicanol, (-)-cyclocoulterone, (-)-coulterone, (-)-obtusinone D, and (-)-obtusinone E have been synthesized for the first time. In addition, the hypothesis for the non-enzymatic biogenesis of benzo[1,3]dioxole natural products has been experimentally investigated. Additional experimental evidence for the abiotic formation of the methylenedioxy unit is provided, as photolysis of the quinone (+)-komaroviquinone resulted in the formation of the [1,3]dioxole-containing natural product (-)-cyclocoulterone and (+)-komarovispirone. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Isolation and purification of series bioactive components from Hypericum perforatum L. by counter-current chromatography.

PubMed

Cao, Xueli; Wang, Qiaoe; Li, Yan; Bai, Ge; Ren, Hong; Xu, Chunming; Ito, Yoichiro

2011-03-01

Counter-current chromatography (CCC) combined with pre-separation by ultrasonic solvent extraction was successively used for the separation of series bioactive compounds from the crude extract of Hypericum perforatum L. The petroleum ether extract was separated by the solvent system of n-heptane-methanol-acetonitrile (1.5:0.5:0.5, v/v) and n-heptane-methanol (1.5:1, v/v) in gradient elution, yielding a phloroglucinol compound, hyperforin with HPLC purity over 98%. The ethyl acetate extract was separated by using the solvent system composed of hexane-ethyl acetate-methanol-water (1:1:1:1 and 1:3:1:3, v/v) in gradient through both reverse phase and normal phase elution mode, yielding a naphthodianthrone compound, hypericin with HPLC purity about 95%. The n-butanol extract was separated with the solvent system composed of n-butanol-ethyl acetate-water (1:4:5 and 1.5:3.5:5, v/v) in elution and back-extrusion mode, yielding two of flavones, rutin and hyperoside, with HPLC purity over 95%. HPLC-MS, reference sample and UV spectrum were selectively used in separation to search for target compounds from HPLC-DAD profiles of different sub-extracts. The structures of isolated compounds were further identified by ESI-MS, ¹HNMR and ¹³CNMR. Copyright © 2011 Elsevier B.V. All rights reserved.

Natural-product-derived fragments for fragment-based ligand discovery

NASA Astrophysics Data System (ADS)

Over, Björn; Wetzel, Stefan; Grütter, Christian; Nakai, Yasushi; Renner, Steffen; Rauh, Daniel; Waldmann, Herbert

2013-01-01

Fragment-based ligand and drug discovery predominantly employs sp2-rich compounds covering well-explored regions of chemical space. Despite the ease with which such fragments can be coupled, this focus on flat compounds is widely cited as contributing to the attrition rate of the drug discovery process. In contrast, biologically validated natural products are rich in stereogenic centres and populate areas of chemical space not occupied by average synthetic molecules. Here, we have analysed more than 180,000 natural product structures to arrive at 2,000 clusters of natural-product-derived fragments with high structural diversity, which resemble natural scaffolds and are rich in sp3-configured centres. The structures of the cluster centres differ from previously explored fragment libraries, but for nearly half of the clusters representative members are commercially available. We validate their usefulness for the discovery of novel ligand and inhibitor types by means of protein X-ray crystallography and the identification of novel stabilizers of inactive conformations of p38α MAP kinase and of inhibitors of several phosphatases.

Survey of natural products reported by Asian research groups in 2016.

PubMed

Liu, Yan-Fei; Yu, Shi-Shan

2017-11-01

The new natural products reported in peer-reviewed articles in 2016 in journals with good reputations were reviewed and analyzed. The advances that Asian research groups made in the field of natural products chemistry in 2016 were summarized. Compounds with unique structural features and/or promising bioactivities originating from Asian natural sources were discussed based on structural classification.

Quantifying methane emissions from natural gas production in north-eastern Pennsylvania

NASA Astrophysics Data System (ADS)

Barkley, Zachary R.; Lauvaux, Thomas; Davis, Kenneth J.; Deng, Aijun; Miles, Natasha L.; Richardson, Scott J.; Cao, Yanni; Sweeney, Colm; Karion, Anna; Smith, MacKenzie; Kort, Eric A.; Schwietzke, Stefan; Murphy, Thomas; Cervone, Guido; Martins, Douglas; Maasakkers, Joannes D.

2017-11-01

Natural gas infrastructure releases methane (CH4), a potent greenhouse gas, into the atmosphere. The estimated emission rate associated with the production and transportation of natural gas is uncertain, hindering our understanding of its greenhouse footprint. This study presents a new application of inverse methodology for estimating regional emission rates from natural gas production and gathering facilities in north-eastern Pennsylvania. An inventory of CH4 emissions was compiled for major sources in Pennsylvania. This inventory served as input emission data for the Weather Research and Forecasting model with chemistry enabled (WRF-Chem), and atmospheric CH4 mole fraction fields were generated at 3 km resolution. Simulated atmospheric CH4 enhancements from WRF-Chem were compared to observations obtained from a 3-week flight campaign in May 2015. Modelled enhancements from sources not associated with upstream natural gas processes were assumed constant and known and therefore removed from the optimization procedure, creating a set of observed enhancements from natural gas only. Simulated emission rates from unconventional production were then adjusted to minimize the mismatch between aircraft observations and model-simulated mole fractions for 10 flights. To evaluate the method, an aircraft mass balance calculation was performed for four flights where conditions permitted its use. Using the model optimization approach, the weighted mean emission rate from unconventional natural gas production and gathering facilities in north-eastern Pennsylvania approach is found to be 0.36 % of total gas production, with a 2σ confidence interval between 0.27 and 0.45 % of production. Similarly, the mean emission estimates using the aircraft mass balance approach are calculated to be 0.40 % of regional natural gas production, with a 2σ confidence interval between 0.08 and 0.72 % of production. These emission rates as a percent of production are lower than rates found in any

Importance of microbial natural products and the need to revitalize their discovery.

PubMed

Demain, Arnold L

2014-02-01

Microbes are the leading producers of useful natural products. Natural products from microbes and plants make excellent drugs. Significant portions of the microbial genomes are devoted to production of these useful secondary metabolites. A single microbe can make a number of secondary metabolites, as high as 50 compounds. The most useful products include antibiotics, anticancer agents, immunosuppressants, but products for many other applications, e.g., antivirals, anthelmintics, enzyme inhibitors, nutraceuticals, polymers, surfactants, bioherbicides, and vaccines have been commercialized. Unfortunately, due to the decrease in natural product discovery efforts, drug discovery has decreased in the past 20 years. The reasons include excessive costs for clinical trials, too short a window before the products become generics, difficulty in discovery of antibiotics against resistant organisms, and short treatment times by patients for products such as antibiotics. Despite these difficulties, technology to discover new drugs has advanced, e.g., combinatorial chemistry of natural product scaffolds, discoveries in biodiversity, genome mining, and systems biology. Of great help would be government extension of the time before products become generic.

Seeking new anti-cancer agents from autophagy-regulating natural products.

PubMed

Hua, Fang; Shang, Shuang; Hu, Zhuo-Wei

2017-04-01

Natural products are an important original source of many widely used drugs, including anti-cancer drugs. Early research efforts for seeking anti-cancer therapy from the natural products are mainly focused on the compounds with cytotoxicity capability. The good examples include vinblastine, vincristine, the camptothecin derivatives; topotecan, irinotecan, epipodophyllotoxin derivatives and paclitaxel. In a recent decade, the fundamental progression has been made in the understanding of molecular and cellular mechanisms regarding tumor initiation, metastasis, therapeutic resistance, immune escape, and relapse, which provide a great opportunity for the development of new mechanism-based anticancer drugs, especially drugs against new molecular and cellular targets. Autophagy, a critical cell homeostasis mechanism and promising drug target involved in a verity of human diseases including cancer, can be modulated by many compounds derived from natural products. In this review, we'll give a short introduction of autophagy and discuss the roles of autophagy in the tumorigenesis and progression. And then, we summarize the accumulated evidences to show the anti-tumor effects of several compounds derived from natural products through modulation of autophagy activity.

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM)

PubMed Central

Skinnider, Michael A.; Dejong, Chris A.; Rees, Philip N.; Johnston, Chad W.; Li, Haoxin; Webster, Andrew L. H.; Wyatt, Morgan A.; Magarvey, Nathan A.

2015-01-01

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. PMID:26442528

Advances in identification and validation of protein targets of natural products without chemical modification.

PubMed

Chang, J; Kim, Y; Kwon, H J

2016-05-04

Covering: up to February 2016Identification of the target proteins of natural products is pivotal to understanding the mechanisms of action to develop natural products for use as molecular probes and potential therapeutic drugs. Affinity chromatography of immobilized natural products has been conventionally used to identify target proteins, and has yielded good results. However, this method has limitations, in that labeling or tagging for immobilization and affinity purification often result in reduced or altered activity of the natural product. New strategies have recently been developed and applied to identify the target proteins of natural products and synthetic small molecules without chemical modification of the natural product. These direct and indirect methods for target identification of label-free natural products include drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation (SPROX), cellular thermal shift assay (CETSA), thermal proteome profiling (TPP), and bioinformatics-based analysis of connectivity. This review focuses on and reports case studies of the latest advances in target protein identification methods for label-free natural products. The integration of newly developed technologies will provide new insights and highlight the value of natural products for use as biological probes and new drug candidates.

Mapping of Sample Collection Data: GIS Tools for the Natural Product Researcher

PubMed Central

Oberlies, Nicholas H.; Rineer, James I.; Alali, Feras Q.; Tawaha, Khaled; Falkinham, Joseph O.; Wheaton, William D.

2009-01-01

Scientists engaged in the research of natural products often either conduct field collections themselves or collaborate with partners who do, such as botanists, mycologists, or SCUBA divers. The information gleaned from such collecting trips (e.g. longitude/latitude coordinates, geography, elevation, and a multitude of other field observations) have provided valuable data to the scientific community (e.g., biodiversity), even if it is tangential to the direct aims of the natural products research, which are often focused on drug discovery and/or chemical ecology. Geographic Information Systems (GIS) have been used to display, manage, and analyze geographic data, including collection sites for natural products. However, to the uninitiated, these tools are often beyond the financial and/or computational means of the natural product scientist. With new, free, and easy-to-use geospatial visualization tools, such as Google Earth, mapping and geographic imaging of sampling data are now within the reach of natural products scientists. The goals of the present study were to develop simple tools that are tailored for the natural products setting, thereby presenting a means to map such information, particularly via open source software like Google Earth. PMID:20161345

A comprehensive review of glycosylated bacterial natural products

PubMed Central

Elshahawi, Sherif I.; Shaaban, Khaled A.; Kharel, Madan K.

2015-01-01

A systematic analysis of all naturally-occurring glycosylated bacterial secondary metabolites reported in the scientific literature up through early 2013 is presented. This comprehensive analysis of 15 940 bacterial natural products revealed 3426 glycosides containing 344 distinct appended carbohydrates and highlights a range of unique opportunities for future biosynthetic study and glycodiversification efforts. PMID:25735878

Informatic search strategies to discover analogues and variants of natural product archetypes.

PubMed

Johnston, Chad W; Connaty, Alex D; Skinnider, Michael A; Li, Yong; Grunwald, Alyssa; Wyatt, Morgan A; Kerr, Russell G; Magarvey, Nathan A

2016-03-01

Natural products are a crucial source of antimicrobial agents, but reliance on low-resolution bioactivity-guided approaches has led to diminishing interest in discovery programmes. Here, we demonstrate that two in-house automated informatic platforms can be used to target classes of biologically active natural products, specifically, peptaibols. We demonstrate that mass spectrometry-based informatic approaches can be used to detect natural products with high sensitivity, identifying desired agents present in complex microbial extracts. Using our specialised software packages, we could elaborate specific branches of chemical space, uncovering new variants of trichopolyn and demonstrating a way forward in mining natural products as a valuable source of potential pharmaceutical agents.

Bioactive natural products in cancer prevention and therapy: Progress and promise.

PubMed

Bishayee, Anupam; Sethi, Gautam

2016-10-01

Natural products represent a rich source for the discovery and development of cancer preventive and anticancer drugs. Nearly, 80% of all drugs approved by the United States Food and Drug Administration during the last three decades for cancer therapy are either natural products per se or are based thereon, or mimicked natural products in one form or another. With the advent and refinement of new technologies, such as genetic techniques for production of secondary plant metabolites, combinatorial synthesis and high-throughput screening, it is expected that novel compounds from natural sources, including medicinal plants, would be identified and developed as safe and effective chemopreventive and anticancer drugs. Numerous bioactive natural compounds have been shown to be useful in prevention and therapy of cancer by targeting various signaling molecules and pathways. Extensive literature underscores the anticancer and chemopreventive activity of a plethora of naturally occurring agents, including phytochemicals. Several of these molecules have been tested in clinical trials and some of them have shown promise in combination therapy when administered along with standard chemotherapeutic agents. Thus, accelerated chemopreventive and chemotherapeutic drug development from natural sources is of great importance. In this special theme issue, contributions from eminent scientists and scholars around the world presented critical analysis of the current progress and promise of natural bioactive constituents in cancer prevention and therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

A systematic approach to identify therapeutic effects of natural products based on human metabolite information.

PubMed

Noh, Kyungrin; Yoo, Sunyong; Lee, Doheon

2018-06-13

Natural products have been widely investigated in the drug development field. Their traditional use cases as medicinal agents and their resemblance of our endogenous compounds show the possibility of new drug development. Many researchers have focused on identifying therapeutic effects of natural products, yet the resemblance of natural products and human metabolites has been rarely touched. We propose a novel method which predicts therapeutic effects of natural products based on their similarity with human metabolites. In this study, we compare the structure, target and phenotype similarities between natural products and human metabolites to capture molecular and phenotypic properties of both compounds. With the generated similarity features, we train support vector machine model to identify similar natural product and human metabolite pairs. The known functions of human metabolites are then mapped to the paired natural products to predict their therapeutic effects. With our selected three feature sets, structure, target and phenotype similarities, our trained model successfully paired similar natural products and human metabolites. When applied to the natural product derived drugs, we could successfully identify their indications with high specificity and sensitivity. We further validated the found therapeutic effects of natural products with the literature evidence. These results suggest that our model can match natural products to similar human metabolites and provide possible therapeutic effects of natural products. By utilizing the similar human metabolite information, we expect to find new indications of natural products which could not be covered by previous in silico methods.

Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products.

PubMed

Jamison, Christopher R; Badillo, Joseph J; Lipshultz, Jeffrey M; Comito, Robert J; MacMillan, David W C

2017-12-01

In nature, many organisms generate large families of natural product metabolites that have related molecular structures as a means to increase functional diversity and gain an evolutionary advantage against competing systems within the same environment. One pathway commonly employed by living systems to generate these large classes of structurally related families is oligomerization, wherein a series of enzymatically catalysed reactions is employed to generate secondary metabolites by iteratively appending monomers to a growing serial oligomer chain. The polypyrroloindolines are an interesting class of oligomeric natural products that consist of multiple cyclotryptamine subunits. Herein we describe an iterative application of asymmetric copper catalysis towards the synthesis of six distinct oligomeric polypyrroloindoline natural products: hodgkinsine, hodgkinsine B, idiospermuline, quadrigemine H and isopsychotridine B and C. Given the customizable nature of the small-molecule catalysts employed, we demonstrate that this strategy is further amenable to the construction of quadrigemine H-type alkaloids not isolated previously from natural sources.

Catalyst-controlled oligomerization for the collective synthesis of polypyrroloindoline natural products

NASA Astrophysics Data System (ADS)

Jamison, Christopher R.; Badillo, Joseph J.; Lipshultz, Jeffrey M.; Comito, Robert J.; MacMillan, David W. C.

2017-12-01

In nature, many organisms generate large families of natural product metabolites that have related molecular structures as a means to increase functional diversity and gain an evolutionary advantage against competing systems within the same environment. One pathway commonly employed by living systems to generate these large classes of structurally related families is oligomerization, wherein a series of enzymatically catalysed reactions is employed to generate secondary metabolites by iteratively appending monomers to a growing serial oligomer chain. The polypyrroloindolines are an interesting class of oligomeric natural products that consist of multiple cyclotryptamine subunits. Herein we describe an iterative application of asymmetric copper catalysis towards the synthesis of six distinct oligomeric polypyrroloindoline natural products: hodgkinsine, hodgkinsine B, idiospermuline, quadrigemine H and isopsychotridine B and C. Given the customizable nature of the small-molecule catalysts employed, we demonstrate that this strategy is further amenable to the construction of quadrigemine H-type alkaloids not isolated previously from natural sources.

Efficacy of Cimicifuga racemosa, Hypericum perforatum and Agnus castus in the treatment of climacteric complaints: a systematic review.

PubMed

Laakmann, Elena; Grajecki, Donata; Doege, Katja; zu Eulenburg, Christine; Buhling, Kai J

2012-09-01

The systematic review examines whether Cimicifuga racemosa (CR), Hypericum perforatum (HP), Agnus castus, vitamins and minerals, either as monotherapy or in combination, have an evidence-based impact on vasomotor, genital and psychological climacteric complaints. DATA SOURCES AND METHODS OF STUDY SELECTION: We searched in the databases EMBASE, OVID and PubMed using the keywords "vasomotor symptoms, hot flashes, vaginal atrophy, psychological problems, endometrium, sleep, concentration, cognition in combination with vitamins, multivitamins, minerals, multiminerals, black cohosh, Cimicifuga, Agnus castus, chasteberry, chaste tree, monk's pepper and menopause" for randomized controlled trials (RCT). Relevant studies were reviewed by four independent reviewers qualitatively. Most of the studies with a comparison of CR vs. placebo do not show an evidence-based significant effect of CR on climacteric symptoms. The combination of CR and HP shows an improvement of climacteric complaints in comparison to placebo. In some RCTs, there was no significant difference between CR and hormone-replacement therapy. The combination of HP and Agnus castus showed no significant difference in the treatment of climacteric complaints. CR monotherapy as well as HP and Agnus castus showed no better effect than placebo. The combination of CR with HP demonstrated a positive effect on climacteric complaints.

Dietary Natural Products for Prevention and Treatment of Liver Cancer

PubMed Central

Zhou, Yue; Li, Ya; Zhou, Tong; Zheng, Jie; Li, Sha; Li, Hua-Bin

2016-01-01

Liver cancer is the most common malignancy of the digestive system with high death rate. Accumulating evidences suggests that many dietary natural products are potential sources for prevention and treatment of liver cancer, such as grapes, black currant, plum, pomegranate, cruciferous vegetables, French beans, tomatoes, asparagus, garlic, turmeric, ginger, soy, rice bran, and some edible macro-fungi. These dietary natural products and their active components could affect the development and progression of liver cancer in various ways, such as inhibiting tumor cell growth and metastasis, protecting against liver carcinogens, immunomodulating and enhancing effects of chemotherapeutic drugs. This review summarizes the potential prevention and treatment activities of dietary natural products and their major bioactive constituents on liver cancer, and discusses possible mechanisms of action. PMID:26978396

Genomic basis for natural product biosynthetic diversity in the actinomycetes†

PubMed Central

Nett, Markus; Ikeda, Haruo; Moore, Bradley S.

2010-01-01

The phylum Actinobacteria hosts diverse high G + C, Gram-positive bacteria that have evolved a complex chemical language of natural product chemistry to help navigate their fascinatingly varied lifestyles. To date, 71 Actinobacteria genomes have been completed and annotated, with the vast majority representing the Actinomycetales, which are the source of numerous antibiotics and other drugs from genera such as Streptomyces, Saccharopolyspora and Salinispora. These genomic analyses have illuminated the secondary metabolic proficiency of these microbes – underappreciated for years based on conventional isolation programs – and have helped set the foundation for a new natural product discovery paradigm based on genome mining. Trends in the secondary metabolomes of natural product-rich actinomycetes are highlighted in this review article, which contains 199 references. PMID:19844637

Supercritical Fluid Chromatography in Natural Product Analysis - An Update.

PubMed

Gibitz Eisath, Nora; Sturm, Sonja; Stuppner, Hermann

2018-04-01

The wide chemical diversity of natural products has challenged analysts all over the world and has been a driving force for the development of innovative technologies since decades. In the last years, supercritical fluid chromatography (SFC) has finally emerged from the shadow of liquid chromatography (LC) and gas chromatography (GC) and has become a powerful tool in modern natural product analysis. Whereas in the past the technique had mainly been restricted to a small group of nonpolar compounds, it has largely expanded its suitability in the last years and has demonstrated possibilities without boundaries. This mini-review, focused on the latest applications, provides a brief update on the current status of SFC in natural product analysis with the aim to demonstrate its applicability for both polar and nonpolar plant constituents. The approaches cover the whole range of polarity, including carotenoids, flavonoids, water-unstable ginkgolides, and even highly polar triterpene saponins with several sugar residues. Georg Thieme Verlag KG Stuttgart · New York.

Natural Products: An Alternative to Conventional Therapy for Dermatophytosis?

PubMed

Lopes, Graciliana; Pinto, Eugénia; Salgueiro, Lígia

2017-02-01

The increased incidence of fungal infections, associated with the widespread use of antifungal drugs, has resulted in the development of resistance, making it necessary to discover new therapeutic alternatives. Among fungal infections, dermatophytoses constitute a serious public health problem, affecting 20-25 % of the world population. Medicinal plants represent an endless source of bioactive molecules, and their volatile and non-volatile extracts are clearly recognized for being the historical basis of therapeutic health care. Because of this, the research on natural products with antifungal activity against dermatophytes has considerably increased in recent years. However, despite the recognized anti-dermatophytic potential of natural products, often advantageous face to commercial drugs, there is still a long way to go until their use in therapeutics. This review attempts to summarize the current status of anti-dermatophytic natural products, focusing on their mechanism of action, the developed pharmaceutical formulations and their effectiveness in human and animal models of infection.

Effect of natural products on diabetes associated neurological disorders.

PubMed

Patel, Sita Sharan; Udayabanu, Malairaman

2017-04-01

Diabetes mellitus, a metabolic disorder, is associated with neurological complications such as depression, anxiety, hypolocomotion, cognitive dysfunction, phobias, anorexia, stroke, pain, etc. Traditional system of medicine is long known for its efficient management of diabetes. The current review discusses the scope of some common medicinal herbs as well as secondary metabolites with a special focus on diabetes-mediated central nervous system complications. Literatures suggest that natural products reduce diabetes-mediated neurological complications partly by reducing oxidative stress and/or inflammation or apoptosis in certain brain regions. Natural products are known to modulate diabetes-mediated alterations in the level of acetylcholinesterase, choline acetyltransferase, monoamine oxidase, serotonin receptors, muscarinic receptors, insulin receptor, nerve growth factor, brain-derived neurotrophic factor, and neuropeptide in brain. Further, there are several natural products reported to manage diabetic complications with unknown mechanism. In conclusion, medicinal plants or their secondary metabolites have a wide scope and possess therapeutic potential to effectively manage neurological complications associated with chronic diabetes.

Dereplication of peptidic natural products through database search of mass spectra

PubMed Central

Mohimani, Hosein; Gurevich, Alexey; Mikheenko, Alla; Garg, Neha; Nothias, Louis-Felix; Ninomiya, Akihiro; Takada, Kentaro; Dorrestein, Pieter C.; Pevzner, Pavel A.

2016-01-01

Peptidic Natural Products (PNPs) are widely used compounds that include many antibiotics and a variety of other bioactive peptides. While recent breakthroughs in PNP discovery raised the challenge of developing new algorithms for their analysis, identification of PNPs via database search of tandem mass spectra remains an open problem. To address this problem, natural product researchers utilize dereplication strategies that identify known PNPs and lead to the discovery of new ones even in cases when the reference spectra are not present in existing spectral libraries. DEREPLICATOR is a new dereplication algorithm that enabled high-throughput PNP identification and that is compatible with large-scale mass spectrometry-based screening platforms for natural product discovery. After searching nearly one hundred million tandem mass spectra in the Global Natural Products Social (GNPS) molecular networking infrastructure, DEREPLICATOR identified an order of magnitude more PNPs (and their new variants) than any previous dereplication efforts. PMID:27820803

Anti-Biofilm Performance of Three Natural Products against Initial Bacterial Attachment

PubMed Central

Salta, Maria; Wharton, Julian A.; Dennington, Simon P.; Stoodley, Paul; Stokes, Keith R.

2013-01-01

Marine bacteria contribute significantly towards the fouling consortium, both directly (modern foul release coatings fail to prevent “slime” attachment) and indirectly (biofilms often excrete chemical cues that attract macrofouling settlement). This study assessed the natural product anti-biofilm performance of an extract of the seaweed, Chondrus crispus, and two isolated compounds from terrestrial sources, (+)-usnic acid and juglone, against two marine biofilm forming bacteria, Cobetia marina and Marinobacter hydrocarbonoclasticus. Bioassays were developed using quantitative imaging and fluorescent labelling to test the natural products over a range of concentrations against initial bacterial attachment. All natural products affected bacterial attachment; however, juglone demonstrated the best anti-biofilm performance against both bacterial species at a concentration range between 5–20 ppm. In addition, for the first time, a dose-dependent inhibition (hormetic) response was observed for natural products against marine biofilm forming bacteria. PMID:24192819

Natural Product Potential of the Genus Nocardiopsis

PubMed Central

Ibrahim, Alyaa Hatem; Desoukey, Samar Yehia; Fouad, Mostafa A.; Kamel, Mohamed Salah; Gulder, Tobias A. M.; Abdelmohsen, Usama Ramadan

2018-01-01

Actinomycetes are a relevant source of novel bioactive compounds. One of the pharmaceutically and biotechnologically important genera that attract natural products research is the genus Nocardiopsis, mainly for its ability to produce a wide variety of secondary metabolites accounting for its wide range of biological activities. This review covers the literature from January 2015 until February 2018 making a complete survey of all the compounds that were isolated from the genus Nocardiopsis, their biological activities, and natural sources, whenever applicable. PMID:29710816

Opportunities and Challenges for Natural Products as Novel Antituberculosis Agents.

PubMed

Farah, Shrouq I; Abdelrahman, Abd Almonem; North, E Jeffrey; Chauhan, Harsh

2016-01-01

Current tuberculosis (TB) treatment suffers from complexity of the dosage regimens, length of treatment, and toxicity risks. Many natural products have shown activity against drug-susceptible, drug-resistant, and latent/dormant Mycobacterium tuberculosis, the pathogen responsible for TB infections. Natural sources, including plants, fungi, and bacteria, provide a rich source of chemically diverse compounds equipped with unique pharmacological, pharmacokinetic, and pharmacodynamic properties. This review focuses on natural products as starting points for the discovery and development of novel anti-TB chemotherapy and classifies them based on their chemical nature. The classes discussed are divided into alkaloids, chalcones, flavonoids, peptides, polyketides, steroids, and terpenes. This review also highlights the importance of collaboration between phytochemistry, medicinal chemistry, and physical chemistry, which is very important for the development of these natural compounds.

Metabolic Profile and Root Development of Hypericum perforatum L. In vitro Roots under Stress Conditions Due to Chitosan Treatment and Culture Time.

PubMed

Brasili, Elisa; Miccheli, Alfredo; Marini, Federico; Praticò, Giulia; Sciubba, Fabio; Di Cocco, Maria E; Cechinel, Valdir Filho; Tocci, Noemi; Valletta, Alessio; Pasqua, Gabriella

2016-01-01

The responses of Hypericum perforatum root cultures to chitosan elicitation had been investigated through (1)H-NMR-based metabolomics associated with morpho-anatomical analyses. The root metabolome was influenced by two factors, i.e., time of culture (associated with biomass growth and related "overcrowding stress") and chitosan elicitation. ANOVA simultaneous component analysis (ASCA) modeling showed that these factors act independently. In response to the increase of biomass density over time, a decrease in the synthesis of isoleucine, valine, pyruvate, methylamine, etanolamine, trigonelline, glutamine and fatty acids, and an increase in the synthesis of phenolic compounds, such as xanthones, epicatechin, gallic, and shikimic acid were observed. Among the xanthones, brasilixanthone B has been identified for the first time in chitosan-elicited root cultures of H. perforatum. Chitosan treatment associated to a slowdown of root biomass growth caused an increase in DMAPP and a decrease in stigmasterol, shikimic acid, and tryptophan levels. The histological analysis of chitosan-treated roots revealed a marked swelling of the root apex, mainly due to the hypertrophy of the first two sub-epidermal cell layers. In addition, periclinal divisions in hypertrophic cortical cells, resulting in an increase of cortical layers, were frequently observed. Most of the metabolic variations as well as the morpho-anatomical alterations occurred within 72 h from the elicitation, suggesting an early response of H. perforatum roots to chitosan elicitation. The obtained results improve the knowledge of the root responses to biotic stress and provide useful information to optimize the biotechnological production of plant compounds of industrial interest.

Metabolic Profile and Root Development of Hypericum perforatum L. In vitro Roots under Stress Conditions Due to Chitosan Treatment and Culture Time

PubMed Central

Brasili, Elisa; Miccheli, Alfredo; Marini, Federico; Praticò, Giulia; Sciubba, Fabio; Di Cocco, Maria E.; Cechinel, Valdir Filho; Tocci, Noemi; Valletta, Alessio; Pasqua, Gabriella

2016-01-01

The responses of Hypericum perforatum root cultures to chitosan elicitation had been investigated through 1H-NMR-based metabolomics associated with morpho-anatomical analyses. The root metabolome was influenced by two factors, i.e., time of culture (associated with biomass growth and related “overcrowding stress”) and chitosan elicitation. ANOVA simultaneous component analysis (ASCA) modeling showed that these factors act independently. In response to the increase of biomass density over time, a decrease in the synthesis of isoleucine, valine, pyruvate, methylamine, etanolamine, trigonelline, glutamine and fatty acids, and an increase in the synthesis of phenolic compounds, such as xanthones, epicatechin, gallic, and shikimic acid were observed. Among the xanthones, brasilixanthone B has been identified for the first time in chitosan-elicited root cultures of H. perforatum. Chitosan treatment associated to a slowdown of root biomass growth caused an increase in DMAPP and a decrease in stigmasterol, shikimic acid, and tryptophan levels. The histological analysis of chitosan-treated roots revealed a marked swelling of the root apex, mainly due to the hypertrophy of the first two sub-epidermal cell layers. In addition, periclinal divisions in hypertrophic cortical cells, resulting in an increase of cortical layers, were frequently observed. Most of the metabolic variations as well as the morpho-anatomical alterations occurred within 72 h from the elicitation, suggesting an early response of H. perforatum roots to chitosan elicitation. The obtained results improve the knowledge of the root responses to biotic stress and provide useful information to optimize the biotechnological production of plant compounds of industrial interest. PMID:27148330

Natural products as potential anticonvulsants: caffeoylquinic acids.

PubMed

Kim, Hyo Geun; Oh, Myung Sook

2012-03-01

Current anticonvulsant therapies are generally directed at symptomatic treatment by suppressing excitability within the brain. Consequently, they have adverse effects such as cognitive impairment, dependence, and abuse. The need for more effective and less toxic anticonvulsants has generated renewed interest in natural products for the treatment of convulsions. Caffeoylquinic acids (CQs) are naturally occurring phenolic acids that are distributed widely in plants. There has been increasing interest in the biological activities of CQs in diseases of the central nervous system. In this issue, Nugroho et al. give evidence for the anticonvulsive effect of a CQ-rich extract from Aster glehni Franchet et Sckmidt. They optimized the extract solvent conditions, resulting in high levels of CQs and peroxynitrite-scavenging activity. Then, they investigated the sedative and anticonvulsive effects in pentobarbital- and pentylenetetrazole-induced models in mice. The CQ-rich extract significantly inhibited tonic convulsions as assessed by onset time, tonic extent, and mortality. They suggested that the CQ-rich extract from A. glehni has potential for treating convulsions. This report provides preclinical data which may be used for the development of anticonvulsants from natural products.

Genomes to natural products PRediction Informatics for Secondary Metabolomes (PRISM).

PubMed

Skinnider, Michael A; Dejong, Chris A; Rees, Philip N; Johnston, Chad W; Li, Haoxin; Webster, Andrew L H; Wyatt, Morgan A; Magarvey, Nathan A

2015-11-16

Microbial natural products are an invaluable source of evolved bioactive small molecules and pharmaceutical agents. Next-generation and metagenomic sequencing indicates untapped genomic potential, yet high rediscovery rates of known metabolites increasingly frustrate conventional natural product screening programs. New methods to connect biosynthetic gene clusters to novel chemical scaffolds are therefore critical to enable the targeted discovery of genetically encoded natural products. Here, we present PRISM, a computational resource for the identification of biosynthetic gene clusters, prediction of genetically encoded nonribosomal peptides and type I and II polyketides, and bio- and cheminformatic dereplication of known natural products. PRISM implements novel algorithms which render it uniquely capable of predicting type II polyketides, deoxygenated sugars, and starter units, making it a comprehensive genome-guided chemical structure prediction engine. A library of 57 tailoring reactions is leveraged for combinatorial scaffold library generation when multiple potential substrates are consistent with biosynthetic logic. We compare the accuracy of PRISM to existing genomic analysis platforms. PRISM is an open-source, user-friendly web application available at http://magarveylab.ca/prism/. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

NATURAL PRODUCTS: A CONTINUING SOURCE OF NOVEL DRUG LEADS

PubMed Central

Cragg, Gordon M.; Newman, David J.

2013-01-01

1. Background Nature has been a source of medicinal products for millennia, with many useful drugs developed from plant sources. Following discovery of the penicillins, drug discovery from microbial sources occurred and diving techniques in the 1970s opened the seas. Combinatorial chemistry (late 1980s), shifted the focus of drug discovery efforts from Nature to the laboratory bench. 2. Scope of Review This review traces natural products drug discovery, outlining important drugs from natural sources that revolutionized treatment of serious diseases. It is clear Nature will continue to be a major source of new structural leads, and effective drug development depends on multidisciplinary collaborations. 3. Major Conclusions The explosion of genetic information led not only to novel screens, but the genetic techniques permitted the implementation of combinatorial biosynthetic technology and genome mining. The knowledge gained has allowed unknown molecules to be identified. These novel bioactive structures can be optimized by using combinatorial chemistry generating new drug candidates for many diseases. 4 General Significance: The advent of genetic techniques that permitted the isolation / expression of biosynthetic cassettes from microbes may well be the new frontier for natural products lead discovery. It is now apparent that biodiversity may be much greater in those organisms. The numbers of potential species involved in the microbial world are many orders of magnitude greater than those of plants and multi-celled animals. Coupling these numbers to the number of currently unexpressed biosynthetic clusters now identified (>10 per species) the potential of microbial diversity remains essentially untapped. PMID:23428572

Natural products as inspiration for the development of new synthetic methods.

PubMed

Ma, Zhiqiang; Chen, Chuo

2018-01-01

Natural products have played an important role in shaping modern synthetic organic chemistry. In particular, their complex molecular skeletons have stimulated the development of many new synthetic methods. We highlight in this article some recent examples of synthetic design inspired by the biosynthesis of natural products.

Therapeutic potential of natural products in Parkinson's disease.

PubMed

Mythri, Rajeswara B; Harish, Gangadharappa; Bharath, M M

2012-09-01

The central objective in treating patients with Parkinson's disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents.

Discovery of novel drug targets and their functions using phenotypic screening of natural products.

PubMed

Chang, Junghwa; Kwon, Ho Jeong

2016-03-01

Natural products are valuable resources that provide a variety of bioactive compounds and natural pharmacophores in modern drug discovery. Discovery of biologically active natural products and unraveling their target proteins to understand their mode of action have always been critical hurdles for their development into clinical drugs. For effective discovery and development of bioactive natural products into novel therapeutic drugs, comprehensive screening and identification of target proteins are indispensable. In this review, a systematic approach to understanding the mode of action of natural products isolated using phenotypic screening involving chemical proteomics-based target identification is introduced. This review highlights three natural products recently discovered via phenotypic screening, namely glucopiericidin A, ecumicin, and terpestacin, as representative case studies to revisit the pivotal role of natural products as powerful tools in discovering the novel functions and druggability of targets in biological systems and pathological diseases of interest.

[Advances in the study of anti-MRSA natural products].

PubMed

Song, Hao; Qin, Yong

2016-05-01

Methicillin-resistant Staphylococcus aureus (MRSA) is a multi-drug resistant pathogenic bacteria, which has seriously threatened human health for a long time. Discovery of novel anti-MRSA lead compounds with high efficiency and low toxicity represents an important research focus in the realm of antibiotic studies. Owing to their structural diversity and complexity, natural products have exhibited unique advantages and great potential in the development of anti-MRSA new drugs.This review summarizes the studies of anti-MRSA natural products and their relevant medicinal chemistry reported since 2010.

Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity.

PubMed

Rayan, Anwar; Raiyn, Jamal; Falah, Mizied

2017-01-01

Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab.

HEx: A heterologous expression platform for the discovery of fungal natural products

PubMed Central

Schlecht, Ulrich; Horecka, Joe; Lin, Hsiao-Ching; Naughton, Brian; Miranda, Molly; Li, Yong Fuga; Hennessy, James R.; Vandova, Gergana A.; Steinmetz, Lars M.; Sattely, Elizabeth; Khosla, Chaitan; Hillenmeyer, Maureen E.

2018-01-01

For decades, fungi have been a source of U.S. Food and Drug Administration–approved natural products such as penicillin, cyclosporine, and the statins. Recent breakthroughs in DNA sequencing suggest that millions of fungal species exist on Earth, with each genome encoding pathways capable of generating as many as dozens of natural products. However, the majority of encoded molecules are difficult or impossible to access because the organisms are uncultivable or the genes are transcriptionally silent. To overcome this bottleneck in natural product discovery, we developed the HEx (Heterologous EXpression) synthetic biology platform for rapid, scalable expression of fungal biosynthetic genes and their encoded metabolites in Saccharomyces cerevisiae. We applied this platform to 41 fungal biosynthetic gene clusters from diverse fungal species from around the world, 22 of which produced detectable compounds. These included novel compounds with unexpected biosynthetic origins, particularly from poorly studied species. This result establishes the HEx platform for rapid discovery of natural products from any fungal species, even those that are uncultivable, and opens the door to discovery of the next generation of natural products. PMID:29651464

Research Progress in Reversal of Tumor Multi-drug Resistance via Natural Products.

PubMed

Guo, Qi; Cao, Hongyan; Qi, Xianghui; Li, Huikai; Ye, Peizhi; Wang, Zhiguo; Wang, Danqiao; Sun, Mingyu

2017-11-24

Multidrug resistance occurs when a tumor develops resistance to multiple chemotherapeutic drugs, which may include antitumor drugs with different chemical structures and mechanisms. Multidrug resistance limits the treatment effects of antitumor drugs, and is the main cause of chemotherapy failure. Multidrug resistance is caused by numerous factors including changes in ATP-binding cassette transporters, target proteins, detoxification, deoxyribonucleic acid repair, drug metabolic enzymes, and signal pathways of apoptosis. Clinical research indicates that natural products have great potential to treat tumors and reverse multidrug resistance. Natural products, which often have multiple targets, could play an important role in tumor treatment, have beneficial effects on tumor inhibition, improve symptoms, reduce radiotherapy and chemotherapy side effects, enhance immunity, and prolong survival. Because natural products often have few adverse reactions and less drug resistance, the antitumor activities of natural products have attracted extensive research. We aimed to review the basic research and clinical application of natural products in the reversal of multidrug resistance. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The natural product chitosan enhances the anti-tumor activity of natural killer cells by activating dendritic cells.

PubMed

Li, Xinxin; Dong, Wenjuan; Nalin, Ansel P; Wang, Yufeng; Pan, Pan; Xu, Bo; Zhang, Yibo; Tun, Steven; Zhang, Jianying; Wang, Li-Shu; He, Xiaoming; Caligiuri, Michael A; Yu, Jianhua

2018-01-01

Natural products comprise an important class of biologically active molecules. Many of these compounds derived from natural sources exhibit specific physiologic or biochemical effects. An example of a natural product is chitosan, which is enriched in the shells of certain seafood that are frequently consumed worldwide. Like other natural products, chitosan has the potential for applications in clinical medicine and perhaps in cancer therapy. Toward this end, the immunomodulatory or anti-cancer properties of chitosan have yet to be reported. In this study, we discovered that chitosan enhanced the anti-tumor activity of natural killer (NK) cells by activating dendritic cells (DCs). In the presence of DCs, chitosan augmented IFN-γ production by human NK cells. Mechanistically, chitosan activated DCs to express pro-inflammatory cytokines such as interleukin (IL)-12 and IL-15, which in turn activated the STAT4 and NF-κB signaling pathways, respectively, in NK cells. Moreover, chitosan promoted NK cell survival, and also enhanced NK cell cytotoxicity against leukemia cells. Finally, a related in vivo study demonstrated that chitosan activated NK cells against B16F10 tumor cells in an immunocompetent syngeneic murine melanoma model. This effect was accompanied by in vivo upregulation of IL-12 and IL-15 in DCs, as well as increased IFN-γ production and cytolytic degranulation in NK cells. Collectively, our results demonstrate that chitosan activates DCs leading to enhanced capacity for immune surveillance by NK cells. We believe that our study has future clinical applications for chitosan in the prevention or treatment of cancer and infectious diseases.

Updates on Managing Type 2 Diabetes Mellitus with Natural Products: Towards Antidiabetic Drug Development.

PubMed

Alam, Fahmida; Islam, Md Asiful; Kamal, M A; Gan, Siew Hua

2016-08-13

Over the years, natural products have shown success as antidiabetics in vitro, in vivo and in clinical trials. Because natural product-derived drugs are more affordable and effective with fewer side-effects compared to conventional therapies, pharmaceutical research is increasingly leaning towards the discovery of new antidiabetic drugs from natural products targeting pathways or components associated with type 2 diabetes mellitus (T2DM) pathophysiology. However, the drug discovery process is very lengthy and costly with significant challenges. Therefore, various techniques are currently being developed for the preclinical research phase of drug discovery with the aim of drug development with less time and efforts from natural products. In this review, we have provided an update on natural products including fruits, vegetables, spices, nuts, beverages and mushrooms with potential antidiabetic activities from in vivo, in vitro and clinical studies. Synergistic interactions between natural products and antidiabetic drugs; and potential antidiabetic active compounds from natural products are also documented to pave the way for combination treatment and new drug discovery, respectively. Additionally, a brief idea of the drug discovery process along with the challenges that arise during drug development from natural products and the methods to conquer those challenges are discussed to create a more convenient future drug discovery process.

Prediction of cancer cell sensitivity to natural products based on genomic and chemical properties.

PubMed

Yue, Zhenyu; Zhang, Wenna; Lu, Yongming; Yang, Qiaoyue; Ding, Qiuying; Xia, Junfeng; Chen, Yan

2015-01-01

Natural products play a significant role in cancer chemotherapy. They are likely to provide many lead structures, which can be used as templates for the construction of novel drugs with enhanced antitumor activity. Traditional research approaches studied structure-activity relationship of natural products and obtained key structural properties, such as chemical bond or group, with the purpose of ascertaining their effect on a single cell line or a single tissue type. Here, for the first time, we develop a machine learning method to comprehensively predict natural products responses against a panel of cancer cell lines based on both the gene expression and the chemical properties of natural products. The results on two datasets, training set and independent test set, show that this proposed method yields significantly better prediction accuracy. In addition, we also demonstrate the predictive power of our proposed method by modeling the cancer cell sensitivity to two natural products, Curcumin and Resveratrol, which indicate that our method can effectively predict the response of cancer cell lines to these two natural products. Taken together, the method will facilitate the identification of natural products as cancer therapies and the development of precision medicine by linking the features of patient genomes to natural product sensitivity.

Strain Prioritization for Natural Product Discovery by a High-Throughput Real-Time PCR Method

PubMed Central

2015-01-01

Natural products offer unmatched chemical and structural diversity compared to other small-molecule libraries, but traditional natural product discovery programs are not sustainable, demanding too much time, effort, and resources. Here we report a strain prioritization method for natural product discovery. Central to the method is the application of real-time PCR, targeting genes characteristic to the biosynthetic machinery of natural products with distinct scaffolds in a high-throughput format. The practicality and effectiveness of the method were showcased by prioritizing 1911 actinomycete strains for diterpenoid discovery. A total of 488 potential diterpenoid producers were identified, among which six were confirmed as platensimycin and platencin dual producers and one as a viguiepinol and oxaloterpin producer. While the method as described is most appropriate to prioritize strains for discovering specific natural products, variations of this method should be applicable to the discovery of other classes of natural products. Applications of genome sequencing and genome mining to the high-priority strains could essentially eliminate the chance elements from traditional discovery programs and fundamentally change how natural products are discovered. PMID:25238028

NPCARE: database of natural products and fractional extracts for cancer regulation.

PubMed

Choi, Hwanho; Cho, Sun Young; Pak, Ho Jeong; Kim, Youngsoo; Choi, Jung-Yun; Lee, Yoon Jae; Gong, Byung Hee; Kang, Yeon Seok; Han, Taehoon; Choi, Geunbae; Cho, Yeeun; Lee, Soomin; Ryoo, Dekwoo; Park, Hwangseo

2017-01-01

Natural products have increasingly attracted much attention as a valuable resource for the development of anticancer medicines due to the structural novelty and good bioavailability. This necessitates a comprehensive database for the natural products and the fractional extracts whose anticancer activities have been verified. NPCARE (http://silver.sejong.ac.kr/npcare) is a publicly accessible online database of natural products and fractional extracts for cancer regulation. At NPCARE, one can explore 6578 natural compounds and 2566 fractional extracts isolated from 1952 distinct biological species including plants, marine organisms, fungi, and bacteria whose anticancer activities were validated with 1107 cell lines for 34 cancer types. Each entry in NPCARE is annotated with the cancer type, genus and species names of the biological resource, the cell line used for demonstrating the anticancer activity, PubChem ID, and a wealth of information about the target gene or protein. Besides the augmentation of plant entries up to 743 genus and 197 families, NPCARE is further enriched with the natural products and the fractional extracts of diverse non-traditional biological resources. NPCARE is anticipated to serve as a dominant gateway for the discovery of new anticancer medicines due to the inclusion of a large number of the fractional extracts as well as the natural compounds isolated from a variety of biological resources.

Does natural selection organize ecosystems for the maintenance of high productivity and diversity?

PubMed Central

Leigh, Egbert Giles; Vermeij, Geerat Jacobus

2002-01-01

Three types of evidence suggest that natural ecosystems are organized for high productivity and diversity: (i) changes not previously experienced by a natural ecosystem, such as novel human disturbances, tend to diminish its productivity and/or diversity, just as 'random' changes in a machine designed for a function usually impair its execution of that function; (ii) humans strive to recreate properties of natural ecosystems to enhance productivity of artificial ones, as farmers try to recreate properties of natural soils in their fields; and (iii) productivity and diversity have increased during the Earth's history as a whole, and after every major biotic crisis. Natural selection results in ecosystems organized to maintain high productivity of organic matter and diversity of species, just as competition among individuals in Adam Smith's ideal economy favours high production of wealth and diversity of occupations. In nature, poorly exploited energy attracts more efficient users. This circumstance favours the opening of new ways of life and more efficient recycling of resources, and eliminates most productivity-reducing 'ecological monopolies'. Ecological dominants tend to be replaced by successors with higher metabolism, which respond to more stimuli and engage in more varied interactions. Finally, increasingly efficient predators and herbivores favour faster turnover of resources. PMID:12079531

Targeting arachidonic acid pathway by natural products for cancer prevention and therapy.

PubMed

Yarla, Nagendra Sastry; Bishayee, Anupam; Sethi, Gautam; Reddanna, Pallu; Kalle, Arunasree M; Dhananjaya, Bhadrapura Lakkappa; Dowluru, Kaladhar S V G K; Chintala, Ramakrishna; Duddukuri, Govinda Rao

2016-10-01

Arachidonic acid (AA) pathway, a metabolic process, plays a key role in carcinogenesis. Hence, AA pathway metabolic enzymes phospholipase A 2 s (PLA 2 s), cyclooxygenases (COXs) and lipoxygenases (LOXs) and their metabolic products, such as prostaglandins and leukotrienes, have been considered novel preventive and therapeutic targets in cancer. Bioactive natural products are a good source for development of novel cancer preventive and therapeutic drugs, which have been widely used in clinical practice due to their safety profiles. AA pathway inhibitory natural products have been developed as chemopreventive and therapeutic agents against several cancers. Curcumin, resveratrol, apigenin, anthocyans, berberine, ellagic acid, eugenol, fisetin, ursolic acid, [6]-gingerol, guggulsteone, lycopene and genistein are well known cancer chemopreventive agents which act by targeting multiple pathways, including COX-2. Nordihydroguaiaretic acid and baicalein can be chemopreventive molecules against various cancers by inhibiting LOXs. Several PLA 2 s inhibitory natural products have been identified with chemopreventive and therapeutic potentials against various cancers. In this review, we critically discuss the possible utility of natural products as preventive and therapeutic agents against various oncologic diseases, including prostate, pancreatic, lung, skin, gastric, oral, blood, head and neck, colorectal, liver, cervical and breast cancers, by targeting AA pathway. Further, the current status of clinical studies evaluating AA pathway inhibitory natural products in cancer is reviewed. In addition, various emerging issues, including bioavailability, toxicity and explorability of combination therapy, for the development of AA pathway inhibitory natural products as chemopreventive and therapeutic agents against human malignancy are also discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Chocolate: A Marvelous Natural Product of Chemistry

ERIC Educational Resources Information Center

Tannenbaum, Ginger

2004-01-01

The study of chocolate, a natural product, can be beneficial for the chemistry students as they ask frequently about the relevancy of their chemistry classes. The history of chocolate, its chemical and physical changes during processing, its composition, different crystalline forms, tempering and its viscosity are discussed.

Inhibition of aflatoxin B production of Aspergillus flavus, isolated from soybean seeds by certain natural plant products.

PubMed

Krishnamurthy, Y L; Shashikala, J

2006-11-01

The inhibitory effect of cowdung fumes, Captan, leaf powder of Withania somnifera, Hyptis suaveolens, Eucalyptus citriodora, peel powder of Citrus sinensis, Citrus medica and Punica granatum, neem cake and pongamia cake and spore suspension of Trichoderma harzianum and Aspergillus niger on aflatoxin B(1) production by toxigenic strain of Aspergillus flavus isolated from soybean seeds was investigated. Soybean seed was treated with different natural products and fungicide captan and was inoculated with toxigenic strain of A. flavus and incubated for different periods. The results showed that all the treatments were effective in controlling aflatoxin B(1) production. Captan, neem cake, spore suspension of T. harzianum, A. niger and combination of both reduced the level of aflatoxin B(1) to a great extent. Leaf powder of W. somnifera, H. suaveolens, peel powder of C. sinensis, C. medica and pongamia cake also controlled the aflatoxin B(1) production. All the natural product treatments applied were significantly effective in inhibiting aflatoxin B(1) production on soybean seeds by A. flavus. These natural plant products may successfully replace chemical fungicides and provide an alternative method to protect soybean and other agricultural commodities from aflatoxin B(1) production by A. flavus.

Natural Products: Insights into Leishmaniasis Inflammatory Response

PubMed Central

Rodrigues, Igor A.; Mazotto, Ana Maria; Cardoso, Verônica; Alves, Renan L.; Amaral, Ana Claudia F.; Silva, Jefferson Rocha de Andrade; Pinheiro, Anderson S.; Vermelho, Alane B.

2015-01-01

Leishmaniasis is a vector-borne disease that affects several populations worldwide, against which there are no vaccines available and the chemotherapy is highly toxic. Depending on the species causing the infection, the disease is characterized by commitment of tissues, including the skin, mucous membranes, and internal organs. Despite the relevance of host inflammatory mediators on parasite burden control, Leishmania and host immune cells interaction may generate an exacerbated proinflammatory response that plays an important role in the development of leishmaniasis clinical manifestations. Plant-derived natural products have been recognized as bioactive agents with several properties, including anti-protozoal and anti-inflammatory activities. The present review focuses on the antileishmanial activity of plant-derived natural products that are able to modulate the inflammatory response in vitro and in vivo. The capability of crude extracts and some isolated substances in promoting an anti-inflammatory response during Leishmania infection may be used as part of an effective strategy to fight the disease. PMID:26538837

Atmospheric emissions and air quality impacts from natural gas production and use.

PubMed

Allen, David T

2014-01-01

The US Energy Information Administration projects that hydraulic fracturing of shale formations will become a dominant source of domestic natural gas supply over the next several decades, transforming the energy landscape in the United States. However, the environmental impacts associated with fracking for shale gas have made it controversial. This review examines emissions and impacts of air pollutants associated with shale gas production and use. Emissions and impacts of greenhouse gases, photochemically active air pollutants, and toxic air pollutants are described. In addition to the direct atmospheric impacts of expanded natural gas production, indirect effects are also described. Widespread availability of shale gas can drive down natural gas prices, which, in turn, can impact the use patterns for natural gas. Natural gas production and use in electricity generation are used as a case study for examining these indirect consequences of expanded natural gas availability.

Survey of marine natural product structure revisions: a synergy of spectroscopy and chemical synthesis

PubMed Central

Suyama, Takashi L.; Gerwick, William H.; McPhail, Kerry L.

2011-01-01

The structural assignment of new natural product molecules supports research in a multitude of disciplines that may lead to new therapeutic agents and or new understanding of disease biology. However, reports of numerous structural revisions, even of recently elucidated natural products, inspired the present survey of techniques used in structural misassignments and subsequent revisions in the context of constitutional or configurational errors. Given the comparatively recent development of marine natural products chemistry, coincident with the modern spectroscopy, it is of interest to consider the relative roles of spectroscopy and chemical synthesis in the structure elucidation and revision of those marine natural products which were initially misassigned. Thus, a tabulated review of all marine natural product structural revisions from 2005 to 2010 is organized according to structural motif revised. Misassignments of constitution are more frequent than perhaps anticipated by reliance on HMBC and other advanced NMR experiments, especially considering the full complement of all natural products. However, these techniques also feature prominently in structural revisions, specifically of marine natural products. Nevertheless, as is the case for revision of relative and absolute configuration, total synthesis is a proven partner for marine, as well as terrestrial, natural products structure elucidation. It also becomes apparent that considerable ‘detective work’ remains in structure elucidation, in spite of the spectacular advances in spectroscopic techniques. PMID:21715178

Discovery of the leinamycin family of natural products by mining actinobacterial genomes.

PubMed

Pan, Guohui; Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Yang, Dong; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen; Shen, Ben

2017-12-26

Nature's ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF-SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF-SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm -type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature's rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature's biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity.

Modern Natural Products Drug Discovery and its Relevance to Biodiversity Conservation†

PubMed Central

Kingston, David G. I.

2010-01-01

Natural products continue to provide a diverse and unique source of bioactive lead compounds for drug discovery, but maintaining their continued eminence as source compounds is challenging in the face of the changing face of the pharmaceutical industry and the changing nature of biodiversity prospecting brought about by the Convention of Biodiversity. This review provides an overview of some of these challenges, and suggests ways in which they can be addressed so that natural products research can remain a viable and productive route to drug discovery. Results from International Cooperative Biodiversity Groups (ICBGs) working in Madagascar, Panama, and Suriname are used as examples of what can be achieved when biodiversity conservation is linked to drug discovery. PMID:21138324

Anti-Candida albicans natural products, sources of new antifungal drugs: A review.

PubMed

Zida, A; Bamba, S; Yacouba, A; Ouedraogo-Traore, R; Guiguemdé, R T

2017-03-01

Candida albicans is the most prevalent fungal pathogen in humans. Due to the development of drug resistance, there is today a need for new antifungal agents for the efficient management of C. albicans infections. Therefore, we reviewed antifungal activity, mechanisms of action, possible synergism with antifungal drugs of all natural substances experimented to be efficient against C. albicans for future. An extensive and systematic review of the literature was undertaken and all relevant abstracts and full-text articles analyzed and included in the review. A total of 111 documents were published and highlighted 142 anti-C. albicans natural products. These products are mostly are reported in Asia (44.37%) and America (28.17%). According to in vitro model criteria, from the 142 natural substances, antifungal activity can be considered as important for 40 (28.20%) and moderate for 24 (16.90%). Sixteen products have their antifungal activity confirmed by in vivo gold standard experimentation. Microbial natural products, source of antifungals, have their antifungal mechanism well described in the literature: interaction with ergosterol (polyenes), inhibition 1,3-β-d-glucan synthase (Echinocandins), inhibition of the synthesis of cell wall components (chitin and mannoproteins), inhibition of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase) and inhibition of protein synthesis (sordarins). Natural products from plants mostly exert their antifungal effects by membrane-active mechanism. Some substances from arthropods are also explored to act on the fungal membrane. Interestingly, synergistic effects were found between different classes of natural products as well as between natural products and azoles. Search for anti-C. albicans new drugs is promising since the list of natural substances, which disclose activity against this yeast is today long. Investigations must be pursued not only to found more new anti

Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity

PubMed Central

Rayan, Anwar; Raiyn, Jamal

2017-01-01

Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab. PMID:29121120

Chemical proteomics approaches for identifying the cellular targets of natural products

PubMed Central

Sieber, S. A.

2016-01-01

Covering: 2010 up to 2016 Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied “in situ” – in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide–alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss ‘competitive mode’ approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed. PMID:27098809

Chemical proteomics approaches for identifying the cellular targets of natural products.

PubMed

Wright, M H; Sieber, S A

2016-05-04

Covering: 2010 up to 2016Deconvoluting the mode of action of natural products and drugs remains one of the biggest challenges in chemistry and biology today. Chemical proteomics is a growing area of chemical biology that seeks to design small molecule probes to understand protein function. In the context of natural products, chemical proteomics can be used to identify the protein binding partners or targets of small molecules in live cells. Here, we highlight recent examples of chemical probes based on natural products and their application for target identification. The review focuses on probes that can be covalently linked to their target proteins (either via intrinsic chemical reactivity or via the introduction of photocrosslinkers), and can be applied "in situ" - in living systems rather than cell lysates. We also focus here on strategies that employ a click reaction, the copper-catalysed azide-alkyne cycloaddition reaction (CuAAC), to allow minimal functionalisation of natural product scaffolds with an alkyne or azide tag. We also discuss 'competitive mode' approaches that screen for natural products that compete with a well-characterised chemical probe for binding to a particular set of protein targets. Fuelled by advances in mass spectrometry instrumentation and bioinformatics, many modern strategies are now embracing quantitative proteomics to help define the true interacting partners of probes, and we highlight the opportunities this rapidly evolving technology provides in chemical proteomics. Finally, some of the limitations and challenges of chemical proteomics approaches are discussed.

Genome engineering for microbial natural product discovery.

PubMed

Choi, Si-Sun; Katsuyama, Yohei; Bai, Linquan; Deng, Zixin; Ohnishi, Yasuo; Kim, Eung-Soo

2018-03-03

The discovery and development of microbial natural products (MNPs) have played pivotal roles in the fields of human medicine and its related biotechnology sectors over the past several decades. The post-genomic era has witnessed the development of microbial genome mining approaches to isolate previously unsuspected MNP biosynthetic gene clusters (BGCs) hidden in the genome, followed by various BGC awakening techniques to visualize compound production. Additional microbial genome engineering techniques have allowed higher MNP production titers, which could complement a traditional culture-based MNP chasing approach. Here, we describe recent developments in the MNP research paradigm, including microbial genome mining, NP BGC activation, and NP overproducing cell factory design. Copyright © 2018 Elsevier Ltd. All rights reserved.

Synthesis and characterization of a small analogue of the anticancer natural product leinamycin.

PubMed

Keerthi, Kripa; Rajapakse, Anuruddha; Sun, Daekyu; Gates, Kent S

2013-01-01

Leinamycin (1) is a Streptomyces-derived natural product that displays nanomolar IC(50) values against human cancer cell lines. In the work described here, we report the synthesis and characterization of a small leinamycin analogue 19 that closely resembles the 'upper-right quadrant' of the natural product, consisting of an alicyclic 1,2-dithiolan-3-one 1-oxide heterocycle connected to an alkene by a two-carbon linker. The results indicate that this small analogue contains the core set of functional groups required to enable thiol-triggered generation of both redox active polysulfides and an episulfonium ion intermediate via the complex reaction cascade first seen in the natural product leinamycin. The small leinamycin analogue 19 caused thiol-triggered oxidative DNA strand cleavage in a manner similar to the natural product, but did not alkyate duplex DNA effectively. This highlights the central role of the 18-membered macrocycle of leinamycin in driving efficient DNA alkylation by the natural product. Copyright © 2012 Elsevier Ltd. All rights reserved.

"Pruning of biomolecules and natural products (PBNP)": an innovative paradigm in drug discovery.

PubMed

Bathula, Surendar Reddy; Akondi, Srirama Murthy; Mainkar, Prathama S; Chandrasekhar, Srivari

2015-06-21

The source or inspiration of many marketed drugs can be traced back to natural product research. However, the chemical structure of natural products covers a wide spectrum from very simple to complex. With more complex structures it is often desirable to simplify the molecule whilst retaining the desired biological activity. This approach seeks to identify the structural unit or pharmacophore responsible for the desired activity. Such pharmacophores have been the start point for a wide range of lead generation and optimisation programmes using techniques such as Biology Oriented Synthesis, Diversity Oriented Synthesis, Diverted Total Synthesis, and Fragment Based Drug Discovery. This review discusses the literature precedence of simplification strategies in four areas of natural product research: proteins, polysaccharides, nucleic acids, and compounds isolated from natural product extracts, and their impact on identifying therapeutic products.

Natural gas production problems : solutions, methodologies, and modeling.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rautman, Christopher Arthur; Herrin, James M.; Cooper, Scott Patrick

2004-10-01

Natural gas is a clean fuel that will be the most important domestic energy resource for the first half the 21st centtuy. Ensuring a stable supply is essential for our national energy security. The research we have undertaken will maximize the extractable volume of gas while minimizing the environmental impact of surface disturbances associated with drilling and production. This report describes a methodology for comprehensive evaluation and modeling of the total gas system within a basin focusing on problematic horizontal fluid flow variability. This has been accomplished through extensive use of geophysical, core (rock sample) and outcrop data to interpretmore » and predict directional flow and production trends. Side benefits include reduced environmental impact of drilling due to reduced number of required wells for resource extraction. These results have been accomplished through a cooperative and integrated systems approach involving industry, government, academia and a multi-organizational team within Sandia National Laboratories. Industry has provided essential in-kind support to this project in the forms of extensive core data, production data, maps, seismic data, production analyses, engineering studies, plus equipment and staff for obtaining geophysical data. This approach provides innovative ideas and technologies to bring new resources to market and to reduce the overall environmental impact of drilling. More importantly, the products of this research are not be location specific but can be extended to other areas of gas production throughout the Rocky Mountain area. Thus this project is designed to solve problems associated with natural gas production at developing sites, or at old sites under redevelopment.« less

Natural and engineered polyhydroxyalkanoate (PHA) synthase: key enzyme in biopolyester production.

PubMed

Zou, Huibin; Shi, Mengxun; Zhang, Tongtong; Li, Lei; Li, Liangzhi; Xian, Mo

2017-10-01

With the finite supply of petroleum and increasing concern with environmental issues associated with their harvest and processing, the development of more eco-friendly, sustainable alternative biopolymers that can effectively fill the role of petro-polymers has become a major focus. Polyhydroxyalkanoate (PHA) can be naturally produced by many species of bacteria and the PHA synthase is believed to be key enzyme in this natural pathway. Natural PHA synthases are diverse and can affect the properties of the produced PHAs, such as monomer composition, molecular weights, and material properties. Moreover, recent studies have led to major advances in the searching of PHA synthases that display specific properties, as well as engineering efforts that offer more efficient PHA synthases, increased PHA compound production, or even novel biopolyesters which cannot be naturally produced. In this article, we review the updated information of natural PHA synthases and their engineering strategies for improved performance in polyester production. We also speculate future trends on the development of robust PHA synthases and their application in biopolyester production.

Natural products used as a chemical library for protein-protein interaction targeted drug discovery.

PubMed

Jin, Xuemei; Lee, Kyungro; Kim, Nam Hee; Kim, Hyun Sil; Yook, Jong In; Choi, Jiwon; No, Kyoung Tai

2018-01-01

Protein-protein interactions (PPIs), which are essential for cellular processes, have been recognized as attractive therapeutic targets. Therefore, the construction of a PPI-focused chemical library is an inevitable necessity for future drug discovery. Natural products have been used as traditional medicines to treat human diseases for millennia; in addition, their molecular scaffolds have been used in diverse approved drugs and drug candidates. The recent discovery of the ability of natural products to inhibit PPIs led us to use natural products as a chemical library for PPI-targeted drug discovery. In this study, we collected natural products (NPDB) from non-commercial and in-house databases to analyze their similarities to small-molecule PPI inhibitors (iPPIs) and FDA-approved drugs by using eight molecular descriptors. Then, we evaluated the distribution of NPDB and iPPIs in the chemical space, represented by the molecular fingerprint and molecular scaffolds, to identify the promising scaffolds, which could interfere with PPIs. To investigate the ability of natural products to inhibit PPI targets, molecular docking was used. Then, we predicted a set of high-potency natural products by using the iPPI-likeness score based on a docking score-weighted model. These selected natural products showed high binding affinities to the PPI target, namely XIAP, which were validated in an in vitro experiment. In addition, the natural products with novel scaffolds might provide a promising starting point for further medicinal chemistry developments. Overall, our study shows the potency of natural products in targeting PPIs, which might help in the design of a PPI-focused chemical library for future drug discovery. Copyright © 2017 Elsevier Inc. All rights reserved.

Current perspectives in drug discovery against tuberculosis from natural products.

PubMed

Nguta, Joseph Mwanzia; Appiah-Opong, Regina; Nyarko, Alexander K; Yeboah-Manu, Dorothy; Addo, Phyllis G A

2015-09-01

Currently, one third of the world's population is latently infected with Mycobacterium tuberculosis (MTB), while 8.9-9.9 million new and relapse cases of tuberculosis (TB) are reported yearly. The renewed research interests in natural products in the hope of discovering new and novel antitubercular leads have been driven partly by the increased incidence of multidrug-resistant strains of MTB and the adverse effects associated with the first- and second-line antitubercular drugs. Natural products have been, and will continue to be a rich source of new drugs against many diseases. The depth and breadth of therapeutic agents that have their origins in the secondary metabolites produced by living organisms cannot be compared with any other source of therapeutic agents. Discovery of new chemical molecules against active and latent TB from natural products requires an interdisciplinary approach, which is a major challenge facing scientists in this field. In order to overcome this challenge, cutting edge techniques in mycobacteriology and innovative natural product chemistry tools need to be developed and used in tandem. The present review provides a cross-linkage to the most recent literature in both fields and their potential to impact the early phase of drug discovery against TB if seamlessly combined. Copyright © 2015 Asian African Society for Mycobacteriology. Published by Elsevier Ltd. All rights reserved.

Marine natural products: a new wave of drugs?

PubMed Central

Montaser, Rana; Luesch, Hendrik

2011-01-01

The largely unexplored marine world that presumably harbors the most biodiversity may be the vastest resource to discover novel ‘validated’ structures with novel modes of action that cover biologically relevant chemical space. Several challenges, including the supply problem and target identification, need to be met for successful drug development of these often complex molecules; however, approaches are available to overcome the hurdles. Advances in technologies such as sampling strategies, nanoscale NMR for structure determination, total chemical synthesis, fermentation and biotechnology are all crucial to the success of marine natural products as drug leads. We illustrate the high degree of innovation in the field of marine natural products, which in our view will lead to a new wave of drugs that flow into the market and pharmacies in the future. PMID:21882941

2013-2014 Production of guayule natural rubber in Arizona, U.S.A.

USDA-ARS?s Scientific Manuscript database

Natural rubber is a unique biopolymer whose physical properties cannot be replicated in synthetic alternatives; therefore, it is required for production of tires (passenger, truck, and aircraft) and thousands of consumer and medical products. While demand for natural rubber is expected to increase ...

Nde of Lumber and Natural Fiber Based Products with Air Coupled Ultrasound

NASA Astrophysics Data System (ADS)

Hsu, David K.; Utrata, David; Kuo, Monlin

2010-02-01

Due to the porous nature of wood and natural fiber based products, conventional fluid or gel coupled ultrasonic inspection is unsuitable. Air-coupled ultrasonic transmission scanning, being non-contact, is ideally suited for inspecting lumber, wood and natural fiber based products. We report here several successful applications of air-coupled ultrasound for the inspection of wood. Air-coupled ultrasonic scan at 120 kHz can easily detect "sinker-stock" lumber in which bacterial damage of ray tissue cells had occurred during anaerobic pond storage. Channels in ash lumber board caused by insect bore were imaged in transmission scan. Delamination and material inhomogeneities were mapped out in manufactured wood and natural fiber products including medium density fiberboards, compression molded shredded waste wood with formaldehyde resin, and acoustic panels molded with kenaf fibers. The study has demonstrated some of the capabilities of air-coupled ultrasound in the NDE of forest products.

Hyperforin plasma level as a marker of treatment adherence in the National Institutes of Health Hypericum Depression Trial.

PubMed

Vitiello, Benedetto; Shader, Richard I; Parker, Corette B; Ritz, Louise; Harlan, William; Greenblatt, David J; Gadde, Kishore M; Krishnan, K Ranga R; Davidson, Jonathan R T

2005-06-01

A previously reported clinical trial of Hypericum perforatum (St John's wort) in depression did not demonstrate efficacy. We assessed treatment adherence by measuring plasma hyperforin and evaluated the possible impact of adherence on study results. Outpatients with major depression (N = 340) were randomized to an 8-week trial of H. perforatum (900-1500 mg/d), sertraline (50-100 mg/d) as active comparator, or placebo. Plasma was available from 292 patients (86% of randomized). Samples from the placebo and H. perforatum groups were assayed for hyperforin, and samples from the sertraline group for sertraline/N-desmethyl-sertraline. Of the 104 patients randomized to placebo, 18 (17%) had detectable plasma hyperforin. Of the 97 patients randomized to H. perforatum, 17 (17%) had no detectable plasma hyperforin. All the assayed sertraline patients (N = 91) had plasma sertraline/N-desmethyl-sertraline. The clinical trial conclusions remained unchanged when only patients with plasma assay consistent with random assignment were included in the analyses. One of every 6 patients assigned to placebo had plasma hyperforin, and 1 of every 6 patients assigned to H. perforatum had no detectable plasma hyperforin. The finding underscores the difficulty of enforcing treatment adherence in clinical trials of preparations that are readily available in the community.

Atmospheric hydrocarbon emissions and concentrations in the barnett shale natural gas production region.

PubMed

Zavala-Araiza, Daniel; Sullivan, David W; Allen, David T

2014-05-06

Hourly ambient hydrocarbon concentration data were collected, in the Barnett Shale Natural Gas Production Region, using automated gas chromatography (auto-GC), for the period from April 2010 to December 2011. Data for three sites were compared: a site in the geographical center of the natural gas production region (Eagle Mountain Lake (EML)); a rural/suburban site at the periphery of the production region (Flower Mound Shiloh), and an urban site (Hinton). The dominant hydrocarbon species observed in the Barnett Shale region were light alkanes. Analyses of daily, monthly, and hourly patterns showed little variation in relative composition. Observed concentrations were compared to concentrations predicted using a dispersion model (AERMOD) and a spatially resolved inventory of volatile organic compounds (VOC) emissions from natural gas production (Barnett Shale Special Emissions Inventory) prepared by the Texas Commission on Environmental Quality (TCEQ), and other emissions information. The predicted concentrations of VOC due to natural gas production were 0-40% lower than background corrected measurements, after accounting for potential under-estimation of certain emission categories. Hourly and daily variations in observed, background corrected concentrations were primarily explained by variability in meteorology, suggesting that episodic emission events had little impact on hourly averaged concentrations. Total emissions for VOC from natural gas production sources are estimated to be approximately 25,300 tons/yr, when accounting for potential under-estimation of certain emission categories. This region produced, in 2011, approximately 5 bcf/d of natural gas (100 Gg/d) for a VOC to natural gas production ratio (mass basis) of 0.0006.

Production of bio-synthetic natural gas in Canada.

PubMed

Hacatoglu, Kevork; McLellan, P James; Layzell, David B

2010-03-15

Large-scale production of renewable synthetic natural gas from biomass (bioSNG) in Canada was assessed for its ability to mitigate energy security and climate change risks. The land area within 100 km of Canada's network of natural gas pipelines was estimated to be capable of producing 67-210 Mt of dry lignocellulosic biomass per year with minimal adverse impacts on food and fiber production. Biomass gasification and subsequent methanation and upgrading were estimated to yield 16,000-61,000 Mm(3) of pipeline-quality gas (equivalent to 16-63% of Canada's current gas use). Life-cycle greenhouse gas emissions of bioSNG-based electricity were calculated to be only 8.2-10% of the emissions from coal-fired power. Although predicted production costs ($17-21 GJ(-1)) were much higher than current energy prices, a value for low-carbon energy would narrow the price differential. A bioSNG sector could infuse Canada's rural economy with $41-130 billion of investments and create 410,000-1,300,000 jobs while developing a nation-wide low-carbon energy system.

Do Anti-Bredt Natural Products Exist? Olefin Strain Energy as a Predictor of Isolability.

PubMed

Krenske, Elizabeth H; Williams, Craig M

2015-09-01

Bredt's rule holds a special place in the realm of physical organic chemistry, but its application to natural products chemistry—the field in which the rule was originally formulated—is not well defined. Herein, the use of olefin strain (OS) energy as a readily calculated predictor of the stability of natural products containing a bridgehead alkene is introduced. Schleyer first used OS energies to classify parent bridgehead alkenes into "isolable", "observable", and "unstable" classes. OS calculations on natural products, using contemporary forcefield methods, unequivocally predict all structurally verified bridgehead alkene natural products to be "isolable". Thus, when one assigns the structure of a putative bridgehead alkene natural product, an OS in the "observable" or "unstable" ranges is a red flag for error. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The water-food nexus of natural rubber production

NASA Astrophysics Data System (ADS)

Chiarelli, D. D.; Rosa, L.; Rulli, M. C.; D'Odorico, P.

2017-12-01

The increasing global demand for natural rubber (100% increase in the last 15 years) is for most part met by Malaysia and Indonesia, and - to a lesser extent - other countries in south-east Asia and Africa. The consequent expansion of rubber plantation has often occurred at the expenses of agricultural land for staple food, particularly in southeast Asia, where most of the land suitable for agriculture is already harvested for food crops or other uses. Here we investigate the extent to which the ongoing increase in rubber production is competing with the food system and affecting the livelihoods of rural communities in the areas of production and their appropriation of natural resources, such as water. We also investigate to what extent the expansion of rubber plantations is taking place through large scale land acquisitions (LSLAs) and evaluate the impacts on rural communities. Our results show how rubber production has strong environmental, social and economic impacts. Despite their ability to bring employment and increase the average income of economically disadvantaged areas, rubber plantations may threaten the local water and food security and induce a loss of rural livelihoods, particularly when the new plantations result from LSLAs that displace semi-subsistence forms of production thereby forcing the local populations to depend on global markets.

Plant-environment interactions: Accumulation of hypericin in dark glands of Hypericum perforatum.

PubMed

Zobayed, S M A; Afreen, F; Goto, E; Kozai, T

2006-10-01

Hypericum perforatum is a perennial herbaceous plant and an extract from this plant has a significant antidepressant effect when administered to humans. The plant is characterized by its secretory glands, also known as dark glands, which are mainly visible on leaves and flowers. The current study evaluates the influence of several environmental factors and developmental stages of the plant on the accumulation and synthesis of hypericin and pseudohypericin (Hy-G), the major bioactive constituents, in H. perforatum plants. The appearance of dark glands on different parts of the plant, under several environmental conditions, was monitored by microscopy. Hy-G concentrations were quantified by high-performance liquid chromatography. A significant presence of dark glands accompanying the highest concentrations of Hy-G was observed in the stamen tissues more than in any other organ of H. perforatum. A linear relationship between the number of dark glands and net photosynthetic rate of the leaf and Hy-G concentration in the leaf tissue was also established. A very high concentration of Hy-G was measured in the dark-gland tissues, but in the tissues without any dark glands it was almost absent. The presence of emodin, a precursor of Hy-G, at a high concentration in the dark-gland tissues, and its absence in the surrounding tissues was also observed, suggesting that the site of biosynthesis of Hy-G is in the dark-gland cells. A significantly low concentration of Hy-G (occasionally non-detectable) was measured in the xylem sap of the stem tissues. The dark-gland tissues collected from leaves, stems or flowers contained similar concentrations of Hy-G. The concentration of Hy-G in various organs of H. perforatum plants is dependent on the number of dark glands, their size or area, not on the location of the dark glands on the plant. The study provides the first experimental evidence that Hy-G is synthesized and accumulates in dark glands.

Isolation and purification of series bioactive components from Hypericum Perforatum L. by high-speed counter-current chromatography

PubMed Central

Cao, Xueli; Wang, Qiaoe; Li, Yan; Bai, Ge; Ren, Hong; Ito, Yiochiro

2011-01-01

High-speed counter-current chromatography (HSCCC) combined with pre-separation by ultrasonic solvent extraction was successively used for the separation of series bioactive compounds from the crude extract of Hypericum perforatum L. The petroleum ether extract was separated by the solvent system of n-heptane-methanol-acetonitrile (1.5:0.5:0.5, v/v) and n-heptane-methanol (1.5:1, v/v) in gradient elution, yielding a phloroglucinol compound, hyperforin with HPLC purity over 98%. The ethyl acetate extract was separated by using the solvent system composed of hexane-ethyl acetate-methanol-water (1:1:1:1 and 1:3:1:3, v/v) in gradient through both reverse phase and normal phase elution mode, yielding a naphthodianthrone compound, hypericin with HPLC purity about 95%. The n-butanol extract was separated with the solvent system composed of n-butanol-ethyl acetate–water (1:4:5 and 1.5:3.5:5, v/v) in elution and back-extrusion mode, yielding two of flavones, rutin and hyperoside, with HPLC purity over 95%. HPLC-MS, reference sample and UV spectrum were selectively used in separation to search for target compounds from HPLC-DAD profiles of different sub-extracts. The structures of isolated compounds were further identified by ESI-MS, 1HNMR and 13CNMR. PMID:21306961

Biosynthetic Potential-Based Strain Prioritization for Natural Product Discovery: A Showcase for Diterpenoid-Producing Actinomycetes

PubMed Central

2015-01-01

Natural products remain the best sources of drugs and drug leads and serve as outstanding small-molecule probes to dissect fundamental biological processes. A great challenge for the natural product community is to discover novel natural products efficiently and cost effectively. Here we report the development of a practical method to survey biosynthetic potential in microorganisms, thereby identifying the most promising strains and prioritizing them for natural product discovery. Central to our approach is the innovative preparation, by a two-tiered PCR method, of a pool of pathway-specific probes, thereby allowing the survey of all variants of the biosynthetic machineries for the targeted class of natural products. The utility of the method was demonstrated by surveying 100 strains, randomly selected from our actinomycete collection, for their biosynthetic potential of four classes of natural products, aromatic polyketides, reduced polyketides, nonribosomal peptides, and diterpenoids, identifying 16 talented strains. One of the talented strains, Streptomyces griseus CB00830, was finally chosen to showcase the discovery of the targeted classes of natural products, resulting in the isolation of three diterpenoids, six nonribosomal peptides and related metabolites, and three polyketides. Variations of this method should be applicable to the discovery of other classes of natural products. PMID:24484381

30 CFR 260.116 - How do I measure natural gas production on my eligible lease?

Code of Federal Regulations, 2010 CFR

2010-07-01

... 30 Mineral Resources 2 2010-07-01 2010-07-01 false How do I measure natural gas production on my... do I measure natural gas production on my eligible lease? You must measure natural gas production on... natural gas, measured according to part 250, subpart L of this title, equals one barrel of oil equivalent...

Amorfrutins are potent antidiabetic dietary natural products

PubMed Central

Weidner, Christopher; de Groot, Jens C.; Prasad, Aman; Freiwald, Anja; Quedenau, Claudia; Kliem, Magdalena; Witzke, Annabell; Kodelja, Vitam; Han, Chung-Ting; Giegold, Sascha; Baumann, Matthias; Klebl, Bert; Siems, Karsten; Müller-Kuhrt, Lutz; Schürmann, Annette; Schüler, Rita; Pfeiffer, Andreas F. H.; Schroeder, Frank C.; Büssow, Konrad; Sauer, Sascha

2012-01-01

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPARγ-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPARγ, which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPARγ drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPARγ-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease. PMID:22509006

Natural products as an inspiration in the diversity-oriented synthesis of bioactive compound libraries

PubMed Central

Cordier, Christopher; Morton, Daniel; Murrison, Sarah; O'Leary-Steele, Catherine

2008-01-01

The purpose of diversity-oriented synthesis is to drive the discovery of small molecules with previously unknown biological functions. Natural products necessarily populate biologically relevant chemical space, since they bind both their biosynthetic enzymes and their target macromolecules. Natural product families are, therefore, libraries of pre-validated, functionally diverse structures in which individual compounds selectively modulate unrelated macromolecular targets. This review describes examples of diversity-oriented syntheses which have, to some extent, been inspired by the structures of natural products. Particular emphasis is placed on innovations that allow the synthesis of compound libraries that, like natural products, are skeletally diverse. Mimicking the broad structural features of natural products may allow the discovery of compounds that modulate the functions of macromolecules for which ligands are not known. The ability of innovations in diversity-oriented synthesis to deliver such compounds is critically assessed. PMID:18663392

Discovery and characterization of natural products that act as pheromones in fish.

PubMed

Li, Ke; Buchinger, Tyler J; Li, Weiming

2018-06-20

Covering: up to 2018 Fish use a diverse collection of molecules to communicate with conspecifics. Since Karlson and Lüscher termed these molecules 'pheromones', chemists and biologists have joined efforts to characterize their structures and functions. In particular, the understanding of insect pheromones developed at a rapid pace, set, in part, by the use of bioassay-guided fractionation and natural product chemistry. Research on vertebrate pheromones, however, has progressed more slowly. Initially, biologists characterized fish pheromones by screening commercially available compounds suspected to act as pheromones based upon their physiological function. Such biology-driven screening has proven a productive approach to studying pheromones in fish. However, the many functions of fish pheromones and diverse metabolites that fish release make predicting pheromone identity difficult and necessitate approaches led by chemistry. Indeed, the few cases in which pheromone identification was led by natural product chemistry indicated novel or otherwise unpredicted compounds act as pheromones. Here, we provide a brief review of the approaches to identifying pheromones, placing particular emphasis on the promise of using natural product chemistry together with assays of biological activity. Several case studies illustrate bioassay-guided fractionation as an approach to pheromone identification in fish and the unexpected diversity of pheromone structures discovered by natural product chemistry. With recent advances in natural product chemistry, bioassay-guided fractionation is likely to unveil an even broader collection of pheromone structures and enable research that spans across disciplines.

Pyranone natural products as inspirations for catalytic reaction discovery and development.

PubMed

McDonald, Benjamin R; Scheidt, Karl A

2015-04-21

Natural products continue to provide a wealth of opportunities in the areas of chemical and therapeutic development. These structures are effective measuring sticks for the current state of chemical synthesis as a field and constantly inspire new approaches and strategies. Tetrahydropryans and tetrahydropyran-4-ones are found in numerous bioactive marine natural products and medicinal compounds. Our interest in exploring the therapeutic potential of natural products containing these motifs provided the impetus to explore new methods to access highly functionalized, chiral pyran molecules in the most direct and rapid fashion possible. This goal led to exploration and development of a Lewis acid-mediated Prins reaction between a chiral β-hydroxy-dioxinone and aldehyde to produce a pyran-dioxinone fused product that can be processed in a single pot operation to the desired tetrahydropyran-4-ones in excellent yield and stereoselectivity. Although the Prins reaction is a commonly employed approach toward pyrans, this method uniquely provides a 3-carboxy-trisubstituted pyran and utilizes dioxinones in a manner that was underexplored at the time. The 3-carboxy substituent served as a key synthetic handhold when this method was applied to the synthesis of highly functionalized pyrans within the macrocyclic natural products neopeltolide, okilactiomycin, and exiguolide. When employed in challenging macrocyclizations, this tetrahydropyranone forming reaction proved highly stereoselective and robust. Another major thrust in our lab has been the synthesis of benzopyranone natural products, specifically flavonoids, because this broad and diverse family of compounds possesses an equally broad range of biological and medicinal applications. With the goal of developing a broad platform toward the synthesis of enantioenriched flavonoid analogs and natural products, a biomimetic, asymmetric catalytic approach toward the synthesis of 2-aryl benzopyranones was developed. A

Natural products for chronic cough: Text mining the East Asian historical literature for future therapeutics.

PubMed

Shergis, Johannah Linda; Wu, Lei; May, Brian H; Zhang, Anthony Lin; Guo, Xinfeng; Lu, Chuanjian; Xue, Charlie Changli

2015-08-01

Chronic cough is a significant health burden. Patients experience variable benefits from over the counter and prescribed products, but there is an unmet need to provide more effective treatments. Natural products have been used to treat cough and some plant compounds such as pseudoephedrine from ephedra and codeine from opium poppy have been developed into drugs. Text mining historical literature may offer new insight for future therapeutic development. We identified natural products used in the East Asian historical literature to treat chronic cough. Evaluation of the historical literature revealed 331 natural products used to treat chronic cough. Products included plants, minerals and animal substances. These natural products were found in 75 different books published between AD 363 and 1911. Of the 331 products, the 10 most frequently and continually used products were examined, taking into consideration findings from contemporary experimental studies. The natural products identified are promising and offer new directions in therapeutic development for treating chronic cough. © The Author(s) 2015.

Identifying the cellular targets of natural products using T7 phage display.

PubMed

Piggott, Andrew M; Karuso, Peter

2016-05-04

Covering: up to the end of 2015While Nature continues to deliver a myriad of potent and structurally diverse biologically active small molecules, the cellular targets and modes of action of these natural products are rarely identified, significantly hindering their development as new chemotherapeutic agents. This article provides an introductory tutorial on the use of T7 phage display as a tool to rapidly identify the cellular targets of natural products and is aimed specifically at natural products chemists who may have only limited experience in molecular biology. A brief overview of T7 phage display is provided, including its strengths, weaknesses, and the type of problems that can and cannot be tackled with this technology. Affinity probe construction is reviewed, including linker design and natural product derivatisation strategies. A detailed description of the T7 phage biopanning procedure is provided, with valuable tips for optimising each step in the process, as well as advice for identifying and avoiding the most commonly encountered challenges and pitfalls along the way. Finally, a brief discussion is provided on techniques for validating the cellular targets identified using T7 phage display.

Biosynthesis and Function of Polyacetylenes and Allied Natural Products

PubMed Central

Minto, Robert E.; Blacklock, Brenda J.

2008-01-01

Polyacetylenic natural products are a substantial class of often unstable compounds containing a unique carbon-carbon triple bond functionality, that are intriguing for their wide variety of biochemical and ecological functions, economic potential, and surprising mode of biosynthesis. Isotopic tracer experiments between 1960 and 1990 demonstrated that the majority of these compounds are derived from fatty acid and polyketide precursors. During the past decade, research into the metabolism of polyacetylenes has swiftly advanced, driven by the cloning of the first genes responsible for polyacetylene biosynthesis in plants, moss, fungi, and actinomycetes, and the initial characterization of the gene products. The current state of knowledge of the biochemistry and molecular genetics of polyacetylenic secondary metabolic pathways will be presented together with an up-to-date survey of new terrestrial and marine natural products, their known biological activities, and a discussion of their likely metabolic origins. PMID:18387369

Discovery and resupply of pharmacologically active plant-derived natural products: A review

PubMed Central

Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H.; Rollinger, Judith M.; Schuster, Daniela; Breuss, Johannes M.; Bochkov, Valery; Mihovilovic, Marko D.; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M.; Stuppner, Hermann

2016-01-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. PMID:26281720

Discovery and resupply of pharmacologically active plant-derived natural products: A review.

PubMed

Atanasov, Atanas G; Waltenberger, Birgit; Pferschy-Wenzig, Eva-Maria; Linder, Thomas; Wawrosch, Christoph; Uhrin, Pavel; Temml, Veronika; Wang, Limei; Schwaiger, Stefan; Heiss, Elke H; Rollinger, Judith M; Schuster, Daniela; Breuss, Johannes M; Bochkov, Valery; Mihovilovic, Marko D; Kopp, Brigitte; Bauer, Rudolf; Dirsch, Verena M; Stuppner, Hermann

2015-12-01

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a "screening hit" through a "drug lead" to a "marketed drug" is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis. While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Natural Products for Management of Oral Mucositis Induced by Radiotherapy and Chemotherapy

PubMed Central

Aghamohamamdi, Azar; Hosseinimehr, Seyed Jalal

2015-01-01

Oral mucositis is a common side effect of systemic chemotherapy and radiotherapy of head and neck in patients with cancer. Severe oral mucositis is painful and affects oral functions, including intake of food and medications and speech. Prevention of oral mucositis affects the life quality of patients. Recent studies have been focused on natural products to improve or reduce this complication. Many clinical trials have been performed to assess natural products for treatment of mucositis and their results are promising. The authors reviewed the evidence for natural products in the prevention and treatment of oral mucositis induced by radiation therapy and chemotherapy. PMID:26306626

A natural product based DOS library of hybrid systems.

PubMed

Prabhu, Ganesh; Agarwal, Shalini; Sharma, Vijeta; Madurkar, Sanjay M; Munshi, Parthapratim; Singh, Shailja; Sen, Subhabrata

2015-05-05

Here we described a natural product inspired modular DOS strategy for the synthesis of a library of hybrid systems that are structurally and stereochemically disparate. The main scaffold is a pyrroloisoquinoline motif, that is synthesized from tandem Pictet-Spengler lactamization. The structural diversity is generated via "privileged scaffolds" that are attached at the appropriate site of the motif. Screening of the library compounds for their antiplasmodial activity against chloroquine sensitive 3D7 cells indicated few compounds with moderate activity (20-50 μM). A systematic comparison of structural intricacy between the library members and a natural product dataset obtained from ZINC(®) revealed comparable complexity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

In-use product stocks link manufactured capital to natural capital.

PubMed

Chen, Wei-Qiang; Graedel, T E

2015-05-19

In-use stock of a product is the amount of the product in active use. In-use product stocks provide various functions or services on which we rely in our daily work and lives, and the concept of in-use product stock for industrial ecologists is similar to the concept of net manufactured capital stock for economists. This study estimates historical physical in-use stocks of 91 products and 9 product groups and uses monetary data on net capital stocks of 56 products to either approximate or compare with in-use stocks of the corresponding products in the United States. Findings include the following: (i) The development of new products and the buildup of their in-use stocks result in the increase in variety of in-use product stocks and of manufactured capital; (ii) substitution among products providing similar or identical functions reflects the improvement in quality of in-use product stocks and of manufactured capital; and (iii) the historical evolution of stocks of the 156 products or product groups in absolute, per capita, or per-household terms shows that stocks of most products have reached or are approaching an upper limit. Because the buildup, renewal, renovation, maintenance, and operation of in-use product stocks drive the anthropogenic cycles of materials that are used to produce products and that originate from natural capital, the determination of in-use product stocks together with modeling of anthropogenic material cycles provides an analytic perspective on the material linkage between manufactured capital and natural capital.

In-use product stocks link manufactured capital to natural capital

PubMed Central

Chen, Wei-Qiang; Graedel, T. E.

2015-01-01

In-use stock of a product is the amount of the product in active use. In-use product stocks provide various functions or services on which we rely in our daily work and lives, and the concept of in-use product stock for industrial ecologists is similar to the concept of net manufactured capital stock for economists. This study estimates historical physical in-use stocks of 91 products and 9 product groups and uses monetary data on net capital stocks of 56 products to either approximate or compare with in-use stocks of the corresponding products in the United States. Findings include the following: (i) The development of new products and the buildup of their in-use stocks result in the increase in variety of in-use product stocks and of manufactured capital; (ii) substitution among products providing similar or identical functions reflects the improvement in quality of in-use product stocks and of manufactured capital; and (iii) the historical evolution of stocks of the 156 products or product groups in absolute, per capita, or per-household terms shows that stocks of most products have reached or are approaching an upper limit. Because the buildup, renewal, renovation, maintenance, and operation of in-use product stocks drive the anthropogenic cycles of materials that are used to produce products and that originate from natural capital, the determination of in-use product stocks together with modeling of anthropogenic material cycles provides an analytic perspective on the material linkage between manufactured capital and natural capital. PMID:25733904

Natural products as modulators of spermatogenesis: the search for a male contraceptive.

PubMed

Dias, Tania R; Alves, Marco G; Oliveira, Pedro F; Silva, Branca M

2014-01-01

Population growth in the last century has raised important social and economic questions. Thus, current methods of fertility control have been under debate for a long period. Birth rates are essentially dependent on several environmental and social factors but women, who are great users of contraceptives, play a major role. Regulation of male fertility has been widely studied in recent years with the aim of developing a new male contraceptive for further inclusion of men's choice in family planning. Based on the ancient people techniques to control the birth rates, natural products appeared as a promising source for the development of a male contraceptive. Over the years, many plants and their main constituents have been studied in the search for their antifertility properties. Interestingly, some antispermatogenic effects have been reported. Herein, we will discuss the antispermatogenic properties of some natural products. We propose to discuss specific targets and sites of action of the selected natural products. Despite the advances in this field in the last years, the molecular mechanisms by which natural products can control fertility, need to be disclosed to develop an effective, reversible and safe male contraceptive and avoid undesired toxicity in other organs. To date, no natural-based male contraceptive is available in the commercial market, mostly due to the difficulty in reversing the effects of these products in male fertility.

Using natural products for drug discovery: the impact of the genomics era.

PubMed

Zhang, Mingzi M; Qiao, Yuan; Ang, Ee Lui; Zhao, Huimin

2017-05-01

Evolutionarily selected over billions of years for their interactions with biomolecules, natural products have been and continue to be a major source of pharmaceuticals. In the 1990s, pharmaceutical companies scaled down their natural product discovery programs in favor of synthetic chemical libraries due to major challenges such as high rediscovery rates, challenging isolation, and low production titers. Propelled by advances in DNA sequencing and synthetic biology technologies, insights into microbial secondary metabolism provided have inspired a number of strategies to address these challenges. Areas covered: This review highlights the importance of genomics and metagenomics in natural product discovery, and provides an overview of the technical and conceptual advances that offer unprecedented access to molecules encoded by biosynthetic gene clusters. Expert opinion: Genomics and metagenomics revealed nature's remarkable biosynthetic potential and her vast chemical inventory that we can now prioritize and systematically mine for novel chemical scaffolds with desirable bioactivities. Coupled with synthetic biology and genome engineering technologies, significant progress has been made in identifying and predicting the chemical output of biosynthetic gene clusters, as well as in optimizing cluster expression in native and heterologous host systems for the production of pharmaceutically relevant metabolites and their derivatives.

Comparative analysis of chemical similarity methods for modular natural products with a hypothetical structure enumeration algorithm.

PubMed

Skinnider, Michael A; Dejong, Chris A; Franczak, Brian C; McNicholas, Paul D; Magarvey, Nathan A

2017-08-16

Natural products represent a prominent source of pharmaceutically and industrially important agents. Calculating the chemical similarity of two molecules is a central task in cheminformatics, with applications at multiple stages of the drug discovery pipeline. Quantifying the similarity of natural products is a particularly important problem, as the biological activities of these molecules have been extensively optimized by natural selection. The large and structurally complex scaffolds of natural products distinguish their physical and chemical properties from those of synthetic compounds. However, no analysis of the performance of existing methods for molecular similarity calculation specific to natural products has been reported to date. Here, we present LEMONS, an algorithm for the enumeration of hypothetical modular natural product structures. We leverage this algorithm to conduct a comparative analysis of molecular similarity methods within the unique chemical space occupied by modular natural products using controlled synthetic data, and comprehensively investigate the impact of diverse biosynthetic parameters on similarity search. We additionally investigate a recently described algorithm for natural product retrobiosynthesis and alignment, and find that when rule-based retrobiosynthesis can be applied, this approach outperforms conventional two-dimensional fingerprints, suggesting it may represent a valuable approach for the targeted exploration of natural product chemical space and microbial genome mining. Our open-source algorithm is an extensible method of enumerating hypothetical natural product structures with diverse potential applications in bioinformatics.

Management of natural health products in pediatrics: a provider-focused quality improvement project.

PubMed

Gutierrez, Emily; Silbert-Flagg, JoAnne; Vohra, Sunita

2015-01-01

The use of natural health products by pediatric patients is common, yet health care providers often do not provide management guidance. The purpose of this project was to improve management of natural health products by pediatric nurse practitioners. Pediatric nurse practitioners from large metropolitan city were recruited (n = 32). A paired pretest-posttest design was used. Study participants were engaged to improve knowledge of natural health products, and a management toolkit was created and tested. Mean knowledge scores increased from 59.19 to 76.3 (p < .01). Management practices improved with regard to patient guidance (p < .01) and resource utilization (p < .01). Assessments of product use (p = .51) and drug/herb interactions (p = .35) were not significant. This investigation is the first known study to improve knowledge and management of natural health products in pediatric clinical practice. Copyright © 2015 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.

Modulation of Toll-like receptor signaling in innate immunity by natural products.

PubMed

Chen, Luxi; Yu, Jianhua

2016-08-01

For centuries, natural products and their derivatives have provided a rich source of compounds for the development of new immunotherapies in the treatment of human disease. Many of these compounds are currently undergoing clinical trials, particularly as anti-oxidative, anti-microbial, and anti-cancer agents. However, the function and mechanism of natural products in how they interact with our immune system has yet to be extensively explored. Natural immune modulators may provide the key to control and ultimately defeat disorders affecting the immune system. They can either up- or down-regulate the immune response with few undesired adverse effects. In this review, we summarize the recent advancements made in utilizing natural products for immunomodulation and their important molecular targets, members of the Toll-like receptor (TLR) family, in the innate immune system. Copyright © 2016 Elsevier B.V. All rights reserved.

Natural fiber production, harvesting, and preliminary processing: options and opportunities

USDA-ARS?s Scientific Manuscript database

The utilization of natural fibers and plant oils in bio-products introduces numerous logistical challenges not typically encountered with non-agricultural resources. Once it has been determined that a plant material is suitable for commercial development, the production, harvesting, and processing s...

Covalent Ligand Discovery against Druggable Hotspots Targeted by Anti-cancer Natural Products.

PubMed

Grossman, Elizabeth A; Ward, Carl C; Spradlin, Jessica N; Bateman, Leslie A; Huffman, Tucker R; Miyamoto, David K; Kleinman, Jordan I; Nomura, Daniel K

2017-11-16

Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation. We developed a more synthetically tractable cysteine-reactive covalent ligand, JNS 1-40, that selectively targets C377 of PPP2R1A to impair breast cancer signaling, proliferation, and in vivo tumor growth. Our study highlights the utility of using chemoproteomics to map druggable hotspots targeted by complex natural products and subsequently interrogating these sites with more synthetically tractable covalent ligands for cancer therapy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Principal component analysis as a tool for library design: a case study investigating natural products, brand-name drugs, natural product-like libraries, and drug-like libraries.

PubMed

Wenderski, Todd A; Stratton, Christopher F; Bauer, Renato A; Kopp, Felix; Tan, Derek S

2015-01-01

Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design.

Principal Component Analysis as a Tool for Library Design: A Case Study Investigating Natural Products, Brand-Name Drugs, Natural Product-Like Libraries, and Drug-Like Libraries

PubMed Central

Wenderski, Todd A.; Stratton, Christopher F.; Bauer, Renato A.; Kopp, Felix; Tan, Derek S.

2015-01-01

Principal component analysis (PCA) is a useful tool in the design and planning of chemical libraries. PCA can be used to reveal differences in structural and physicochemical parameters between various classes of compounds by displaying them in a convenient graphical format. Herein, we demonstrate the use of PCA to gain insight into structural features that differentiate natural products, synthetic drugs, natural product-like libraries, and drug-like libraries, and show how the results can be used to guide library design. PMID:25618349

New Methodology for Natural Gas Production Estimates

EIA Publications

2010-01-01

A new methodology is implemented with the monthly natural gas production estimates from the EIA-914 survey this month. The estimates, to be released April 29, 2010, include revisions for all of 2009. The fundamental changes in the new process include the timeliness of the historical data used for estimation and the frequency of sample updates, both of which are improved.

Marine Natural Products as Prototype Agrochemical Agents

PubMed Central

Peng, Jiangnan; Shen, Xiaoyu; El Sayed, Khalid A.; Dunbar, D. C Harles; Perry, Tony L.; Wilkins, Scott P.; Hamann, Mark T.; Bobzin, Steve; Huesing, Joseph; Camp, Robin; Prinsen, Mike; Krupa, Dan; Wideman, Margaret A.

2016-01-01

In the interest of identifying new leads that could serve as prototype agrochemical agents, 18 structurally diverse marine-derived compounds were examined for insecticidal, herbicidal, and fungicidal activities. Several new classes of compounds have been shown to be insecticidal, herbicidal, and fungicidal, which suggests that marine natural products represent an intriguing source for the discovery of new agrochemical agents. PMID:12670165

Prioritization of anti-malarial hits from nature: chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs.

PubMed

Egieyeh, Samuel Ayodele; Syce, James; Malan, Sarel F; Christoffels, Alan

2016-01-29

A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Natural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure-activity landscape were also carried out on these sets of compounds. A total of 1040 natural products were selected and a total of 13 molecular descriptors were analysed. Significant differences were observed among the sub-groups of NAA and CRAD for at least 11 of the molecular descriptors, including number of hydrogen bond donors and acceptors, molecular weight, polar and hydrophobic surface areas, chiral centres, oxygen and nitrogen atoms, and shape index. The remaining molecular descriptors, including clogP, number of rotatable bonds and number of aromatic rings, did not show any significant difference when comparing the two compound sets. Molecular similarity and chemical space analysis identified natural products that were structurally diverse from CRAD. Prediction of the pharmacokinetic properties and drug-likeness of these natural products identified over 50% with desirable drug-like properties. Nearly 70% of all natural products were identified as potentially promiscuous compounds. Structure-activity landscape analysis highlighted compound pairs that

Spirolactones: Recent Advances in Natural Products, Bioactive Compounds and Synthetic Strategies.

PubMed

Quintavalla, Arianna

2018-01-01

The spirocyclic compounds have always aroused a great interest because this motif is present as structural core in a number of natural products and bioactive compounds. In particular, the spirolactone moiety has been recognized in a wide array of natural and non-natural scaffolds showing a variety of useful pharmacological properties. Extensive literature search using SciFinder (Databases: CA Plus, CAS Registry, CAS React, Chemlist, Chemcat and Medline) and Web of Science (Database: Web of Science Core Collection) was conducted. Nowadays, many efforts are being devoted to the discovery of new natural products containing the promising spirolactone framework and to the disclosure of the potential bioactivities of these chemical entities. Moreover, the medicinal relevance of many spirolactones makes these scaffolds attractive targets for the design and development of innovative and efficient synthetic strategies, enabling the construction of complex and variably substituted products. This review gives an overview on the recent advances in the spirolactones field, in terms of new compounds isolated from natural sources, recently determined bioactivity profiles and innovative synthetic approaches. The collected data demonstrate the key role played by spirolactones in medicinal chemistry and the great attention still devoted by the scientific community to these compounds. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Rational selection of structurally diverse natural product scaffolds with favorable ADME properties for drug discovery.

PubMed

Samiulla, D S; Vaidyanathan, V V; Arun, P C; Balan, G; Blaze, M; Bondre, S; Chandrasekhar, G; Gadakh, A; Kumar, R; Kharvi, G; Kim, H O; Kumar, S; Malikayil, J A; Moger, M; Mone, M K; Nagarjuna, P; Ogbu, C; Pendhalkar, D; Rao, A V S Raja; Rao, G Venkateshwar; Sarma, V K; Shaik, S; Sharma, G V R; Singh, S; Sreedhar, C; Sonawane, R; Timmanna, U; Hardy, L W

2005-01-01

Natural product analogs are significant sources for therapeutic agents. To capitalize efficiently on the effective features of naturally occurring substances, a natural product-based library production platform has been devised at Aurigene for drug lead discovery. This approach combines the attractive biological and physicochemical properties of natural product scaffolds, provided by eons of natural selection, with the chemical diversity available from parallel synthetic methods. Virtual property analysis, using computational methods described here, guides the selection of a set of natural product scaffolds that are both structurally diverse and likely to have favorable pharmacokinetic properties. The experimental characterization of several in vitro ADME properties of twenty of these scaffolds, and of a small set of designed congeners based upon one scaffold, is also described. These data confirm that most of the scaffolds and the designed library members have properties favorable to their utilization for creating libraries of lead-like molecules.

Natural products: a hope for glioblastoma patients.

PubMed

Vengoji, Raghupathy; Macha, Muzafar A; Batra, Surinder K; Shonka, Nicole A

2018-04-24

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT.

Natural products: a hope for glioblastoma patients

PubMed Central

Vengoji, Raghupathy; Macha, Muzafar A.; Batra, Surinder K.; Shonka, Nicole A.

2018-01-01

Glioblastoma (GBM) is one of the most aggressive malignant tumors with an overall dismal survival averaging one year despite multimodality therapeutic interventions including surgery, radiotherapy and concomitant and adjuvant chemotherapy. Few drugs are FDA approved for GBM, and the addition of temozolomide (TMZ) to standard therapy increases the median survival by only 2.5 months. Targeted therapy appeared promising in in vitro monolayer cultures, but disappointed in preclinical and clinical trials, partly due to the poor penetration of drugs through the blood brain barrier (BBB). Cancer stem cells (CSCs) have intrinsic resistance to initial chemoradiation therapy (CRT) and acquire further resistance via deregulation of many signaling pathways. Due to the failure of classical chemotherapies and targeted drugs, research efforts focusing on the use of less toxic agents have increased. Interestingly, multiple natural compounds have shown antitumor and apoptotic effects in TMZ resistant and p53 mutant GBM cell lines and also displayed synergistic effects with TMZ. In this review, we have summarized the current literature on natural products or product analogs used to modulate the BBB permeability, induce cell death, eradicate CSCs and sensitize GBM to CRT. PMID:29774132

Impacts of Marcellus Shale Natural Gas Production on Regional Air Quality

NASA Astrophysics Data System (ADS)

Swarthout, R.; Russo, R. S.; Zhou, Y.; Mitchell, B.; Miller, B.; Lipsky, E. M.; Sive, B. C.

2012-12-01

Natural gas is a clean burning alternative to other fossil fuels, producing lower carbon dioxide (CO2) emissions during combustion. Gas deposits located within shale rock or tight sand formations are difficult to access using conventional drilling techniques. However, horizontal drilling coupled with hydraulic fracturing is now widely used to enhance natural gas extraction. Potential environmental impacts of these practices are currently being assessed because of the rapid expansion of natural gas production in the U.S. Natural gas production has contributed to the deterioration of air quality in several regions, such as in Wyoming and Utah, that were near or downwind of natural gas basins. We conducted a field campaign in southwestern Pennsylvania on 16-18 June 2012 to investigate the impact of gas production operations in the Marcellus Shale on regional air quality. A total of 235 whole air samples were collected in 2-liter electropolished stainless- steel canisters throughout southwestern Pennsylvania in a regular grid pattern that covered an area of approximately 8500 square km. Day and night samples were collected at each grid point and additional samples were collected near active wells, flaring wells, fluid retention reservoirs, transmission pipelines, and a processing plant to assess the influence of different stages of the gas production operation on emissions. The samples were analyzed at Appalachian State University for methane (CH4), CO2, C2-C10 nonmethane hydrocarbons (NMHCs), C1-C2 halocarbons, C1-C5 alkyl nitrates and selected reduced sulfur compounds. In-situ measurements of ozone (O3), CH4, CO2, nitric oxide (NO), total reactive nitrogen (NOy), formaldehyde (HCHO), and a range of volatile organic compounds (VOCs) were carried out at an upwind site and a site near active gas wells using a mobile lab. Emissions associated with gas production were observed throughout the study region. Elevated mixing ratios of CH4 and CO2 were observed in the

30 CFR 260.116 - How do I measure natural gas production on my eligible lease?

Code of Federal Regulations, 2011 CFR

2011-07-01

... 30 Mineral Resources 2 2011-07-01 2011-07-01 false How do I measure natural gas production on my... Bidding Systems Eligible Leases § 260.116 How do I measure natural gas production on my eligible lease? You must measure natural gas production on your eligible lease subject to the royalty suspension...

Modern mass spectrometry for synthetic biology and structure-based discovery of natural products.

PubMed

Henke, Matthew T; Kelleher, Neil L

2016-08-27

Covering: up to 2016In this highlight, we describe the current landscape for dereplication and discovery of natural products based on the measurement of the intact mass by LC-MS. Often it is assumed that because better mass accuracy (provided by higher resolution mass spectrometers) is necessary for absolute chemical formula determination (≤1 part-per-million), that it is also necessary for dereplication of natural products. However, the average ability to dereplicate tapers off at ∼10 ppm, with modest improvement gained from better mass accuracy when querying focused databases of natural products. We also highlight some recent examples of how these platforms are applied to synthetic biology, and recent methods for dereplication and correlation of substructures using tandem MS data. We also offer this highlight to serve as a brief primer for those entering the field of mass spectrometry-based natural products discovery.

SAM-dependent enzyme-catalysed pericyclic reactions in natural product biosynthesis

NASA Astrophysics Data System (ADS)

Ohashi, Masao; Liu, Fang; Hai, Yang; Chen, Mengbin; Tang, Man-Cheng; Yang, Zhongyue; Sato, Michio; Watanabe, Kenji; Houk, K. N.; Tang, Yi

2017-09-01

Pericyclic reactions—which proceed in a concerted fashion through a cyclic transition state—are among the most powerful synthetic transformations used to make multiple regioselective and stereoselective carbon-carbon bonds. They have been widely applied to the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centres. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples (the intramolecular Diels-Alder reaction, and the Cope and the Claisen rearrangements) have been characterized. Here we report a versatile S-adenosyl-L-methionine (SAM)-dependent enzyme, LepI, that can catalyse stereoselective dehydration followed by three pericyclic transformations: intramolecular Diels-Alder and hetero-Diels-Alder reactions via a single ambimodal transition state, and a retro-Claisen rearrangement. Together, these transformations lead to the formation of the dihydropyran core of the fungal natural product, leporin. Combined in vitro enzymatic characterization and computational studies provide insight into how LepI regulates these bifurcating biosynthetic reaction pathways by using SAM as the cofactor. These pathways converge to the desired biosynthetic end product via the (SAM-dependent) retro-Claisen rearrangement catalysed by LepI. We expect that more pericyclic biosynthetic enzymatic transformations remain to be discovered in naturally occurring enzyme ‘toolboxes’. The new role of the versatile cofactor SAM is likely to be found in other examples of enzyme catalysis.

Multimodular biocatalysts for natural product assembly

NASA Astrophysics Data System (ADS)

Schwarzer, Dirk; Marahiel, Mohamed A.

2001-03-01

Nonribosomal peptides and polyketides represent a large class of natural products that show an extreme structural diversity and broad pharmacological relevance. They are synthesized from simple building blocks such as amino or carboxy acids and malonate derivatives on multimodular enzymes called nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs), respectively. Although utilizing different substrates, NRPSs and PKSs show striking similarities in the modular architecture of their catalytic domains and product assembly-line mechanism. Among these compounds are well known antibiotics (penicillin, vancomycin and erythromycin) as well as potent immunosuppressive agents (cyclosporin, rapamycin and FK 506). This review focuses on the modular organization of NRPSs, PKSs and mixed NRPS/PKS systems and how modules and domains that build up the biosynthetic templates can be exploited for the rational design of recombinant enzymes capable of synthesizing novel compounds.

Fruit-based Natural Antioxidants in Meat and Meat Products: A Review.

PubMed

Ahmad, S R; Gokulakrishnan, P; Giriprasad, R; Yatoo, M A

2015-01-01

Due to the potential toxic effects of synthetic antioxidants, natural antioxidant sources especially fruits are being preferred now-a-days for use in different meat products. The majority of the antioxidant capacity of a fruit is especially because of numerous phenolic compounds. Many of the phytochemicals present in fruits may help protect cells against the oxidative damage caused by free radicals, thereby reducing the risk of degenerative diseases such as cardiovascular diseases, various types of cancers, and neurological diseases. Various parts of the fruit including their byproducts like skin and seeds have been used in meat products. Plum has been used as plum puree, prunes (dried plum), and plum extracts. Grape skin, seed, peel extracts, and grape pomace; berries as cakes and powder extracts; pomegranate rind powder and its juice; and most of the citrus fruits have proved beneficial sources of antioxidants. All these natural sources have effectively reduced the thiobarbituric acid-reactive substances (TBARS) values and free radical frequency. Thus, lipid oxidation is prevented and shelf life is greatly enhanced by incorporating various kinds of fruits and their byproducts in meat and meat products. There is a great scope for the use of fruits as natural sources of antioxidants in meat industry. The review is intended to provide an overview of the fruit-based natural antioxidants in meat and meat products.

Metabolomics-based chemotaxonomy of root endophytic fungi for natural products discovery.

PubMed

Maciá-Vicente, Jose G; Shi, Yan-Ni; Cheikh-Ali, Zakaria; Grün, Peter; Glynou, Kyriaki; Kia, Sevda Haghi; Piepenbring, Meike; Bode, Helge B

2018-03-01

Fungi are prolific producers of natural products routinely screened for biotechnological applications, and those living endophytically within plants attract particular attention because of their purported chemical diversity. However, the harnessing of their biosynthetic potential is hampered by a large and often cryptic phylogenetic and ecological diversity, coupled with a lack of large-scale natural products' dereplication studies. To guide efforts to discover new chemistries among root-endophytic fungi, we analyzed the natural products produced by 822 strains using an untargeted UPLC-ESI-MS/MS-based approach and linked the patterns of chemical features to fungal lineages. We detected 17 809 compounds of which 7951 were classified in 1992 molecular families, whereas the remaining were considered unique chemistries. Our approach allowed to annotate 1191 compounds with different degrees of accuracy, many of which had known fungal origins. Approximately 61% of the compounds were specific of a fungal order, and differences were observed across lineages in the diversity and characteristics of their chemistries. Chemical profiles also showed variable chemosystematic values across lineages, ranging from relative homogeneity to high heterogeneity among related fungi. Our results provide an extensive resource to dereplicate fungal natural products and may assist future discovery programs by providing a guide for the selection of target fungi. © 2018 Society for Applied Microbiology and John Wiley & Sons Ltd.

Development of new critical fluid-based processing methods for nutraceuticals and natural products

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, J. W.

2004-01-01

The development of new supercritical fluid processing technology as applied to nutraceuticals and natural products is no longer confined to using just supercritical fluid extraction (SFE) and supercritical carbon dioxide (SC-CO{sub 2}). Recently reported advances have been focused on modifying natural products and improving functionality of an end product using newer experimental techniques and fluid phases. In this presentation four focus areas will be emphasized: (1) control of particle size/morphology and encapsulation of the nutraceutical ingredients, (2) the use of combinatorial methodology to optimize critical fluid processing, (3) application of sub-critical water as a complementary medium for processing natural products,more » and (4) an assessment of the current state of products and processing which use critical fluid to produce nutraceutical and natural products for the food and cosmetic marketplace. Application of the various particle fomiation processes conducted in the presence of critical fluid media, such as: CPF, SAS, DELOS, RESS, PGSS, and GAS, can be used to produce particles of small and uniform distribution, having unique morphologies, that facilitate rapid dissolution or sustained release of many nutraceutical ingredients. These substances have included: therapeutic spices, phystosterols, vitamins, phospholpids, and carotenoids. Accelerating the development of critical fluid processing has been the application of combinatorial methodology to optimize extraction, fractionation, and/or reactions in near-, SC-, or subcritical fluid media. This is frequently accomplished by using sequential or multichannel automated instrumentation that was originally designed for analytical purposes. Several examples will be provided of rapidly assessing the extraction of anthocyanins with sub-critical water and the SFE of natural products. However, differences do exist in conducting experiments on the above instrumentation vs. scaled-up continuous processes

Defining "natural product" between public health and business, 17th to 21st centuries.

PubMed

Stanziani, Alessandro

2008-07-01

The historical definition of a natural product stands at the crossroads of business, health, and the symbolic order of things. Until the end of the 19th century, "natural product" was a synonym of perishable. The emergency of organic chemistry made perishability be replaced with "toxicity". Nowadays, genetics is provoking a radical change in the notion and practises of "natural product". However, these concerns are never entirely opposed to "naturality" as a synonym for sacred and symbolic order. Traceability is largely based upon kosher practices and the association between organic and good for health is hardly based upon sound scientific arguments.

Biosynthesis of nitrogen-containing natural products, C7N aminocyclitols and bis-indoles, from actinomycetes.

PubMed

Asamizu, Shumpei

2017-05-01

Actinomycetes are a major source of bioactive natural products with important pharmaceutical properties. Understanding the natural enzymatic assembly of complex small molecules is important for rational metabolic pathway design to produce "artificial" natural products in bacterial cells. This review will highlight current research on the biosynthetic mechanisms of two classes of nitrogen-containing natural products, C 7 N aminocyclitols and bis-indoles. Validamycin A is a member of C 7 N aminocyclitol natural products from Streptomyces hygroscopicus. Here, two important biosynthetic steps, pseudoglycosyltranferase-catalyzed C-N bond formation, and C 7 -sugar phosphate cyclase-catalyzed divergent carbasugar formation, will be reviewed. In addition, the bis-indolic natural products indolocarbazole, staurosporine from Streptomyces sp. TP-A0274, and rearranged bis-indole violacein from Chromobacterium violaceum are reviewed including the oxidative course of the assembly pathway for the bis-indolic scaffold. The identified biosynthesis mechanisms will be useful to generating new biocatalytic tools and bioactive compounds.

Potential of marine natural products against drug-resistant fungal, viral, and parasitic infections.

PubMed

Abdelmohsen, Usama Ramadan; Balasubramanian, Srikkanth; Oelschlaeger, Tobias A; Grkovic, Tanja; Pham, Ngoc B; Quinn, Ronald J; Hentschel, Ute

2017-02-01

Antibiotics have revolutionised medicine in many aspects, and their discovery is considered a turning point in human history. However, the most serious consequence of the use of antibiotics is the concomitant development of resistance against them. The marine environment has proven to be a very rich source of diverse natural products with significant antibacterial, antifungal, antiviral, antiparasitic, antitumour, anti-inflammatory, antioxidant, and immunomodulatory activities. Many marine natural products (MNPs)-for example, neoechinulin B-have been found to be promising drug candidates to alleviate the mortality and morbidity rates caused by drug-resistant infections, and several MNP-based anti-infectives have already entered phase 1, 2, and 3 clinical trials, with six approved for usage by the US Food and Drug Administration and one by the EU. In this Review, we discuss the diversity of marine natural products that have shown in-vivo efficacy or in-vitro potential against drug-resistant infections of fungal, viral, and parasitic origin, and describe their mechanism of action. We highlight the drug-like physicochemical properties of the reported natural products that have bioactivity against drug-resistant pathogens in order to assess their drug potential. Difficulty in isolation and purification procedures, toxicity associated with the active compound, ecological impacts on natural environment, and insufficient investments by pharmaceutical companies are some of the clear reasons behind market failures and a poor pipeline of MNPs available to date. However, the diverse abundance of natural products in the marine environment could serve as a ray of light for the therapy of drug-resistant infections. Development of resistance-resistant antibiotics could be achieved via the coordinated networking of clinicians, microbiologists, natural product chemists, and pharmacologists together with pharmaceutical venture capitalist companies. Copyright © 2017 Elsevier Ltd

Subclass-specific labeling of protein-reactive natural products with customized nucleophilic probes.

PubMed

Rudolf, Georg C; Koch, Maximilian F; Mandl, Franziska A M; Sieber, Stephan A

2015-02-23

Natural products represent a rich source of bioactive compounds that constitute a large fraction of approved drugs. Among those are molecules with electrophilic scaffolds, such as Michael acceptors, β-lactams, and epoxides that irreversibly inhibit essential enzymes based on their catalytic mechanism. In the search for novel bioactive molecules, current methods are challenged by the frequent rediscovery of known chemical entities. Herein small nucleophilic probes that attack electrophilic natural products and enhance their detection by HPLC-UV and HPLC-MS are introduced. A screen of diverse probe designs revealed one compound with a desired selectivity for epoxide- and maleimide-based antibiotics. Correspondingly, the natural products showdomycin and phosphomycin could be selectively targeted in extracts of their natural producing organism, in which the probe-modified molecules exhibited superior retention and MS detection relative to their unmodified counterparts. This method may thus help to discover small, electrophilic molecules that might otherwise easily elude detection in complex samples. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

DNA Assembly Techniques for Next Generation Combinatorial Biosynthesis of Natural Products

PubMed Central

Cobb, Ryan E.; Ning, Jonathan C.; Zhao, Huimin

2013-01-01

Natural product scaffolds remain important leads for pharmaceutical development. However, transforming a natural product into a drug entity often requires derivatization to enhance the compound’s therapeutic properties. A powerful method by which to perform this derivatization is combinatorial biosynthesis, the manipulation of the genes in the corresponding pathway to divert synthesis towards novel derivatives. While these manipulations have traditionally been carried out via restriction digestion/ligation-based cloning, the shortcomings of such techniques limit their throughput and thus the scope of corresponding combinatorial biosynthesis experiments. In the burgeoning field of synthetic biology, the demand for facile DNA assembly techniques has promoted the development of a host of novel DNA assembly strategies. Here we describe the advantages of these recently-developed tools for rapid, efficient synthesis of large DNA constructs. We also discuss their potential to facilitate the simultaneous assembly of complete libraries of natural product biosynthetic pathways, ushering in the next generation of combinatorial biosynthesis. PMID:24127070

Natural Gas and Cellulosic Biomass: A Clean Fuel Combination? Determining the Natural Gas Blending Wall in Biofuel Production.

PubMed

M Wright, Mark; Seifkar, Navid; Green, William H; Román-Leshkov, Yuriy

2015-07-07

Natural gas has the potential to increase the biofuel production output by combining gas- and biomass-to-liquids (GBTL) processes followed by naphtha and diesel fuel synthesis via Fischer-Tropsch (FT). This study reflects on the use of commercial-ready configurations of GBTL technologies and the environmental impact of enhancing biofuels with natural gas. The autothermal and steam-methane reforming processes for natural gas conversion and the gasification of biomass for FT fuel synthesis are modeled to estimate system well-to-wheel emissions and compare them to limits established by U.S. renewable fuel mandates. We show that natural gas can enhance FT biofuel production by reducing the need for water-gas shift (WGS) of biomass-derived syngas to achieve appropriate H2/CO ratios. Specifically, fuel yields are increased from less than 60 gallons per ton to over 100 gallons per ton with increasing natural gas input. However, GBTL facilities would need to limit natural gas use to less than 19.1% on a LHV energy basis (7.83 wt %) to avoid exceeding the emissions limits established by the Renewable Fuels Standard (RFS2) for clean, advanced biofuels. This effectively constitutes a blending limit that constrains the use of natural gas for enhancing the biomass-to-liquids (BTL) process.

Discovery of the leinamycin family of natural products by mining actinobacterial genomes

PubMed Central

Xu, Zhengren; Guo, Zhikai; Hindra; Ma, Ming; Zhou, Hao; Gansemans, Yannick; Zhu, Xiangcheng; Huang, Yong; Zhao, Li-Xing; Jiang, Yi; Cheng, Jinhua; Van Nieuwerburgh, Filip; Suh, Joo-Won; Duan, Yanwen

2017-01-01

Nature’s ability to generate diverse natural products from simple building blocks has inspired combinatorial biosynthesis. The knowledge-based approach to combinatorial biosynthesis has allowed the production of designer analogs by rational metabolic pathway engineering. While successful, structural alterations are limited, with designer analogs often produced in compromised titers. The discovery-based approach to combinatorial biosynthesis complements the knowledge-based approach by exploring the vast combinatorial biosynthesis repertoire found in Nature. Here we showcase the discovery-based approach to combinatorial biosynthesis by targeting the domain of unknown function and cysteine lyase domain (DUF–SH) didomain, specific for sulfur incorporation from the leinamycin (LNM) biosynthetic machinery, to discover the LNM family of natural products. By mining bacterial genomes from public databases and the actinomycetes strain collection at The Scripps Research Institute, we discovered 49 potential producers that could be grouped into 18 distinct clades based on phylogenetic analysis of the DUF–SH didomains. Further analysis of the representative genomes from each of the clades identified 28 lnm-type gene clusters. Structural diversities encoded by the LNM-type biosynthetic machineries were predicted based on bioinformatics and confirmed by in vitro characterization of selected adenylation proteins and isolation and structural elucidation of the guangnanmycins and weishanmycins. These findings demonstrate the power of the discovery-based approach to combinatorial biosynthesis for natural product discovery and structural diversity and highlight Nature’s rich biosynthetic repertoire. Comparative analysis of the LNM-type biosynthetic machineries provides outstanding opportunities to dissect Nature’s biosynthetic strategies and apply these findings to combinatorial biosynthesis for natural product discovery and structural diversity. PMID:29229819

Biotechnological production of hyperforin for pharmaceutical formulation.

PubMed

Gaid, Mariam; Biedermann, Eline; Füller, Jendrik; Haas, Paul; Behrends, Sönke; Krull, Rainer; Scholl, Stephan; Wittstock, Ute; Müller-Goymann, Christel; Beerhues, Ludger

2018-05-01

Hyperforin is a major active constituent of Hypericum perforatum (St. John's wort). It has amazing pharmacological activities, such as antidepressant properties, but it is labile and difficult to synthesize. Its sensitivity and lipophilicity are challenges for processing and formulation. Its chemical complexity provokes approaches of biotechnological production and modification. Dedifferentiated H. perforatum cell cultures lack appropriate storage sites and hence appreciable hyperforin levels. Shoot cultures are capable of forming hyperforin but less suitable for biomass up-scaling in bioreactors. Roots commonly lack hyperforin but a recently established adventitious root line has been demonstrated to produce hyperforin and derivatives at promising levels. The roots also contained lupulones, the typical constituents of hop (Humulus lupulus). Although shear-sensitive, these root cultures provide a potential production platform for both individual compounds and extracts with novel combinations of constituents and pharmacological activities. Besides in vitro cultivation techniques, the reconstruction of hyperforin biosynthesis in microorganisms is a promising alternative for biotechnological production. The biosynthetic pathway is under study, with omics-technologies being increasingly implemented. These biotechnological approaches may not only yield hyperforin at reasonable productivity but also allow for modifications of its chemical structure and pharmacological profile. Copyright © 2017 Elsevier B.V. All rights reserved.

Natural product-derived small molecule activators of hypoxia-inducible factor-1 (HIF-1).

PubMed

Nagle, Dale G; Zhou, Yu-Dong

2006-01-01

Hypoxia-inducible factor-1 (HIF-1) is a key mediator of oxygen homeostasis that was first identified as a transcription factor that is induced and activated by decreased oxygen tension. Upon activation, HIF-1 upregulates the transcription of genes that promote adaptation and survival under hypoxic conditions. HIF-1 is a heterodimer composed of an oxygen-regulated subunit known as HIF-1alpha and a constitutively expressed HIF-1beta subunit. In general, the availability and activity of the HIF-1alpha subunit determines the activity of HIF-1. Subsequent studies have revealed that HIF-1 is also activated by environmental and physiological stimuli that range from iron chelators to hormones. Preclinical studies suggest that HIF-1 activation may be a valuable therapeutic approach to treat tissue ischemia and other ischemia/hypoxia-related disorders. The focus of this review is natural product-derived small molecule HIF-1 activators. Natural products, relatively low molecular weight organic compounds produced by plants, animals, and microbes, have been and continue to be a major source of new drugs and molecular probes. The majority of known natural product-derived HIF-1 activators were discovered through the pharmacological evaluation of specifically selected individual compounds. On the other hand, the combination of natural products chemistry with appropriate high-throughput screening bioassays may yield novel natural product-derived HIF-1 activators. Potent natural product-derived HIF-1 activators that exhibit a low level of toxicity and side effects hold promise as new treatment options for diseases such as myocardial and peripheral ischemia, and as chemopreventative agents that could be used to reduce the level of ischemia/reperfusion injury following heart attack and stroke.

Clinical use of Hypericum perforatum (St John's wort) in depression: A meta-analysis.

PubMed

Ng, Qin Xiang; Venkatanarayanan, Nandini; Ho, Collin Yih Xian

2017-03-01

St John's wort is a popular herbal remedy recommended by Traditional Chinese Medicine (TCM) practitioners and licensed and widely prescribed for depression in many European countries. However, conflicting data regarding its benefits and risks exist, and the last large meta-analysis on St John's wort use for depression was done in 2008, with no updated meta-analysis available. Using the keywords [St John's Wort OR Hypericum perforatum OR hypericin OR hyperforin OR johanniskraut OR] AND [depression OR antidepressant OR SSRI], a preliminary search (without language restriction) on the PubMed, Ovid, Clinical Trials Register of the Cochrane Collaboration Depression, Anxiety and Neurosis Group, Cochrane Field for Complementary Medicine, China National Knowledge Infrastructure and WanFang database yielded 5428 papers between 1-Jan-1960 and 1-May-2016. 27 clinical trials with a total of 3808 patients were reviewed, comparing the use of St John's wort and SSRI. In patients with depression, St John's wort demonstrated comparable response (pooled RR 0.983, 95% CI 0.924-1.042, p<0.001) and remission (pooled RR 1.013, 95% CI 0.892-1.134, p<0.001) rate, and significantly lower discontinuation/dropout (pooled OR 0.587, 95% CI 0.478-0.697, p<0.001) rate compared to standard SSRIs. The pooled SMD from baseline HAM-D scores (pooled SMD -0.068, 95% CI -0.127 to 0.021, p<0.001) also support its significant clinical efficacy in ameliorating depressive symptoms. Evidence on the long-term efficacy and safety of St. John's wort is limited as the duration of all available studies ranged from 4 to 12 weeks. It is also unclear if St John's wort would be beneficial for patients with severe depression, high suicidality or suicide risk. For patients with mild-to-moderate depression, St John's wort has comparable efficacy and safety when compared to SSRIs. Follow-up studies carried out over a longer duration should be planned to ascertain its benefits. Copyright © 2017 Elsevier B.V. All rights

Emerging Trends in the Discovery of Natural Product Antibacterials

PubMed Central

Bologa, Cristian G.; Ursu, Oleg; Oprea, Tudor; Melançon, Charles E.; Tegos, George P.

2013-01-01

This article highlights current trends and advances in exploiting natural sources for the deployment of novel and potent anti-infective countermeasures. The key challenge is to therapeutically target microbial pathogens exhibiting a variety of puzzling and evolutionary complex resistance mechanisms. Special emphasis is given to the strengths, weaknesses, and opportunities in the natural product antimicrobial drug discovery arena, and to emerging applications driven by advances in bioinformatics, chemical biology, and synthetic biology in concert with exploiting the microbial phenotype. These orchestrated efforts have identified a critical mass of lead natural antimicrobials chemical scaffolds and discovery technologies with high probability of successful implementation against emerging microbial pathogens. PMID:23890825

Natural products as sources of new lead compounds for the treatment of Alzheimer's disease.

PubMed

Huang, Ling; Su, Tao; Li, Xingshu

2013-01-01

Alzheimer's disease (AD) is the most prevalent form of dementia and affects approximately 24 million people worldwide. One possible approach for the treatment of this disease is the restoration of the level of acetylcholine (ACh) through the inhibition of acetylcholinesterase (AChE) with reversible inhibitors. Naturally occurring alkaloids are an important source of AChE inhibitors. Galantamine and huperzine A have been used for the clinical treatment of AD patients. In this review, we summarise the natural products and their derivatives that were reported to act as AChE inhibitors for the treatment of AD in 2010-2013. Several characteristics were summarised from the literature results: 1) Amongst all of the natural products with AChE inhibitory activity, alkaloids appear to be the most promising compound class. 2) Coumarins, flavonoids, stilbenes, and other natural products are also important AChE inhibitors from natural products. Among these inhibitors, 146 (IC50 = 0.573 µM) was identified as the most potent AChE inhibitor. 3) A coumarin derivative (117, IC50 = 0.11 nM) exhibited more than 100-fold superior activity compared with the reference drug donepezil hydrochloride (IC50 = 14 nM). In conclusion, natural products and their derivatives are promising leads for the development of new drugs for the future treatment of AD.

SAM-Dependent Enzyme-Catalysed Pericyclic Reactions in Natural Product Biosynthesis

PubMed Central

Ohashi, Masao; Liu, Fang; Hai, Yang; Chen, Mengbin; Tang, Man-cheng; Yang, Zhongyue; Sato, Michio; Watanabe, Kenji; Houk, K. N.; Tang, Yi

2017-01-01

Pericyclic reactions are among the most powerful synthetic transformations to make multiple regioselective and stereoselective carbon-carbon bonds1. These reactions have been widely applied for the synthesis of biologically active complex natural products containing contiguous stereogenic carbon centers2–6. Despite the prominence of pericyclic reactions in total synthesis, only three naturally existing enzymatic examples, intramolecular Diels-Alder (IMDA) reaction7, Cope8 and Claisen rearrangements9, have been characterized. Here, we report the discovery of a S-adenosyl-L-methionine (SAM) dependent enzyme LepI that can catalyse stereoselective dehydration, bifurcating IMDA/hetero-DA (HDA) reactions via an ambimodal transition state, and a [3,3]-sigmatropic retro-Claisen rearrangement leading to the formation of dihydopyran core in the fungal natural product leporin10. Combined in vitro enzymatic characterization and computational studies provide evidence and mechanistic insight about how the O-methyltransferase-like protein LepI regulates the bifurcating biosynthetic reaction pathways (“direct” HDA and “byproduct recycle” IMDA/retro-Claisen reaction pathways) by utilizing SAM as the cofactor in order to converge to the desired biosynthetic end product. This work highlights that LepI is the first example of an enzyme catalysing a (SAM-dependent) retro-Claisen rearrangement. We suggest that more pericyclic biosynthetic enzymatic transformations are yet to be discovered in the intriguing enzyme toolboxes in Nature11, and propose an ever expanding role of the versatile cofactor SAM in enzyme catalysis. PMID:28902839

Natural Product Molecular Fossils.

PubMed

Falk, Heinz; Wolkenstein, Klaus

The natural products synthesized by organisms that were living a long time ago gave rise to their molecular fossils. These can consist of either the original unchanged compounds or they may undergo peripheral transformations in which their skeletons remain intact. In cases when molecular fossils can be traced to their organismic source, they are termed "geological biomarkers".This contribution describes apolar and polar molecular fossils and, in particular biomarkers, along the lines usually followed in organic chemistry textbooks, and points to their bioprecursors when available. Thus, the apolar compounds are divided in linear and branched alkanes followed by alicyclic compounds and aromatic and heterocyclic molecules, and, in particular, the geoporphyrins. The polar molecular fossils contain as functional groups or constituent units ethers, alcohols, phenols, carbonyl groups, flavonoids, quinones, and acids, or are polymers like kerogen, amber, melanin, proteins, or nucleic acids. The final sections discuss the methodology used and the fundamental processes encountered by the biomolecules described, including diagenesis, catagenesis, and metagenesis.

The ethics of dietary supplements and natural health products in pharmacy practice: a systematic documentary analysis.

PubMed

Boon, Heather; Hirschkorn, Kristine; Griener, Glenn; Cali, Michelle

2009-02-01

Many natural health products and dietary supplements are purchased in pharmacies and it has been argued that pharmacists are in the best position to provide patients with evidence-based information about them. This study was designed to identify how the pharmacist's role with respect to natural health products and dietary supplements is portrayed in the literature. A systematic search was conducted in a variety of health databases to identify all literature that pertained to both pharmacy and natural health products and dietary supplements. Of the 786 articles identified, 665 were broad-coded and 259 were subjected to in-depth qualitative content analysis for emergent themes. Overwhelmingly, support for the sale of natural health products and dietary supplements in pharmacies is strong. Additionally, a role for pharmacist counselling is underscored. But another recurrent theme is that pharmacists are ill-equipped to counsel patients about these products that are available on their shelves. This situation has led some to question the ethics of pharmacists selling natural health products and dietary supplements and to highlight the existence of an ethical conflict stemming from the profit-motive associated with sales of natural health products and dietary supplements. This analysis raises concerns about the ethics of natural health products and dietary supplements being sold in pharmacies, and about pharmacists being expected to provide counselling about products of which they have little knowledge.

Microarray Bactericidal Testing of Natural Products Against Yersinia intermedia and Bacillus anthracis

DTIC Science & Technology

2002-01-01

Based Preservation Systems and Probiotic Bacteria. In Food Microbiology: Fundamentals and Frontiers. M. P. Doyle, L.R. Beuchat and T.J. Montville...Microarray Bactericidal Testing of Natural Products Against Yersinia intermedia and Bacillus anthracis I.J. Fry1, F.K. Lee2, A. Turetsky2 and J.J...effective protection against biological warfare agents (BWA’s), natural products with a historical record of bactericidal efficacy such as

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice

PubMed Central

Johnson, Emily J.; Won, Christina S.; Köck, Kathleen; Paine, Mary F.

2017-01-01

Natural products, including botanical dietary supplements and exotic drinks, represent an ever-increasing share of the health care market. The parallel ever-increasing popularity of self-medicating with natural products increases the likelihood of co-consumption with conventional drugs, raising concerns for unwanted natural product-drug interactions. Assessing the drug interaction liability of natural products is challenging due to the complex and variable chemical composition inherent to these products, necessitating a streamlined preclinical testing approach to prioritize precipitant individual constituents for further investigation. Such an approach was evaluated in the current work to prioritize constituents in the model natural product, grapefruit juice, as inhibitors of intestinal organic anion-transporting peptide (OATP)-mediated uptake. Using OATP2B1-expressing MDCKII cells and the probe substrate estrone 3-sulfate, IC50s were determined for constituents representative of the flavanone (naringin, naringenin, hesperidin), furanocoumarin (bergamottin, 6′,7′-dihydroxybergamottin), and polymethoxyflavone (nobiletin and tangeretin) classes contained in grapefruit juice juice. Nobiletin was the most potent (IC50, 3.7 μM); 6′,7′-dihydroxybergamottin, naringin, naringenin, and tangeretin were moderately potent (IC50, 20–50 μM); and bergamottin and hesperidin were the least potent (IC50, >300 μM) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine ratios of unbound concentration to IC50 for each constituent within enterocytes and to prioritize in order of pre-defined cut-off values. This streamlined approach could be applied to other natural products that contain multiple precipitants of natural product-drug interactions. PMID:28032362

Drug Discovery Prospect from Untapped Species: Indications from Approved Natural Product Drugs

PubMed Central

Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Zhang, Cun Long; Tan, Chun Yan; Chen, Yu Zong; Jiang, Yu Yang

2012-01-01

Due to extensive bioprospecting efforts of the past and technology factors, there have been questions about drug discovery prospect from untapped species. We analyzed recent trends of approved drugs derived from previously untapped species, which show no sign of untapped drug-productive species being near extinction and suggest high probability of deriving new drugs from new species in existing drug-productive species families and clusters. Case histories of recently approved drugs reveal useful strategies for deriving new drugs from the scaffolds and pharmacophores of the natural product leads of these untapped species. New technologies such as cryptic gene-cluster exploration may generate novel natural products with highly anticipated potential impact on drug discovery. PMID:22808057

Effect of St.John's wort (Hypericum perforatum) oily extract for the care and treatment of pressure sores; a case report.

PubMed

Yücel, Ali; Kan, Yüksel; Yesilada, Erdem; Akın, Onat

2017-01-20

Topical formulations such as oily extracts or ointments prepared with the flowering aerial parts of St. John's wort (Hypericum perforatum L., Hypericaceae) have been used in the management of a wide range dermatological problems including superficial wounds and burns, bruises, contusions and many others in the worldwide traditional medicines. This is the first case study reporting the beneficial effects of an oily extract of St. John's wort in the treatment of pressure sores in a intensive care unit (ICU) patient. The oily extract of St. John's wort was applied to a volunteer patient at ICU daily for forty successive days for wound care and treatment. Healing status was monitored macroscopically by measuring the wound size and stages at certain intervals as well as histopathological evaluation of the tissue sections taken at the initial and final dates of treatment. Evaluation of the results obtained from the macroscopical and histopathological experimentation have shown that oily extract of St. John's wort provided significant efficacy for the treatment of pressure sore wounds. St. John's wort oily extract may be suggested as a cost-effective option for the prevention or treatment of pressure sores in ICU patients. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Use of Brown Algae to Demonstrate Natural Products Techniques.

ERIC Educational Resources Information Center

Porter, Lee A.

1985-01-01

Background information is provided on the natural products found in marine organisms in general and the brown algae in particular. Also provided are the procedures needed to isolate D-mannitol (a primary metabolite) and cholesterol from brown algae. (JN)

Spectroscopic and quantum chemical analysis of a natural product - Hayatin hydrochloride

NASA Astrophysics Data System (ADS)

Mishra, Rashmi; Srivastava, Anubha; Tandon, Poonam; Jain, Sudha

2015-08-01

Majority of drugs in use today are natural products, natural product mimics or semi synthetic derivatives. Therefore in recent times, focus on plant research has increased all over the world and large body of evidence has been collected to show immense potential of medicinal plants used in various traditional systems. Therefore, in the present communication to aid that research, structural and spectroscopic analysis of a natural product, an alkaloid Hayatin hydrochloride was performed. Both ab initio Hartree-Fock and density functional theory employing B3LYP with complete relaxation in the potential energy surface using 6-311G (d,p) basis set were used for the calculations. The vibrational frequencies were calculated and scaled values were compared with experimental FT-IR and micro-Raman spectra. The complete assignments were performed on the basis of potential energy distribution. The structure-activity relationship has also been interpreted by mapping electrostatic potential surface, which are valuable information for the quality control of medicines and drug-receptor interactions. Electronic properties have been analysed employing TD-DFT for both gaseous and solvent phase. The calculated HOMO and LUMO energies show that charge transfer occurs within the molecule. Stability of the molecule arising from hyper conjugative interactions, charge delocalization has been analyzed using natural bond orbital (NBO) analysis.

Current Status and Future Prospects of Marine Natural Products (MNPs) as Antimicrobials

PubMed Central

Choudhary, Alka; Naughton, Lynn M.; Montánchez, Itxaso

2017-01-01

The marine environment is a rich source of chemically diverse, biologically active natural products, and serves as an invaluable resource in the ongoing search for novel antimicrobial compounds. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from the ocean moving into clinical trials. The chemical diversity associated with these marine-derived molecules is immense, varying from simple linear peptides and fatty acids to complex alkaloids, terpenes and polyketides, etc. Such an array of structurally distinct molecules performs functionally diverse biological activities against many pathogenic bacteria and fungi, making marine-derived natural products valuable commodities, particularly in the current age of antimicrobial resistance. In this review, we have highlighted several marine-derived natural products (and their synthetic derivatives), which have gained recognition as effective antimicrobial agents over the past five years (2012–2017). These natural products have been categorized based on their chemical structures and the structure-activity mediated relationships of some of these bioactive molecules have been discussed. Finally, we have provided an insight into how genome mining efforts are likely to expedite the discovery of novel antimicrobial compounds. PMID:28846659

Recent progress in doxorubicin-induced cardiotoxicity and protective potential of natural products.

PubMed

Yu, Jie; Wang, Changxi; Kong, Qi; Wu, Xiaxia; Lu, Jin-Jian; Chen, Xiuping

2018-02-01

As an anthracycline antibiotic, doxorubicin (DOX) is one of the most potent and widely used chemotherapeutic agents for various types of solid tumors. Unfortunately, clinical application of this drug results in severe side effects of cardiotoxicity. We aim to review the research focused on elimination or reduction of DOX cardiotoxicity without affecting its anticancer efficacy by natural products. This study is based on pertinent papers that were retrieved by a selective search using relevant keywords in PubMed and ScienceDirect. The literature mainly focusing on natural products and herb extracts with therapeutic efficacies against experimental models both in vitro and in vivo was identified. Current evidence revealed that multiple molecules and signaling pathways, such as oxidative stress, iron metabolism, and inflammation, are associated with DOX-induced cardiotoxicity. Based on these knowledge, various strategies were proposed, and thousands of compounds were screened. A number of natural products and herb extracts demonstrated potency in limiting DOX cardiotoxicity toward cultured cells and experimental animal models. Though a panel of natural products and herb extracts demonstrate protective effects on DOX-induced cardiotoxicity in cells and animal models, their therapeutic potentials for clinical needs further investigation. Copyright © 2018 Elsevier GmbH. All rights reserved.

Current Status and Future Prospects of Marine Natural Products (MNPs) as Antimicrobials.

PubMed

Choudhary, Alka; Naughton, Lynn M; Montánchez, Itxaso; Dobson, Alan D W; Rai, Dilip K

2017-08-28

The marine environment is a rich source of chemically diverse, biologically active natural products, and serves as an invaluable resource in the ongoing search for novel antimicrobial compounds. Recent advances in extraction and isolation techniques, and in state-of-the-art technologies involved in organic synthesis and chemical structure elucidation, have accelerated the numbers of antimicrobial molecules originating from the ocean moving into clinical trials. The chemical diversity associated with these marine-derived molecules is immense, varying from simple linear peptides and fatty acids to complex alkaloids, terpenes and polyketides, etc. Such an array of structurally distinct molecules performs functionally diverse biological activities against many pathogenic bacteria and fungi, making marine-derived natural products valuable commodities, particularly in the current age of antimicrobial resistance. In this review, we have highlighted several marine-derived natural products (and their synthetic derivatives), which have gained recognition as effective antimicrobial agents over the past five years (2012-2017). These natural products have been categorized based on their chemical structures and the structure-activity mediated relationships of some of these bioactive molecules have been discussed. Finally, we have provided an insight into how genome mining efforts are likely to expedite the discovery of novel antimicrobial compounds.

Natural products from Cuscuta reflexa Roxb. with antiproliferation activities in HCT116 colorectal cell lines.

PubMed

Riaz, Muhammad; Bilal, Aishah; Ali, Muhammad Shaiq; Fatima, Itrat; Faisal, Amir; Sherkheli, Muhammad Azhar; Asghar, Adnan

2017-03-01

Parasitic Cuscuta reflexa Roxb. possesses many medicinal properties and is a rich source of a variety of biologically relevant natural products. Natural products are the prime source of leads, drugs, and drug templates, and many of the anticancer and antiviral drugs are either based on natural product or derived from them. Cancer is a devastating disease and one of the leading causes of death worldwide despite improvements in patient survival during the past 50 years; new and improved treatments for cancer are therefore actively sought. Colorectal cancer is the fourth most prevalent cancer worldwide and is responsible for nearly 9% of all cancer deaths. Our search for anticancer natural products from C. reflexa has yielded four natural products: Scoparone (1), p-coumaric acid (2), stigmasta-3,5-diene (3) and 1-O-p-hydroxycinnamoylglucose (4) and among them 1-O-p-hydroxycinnamoyldlucose (4) showed promising antiproliferative activities in HCT116 colorectal cell lines, whereas compounds 1-3 showed moderate activities.

Natural products with hypoglycemic, hypotensive, hypocholesterolemic, antiatherosclerotic and antithrombotic activities.

PubMed

Wang, H X; Ng, T B

1999-01-01

This article reviews compounds of botanical origin which are capable of lowering plasma levels of glucose and cholesterol and blood pressure, as well as compounds inhibiting atherosclerosis and thrombosis. Hypoglycemic natural products comprise flavonoids, xanthones, triterpenoids, alkaloids, glycosides, alkyldisulfides, aminobutyric acid derivatives, guanidine, polysaccharides and peptides. Hypotensive compounds include flavonoids, diterpenes, alkaloids, glycosides, polysaccharides and proteins. Among natural products with hypocholesterolemic activity are beta-carotene, lycopene, cycloartenol, beta-sitosterol, sitostanol, saponin, soybean protein, indoles, dietary fiber, propionate, mevinolin (beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitor) and polysaccharides. Heparins, flavonoids, tocotrienols, beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors (statins), garlic compounds and fungal proteases exert antithrombotic action. Statins and garlic compounds also possess antiatherosclerotic activity.

An introduction to planar chromatography and its application to natural products isolation.

PubMed

Gibbons, Simon

2012-01-01

Thin-layer chromatography (TLC) is an easy, inexpensive, rapid, and the most widely used method for the analysis and isolation of small organic natural and synthetic products. It also has use in the biological evaluation of organic compounds, particularly in the areas of antimicrobial and antioxidant metabolites and for the evaluation of acetylcholinesterase inhibitors which have utility in the treatment of Alzheimer's disease. The ease and inexpensiveness of use of this technique, coupled with the ability to rapidly develop separation and bioassay protocols will ensure that TLC will be used for some considerable time alongside conventional instrumental methods. This chapter deals with the basic principles of TLC and describes methods for the analysis and isolation of natural products. Examples of methods for isolation of several classes of natural product are detailed and protocols for TLC bioassays are given.

The natural product phyllanthusmin C enhances IFN-γ production by human NK cells through upregulation of TLR-mediated NF-κB signaling.

PubMed

Deng, Youcai; Chu, Jianhong; Ren, Yulin; Fan, Zhijin; Ji, Xiaotian; Mundy-Bosse, Bethany; Yuan, Shunzong; Hughes, Tiffany; Zhang, Jianying; Cheema, Baljash; Camardo, Andrew T; Xia, Yong; Wu, Lai-Chu; Wang, Li-Shu; He, Xiaoming; Kinghorn, A Douglas; Li, Xiaohui; Caligiuri, Michael A; Yu, Jianhua

2014-09-15

Natural products are a major source for cancer drug development. NK cells are a critical component of innate immunity with the capacity to destroy cancer cells, cancer-initiating cells, and clear viral infections. However, few reports describe a natural product that stimulates NK cell IFN-γ production and unravel a mechanism of action. In this study, through screening, we found that a natural product, phyllanthusmin C (PL-C), alone enhanced IFN-γ production by human NK cells. PL-C also synergized with IL-12, even at the low cytokine concentration of 0.1 ng/ml, and stimulated IFN-γ production in both human CD56(bright) and CD56(dim) NK cell subsets. Mechanistically, TLR1 and/or TLR6 mediated PL-C's activation of the NF-κB p65 subunit that in turn bound to the proximal promoter of IFNG and subsequently resulted in increased IFN-γ production in NK cells. However, IL-12 and IL-15Rs and their related STAT signaling pathways were not responsible for the enhanced IFN-γ secretion by PL-C. PL-C induced little or no T cell IFN-γ production or NK cell cytotoxicity. Collectively, we identify a natural product with the capacity to selectively enhance human NK cell IFN-γ production. Given the role of IFN-γ in immune surveillance, additional studies to understand the role of this natural product in prevention of cancer or infection in select populations are warranted. Copyright © 2014 by The American Association of Immunologists, Inc.

Marine Natural Products with P-Glycoprotein Inhibitor Properties

PubMed Central

Lopez, Dioxelis; Martinez-Luis, Sergio

2014-01-01

P-glycoprotein (P-gp) is a protein belonging to the ATP-binding cassette (ABC) transporters superfamily that has clinical relevance due to its role in drug metabolism and multi-drug resistance (MDR) in several human pathogens and diseases. P-gp is a major cause of drug resistance in cancer, parasitic diseases, epilepsy and other disorders. This review article aims to summarize the research findings on the marine natural products with P-glycoprotein inhibitor properties. Natural compounds that modulate P-gp offer great possibilities for semi-synthetic modification to create new drugs and are valuable research tools to understand the function of complex ABC transporters. PMID:24451193

Synthesis of four diastereomers of sclerophytin F and structural reassignment of several sclerophytin natural products.

PubMed

Clark, J Stephen; Delion, Laëtitia; Farrugia, Louis J

2015-03-16

Synthesis of the triol that has been proposed to be the marine natural product sclerophytin F has been completed along with the syntheses of three diastereomers. Comparison of the NMR spectroscopic data for all four compounds to the data reported for the natural product reveals that sclerophytin F is not the 3S diastereomer of sclerophytin A as proposed by Friedrich and Paquette. Re-analysis of the NMR spectroscopic data for known sclerophytin natural products and synthetic analogues leads to the conclusion that sclerophytins E and F are the same compound. This finding has allowed structural reassignment of several other cladiellin natural products. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

A New Route to Azafluoranthene Natural Products via Direct Arylation

PubMed Central

Ponnala, Shashikanth; Harding, Wayne W.

2013-01-01

Microwave-assisted direct arylation was successfully employed in the synthesis of azafluoranthene alkaloids for the first time. Direct arylation reactions on a diverse set of phenyltetrahydroisoquinolines produces the indeno[1,2,3-ij]isoquinoline nucleus en route to a high yielding azafluoranthene synthesis. The method was used as a key step in the efficient preparation of the natural products rufescine and triclisine. As demonstrated herein, this synthetic approach should be generally applicable to the preparation of natural and un-natural azafluoranthene alkaloids as well as “azafluoranthene-like” isoquinoline alkaloids. PMID:23503080

An Automated High-Throughput System to Fractionate Plant Natural Products for Drug Discovery

PubMed Central

Tu, Ying; Jeffries, Cynthia; Ruan, Hong; Nelson, Cynthia; Smithson, David; Shelat, Anang A.; Brown, Kristin M.; Li, Xing-Cong; Hester, John P.; Smillie, Troy; Khan, Ikhlas A.; Walker, Larry; Guy, Kip; Yan, Bing

2010-01-01

The development of an automated, high-throughput fractionation procedure to prepare and analyze natural product libraries for drug discovery screening is described. Natural products obtained from plant materials worldwide were extracted and first prefractionated on polyamide solid-phase extraction cartridges to remove polyphenols, followed by high-throughput automated fractionation, drying, weighing, and reformatting for screening and storage. The analysis of fractions with UPLC coupled with MS, PDA and ELSD detectors provides information that facilitates characterization of compounds in active fractions. Screening of a portion of fractions yielded multiple assay-specific hits in several high-throughput cellular screening assays. This procedure modernizes the traditional natural product fractionation paradigm by seamlessly integrating automation, informatics, and multimodal analytical interrogation capabilities. PMID:20232897

Natural or Plant Products for the Treatment of Neurological Disorders: Current Knowledge.

PubMed

Parvez, Mohammad Khalid

2018-01-01

In recent decades, complementary and alternative medicine (CAM) has become very popular in the treatment of several chronic diseases. Natural products as one of the CAM modalities offer potential opportunities to discover lead compounds for novel drug development. The use of CAM or natural products in the prevention of neurodegenerative diseases is comparatively a newer area. A structured online literature search for peer-reviewed research articles was conducted on the PubMed, Europe PMC, Medline and Google Scholar portals, using phrases: natural products for neurologic disorders, phytomedicine for neurodegenerative diseases, natural therapeutics for neurological symptopms etc. Results: The retrieved data showed the natural therapeutics with anti-oxidative and anti-inflammatory salutations evidently plays a crucial role in protecting neurons. Of these, the most promising are caffeine, trigonelline, shogaol, curcumin, resveratrol, baicalein, wogonin, ginsenosides, tanshinones, withanolides, picrosides, parthenolide, cannabinoids, Devil's claw and white willow bark, including Chinese formulations Renshen Shouwu and Shengmai San. Though several herbs and their active ingredients have been studied in laboratory and clinical settings, only a few have been investigated for their molecular mechanisms of action. Notably, despite the promising and safe therapeutic benefits of CAM/herbal medicines, there exists a possible risk when combining them with prescription drugs. As a result, many drugs have shown changes in blood pressure, hepatotoxicity, seizures etc. when combined with certain herbs. Certainly, extensive work is needed to make sure that patients should take a regimen of protective and restorative therapy under an experienced healthcare professional. This article updates on the current knowledge of promising natural products used in neurological disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Highly Stereoselective Synthesis of a Compound Collection Based on the Bicyclic Scaffolds of Natural Products.

PubMed

Annamalai, Murali; Hristeva, Stanimira; Bielska, Martyna; Ortega, Raquel; Kumar, Kamal

2017-05-18

Despite the great contribution of natural products in the history of successful drug discovery, there are significant limitations that persuade the pharmaceutical industry to evade natural products in drug discovery research. The extreme scarcity as well as structural complexity of natural products renders their practical synthetic access and further modifications extremely challenging. Although other alternative technologies, particularly combinatorial chemistry, were embraced by the pharmaceutical industry to get quick access to a large number of small molecules with simple frameworks that often lack three-dimensional complexity, hardly any success was achieved in the discovery of lead molecules. To acquire chemotypes beholding structural features of natural products, for instance high sp ³ character, the synthesis of compound collections based on core-scaffolds of natural products presents a promising strategy. Here, we report a natural product inspired synthesis of six different chemotypes and their derivatives for drug discovery research. These bicyclic hetero- and carbocyclic scaffolds are highly novel, rich in sp ³ features and with ideal physicochemical properties to display drug likeness. The functional groups on the scaffolds were exploited further to generate corresponding compound collections. Synthesis of two of these collections exemplified with ca. 350 compounds are each also presented. The whole compound library is being exposed to various biological screenings within the European Lead Factory consortium.

Prioritizing pharmacokinetic drug interaction precipitants in natural products: application to OATP inhibitors in grapefruit juice.

PubMed

Johnson, Emily J; Won, Christina S; Köck, Kathleen; Paine, Mary F

2017-04-01