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.

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.

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.

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 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.

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

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.

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

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.

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.

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.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting.

PubMed

Zhu, Feng; Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Ma, Xiaohua; Jia, Jia; Tan, Ying; Cui, Cheng; Lin, Jinshun; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2011-08-02

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed.

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.

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."

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.

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.

Quantitative and Systems Pharmacology. 1. In Silico Prediction of Drug-Target Interactions of Natural Products Enables New Targeted Cancer Therapy.

PubMed

Fang, Jiansong; Wu, Zengrui; Cai, Chuipu; Wang, Qi; Tang, Yun; Cheng, Feixiong

2017-11-27

Natural products with diverse chemical scaffolds have been recognized as an invaluable source of compounds in drug discovery and development. However, systematic identification of drug targets for natural products at the human proteome level via various experimental assays is highly expensive and time-consuming. In this study, we proposed a systems pharmacology infrastructure to predict new drug targets and anticancer indications of natural products. Specifically, we reconstructed a global drug-target network with 7,314 interactions connecting 751 targets and 2,388 natural products and built predictive network models via a balanced substructure-drug-target network-based inference approach. A high area under receiver operating characteristic curve of 0.96 was yielded for predicting new targets of natural products during cross-validation. The newly predicted targets of natural products (e.g., resveratrol, genistein, and kaempferol) with high scores were validated by various literature studies. We further built the statistical network models for identification of new anticancer indications of natural products through integration of both experimentally validated and computationally predicted drug-target interactions of natural products with known cancer proteins. We showed that the significantly predicted anticancer indications of multiple natural products (e.g., naringenin, disulfiram, and metformin) with new mechanism-of-action were validated by various published experimental evidence. In summary, this study offers powerful computational systems pharmacology approaches and tools for the development of novel targeted cancer therapies by exploiting the polypharmacology of natural products.

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.

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.

Clustered patterns of species origins of nature-derived drugs and clues for future bioprospecting

PubMed Central

Zhu, Feng; Qin, Chu; Tao, Lin; Liu, Xin; Shi, Zhe; Ma, Xiaohua; Jia, Jia; Tan, Ying; Cui, Cheng; Lin, Jinshun; Tan, Chunyan; Jiang, Yuyang; Chen, Yuzong

2011-01-01

Many drugs are nature derived. Low drug productivity has renewed interest in natural products as drug-discovery sources. Nature-derived drugs are composed of dozens of molecular scaffolds generated by specific secondary-metabolite gene clusters in selected species. It can be hypothesized that drug-like structures probably are distributed in selective groups of species. We compared the species origins of 939 approved and 369 clinical-trial drugs with those of 119 preclinical drugs and 19,721 bioactive natural products. In contrast to the scattered distribution of bioactive natural products, these drugs are clustered into 144 of the 6,763 known species families in nature, with 80% of the approved drugs and 67% of the clinical-trial drugs concentrated in 17 and 30 drug-prolific families, respectively. Four lines of evidence from historical drug data, 13,548 marine natural products, 767 medicinal plants, and 19,721 bioactive natural products suggest that drugs are derived mostly from preexisting drug-productive families. Drug-productive clusters expand slowly by conventional technologies. The lack of drugs outside drug-productive families is not necessarily the result of under-exploration or late exploration by conventional technologies. New technologies that explore cryptic gene clusters, pathways, interspecies crosstalk, and high-throughput fermentation enable the discovery of novel natural products. The potential impact of these technologies on drug productivity and on the distribution patterns of drug-productive families is yet to be revealed. PMID:21768386

[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.

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.

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...

Alternative Fuels Data Center: Renewable Natural Gas (Biomethane)

Science.gov Websites

Production Renewable Natural Gas (Biomethane) Production to someone by E-mail Share Alternative Fuels Data Center: Renewable Natural Gas (Biomethane) Production on Facebook Tweet about Alternative Fuels Data Center: Renewable Natural Gas (Biomethane) Production on Twitter Bookmark Alternative Fuels

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.

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.

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

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.

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.

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.

Influence of experimental subarachnoid hemorrhage on nicotine-induced contraction of the rat basilar artery in relation to arachidonic acid metabolites signaling pathway.

PubMed

Ji, Xu; Wang, Aimin; Trandafir, Cristina C; Kurahashi, Kazuyoshi

2013-10-01

Smoking is one of the most important risk factors for cerebral circulatory disorders. The purpose of this study was to investigate the influence of experimental subarachnoid hemorrhage (SAH) on nicotine-induced contraction (arachidonic acid metabolites) in the basilar arteries of rats. Rats were killed at 1 hour and 1 week after blood injection, and the basilar artery was isolated and cut into a spiral strip. Testing of cyclooxygenase-1 (COX-1) and 5-lipoxygenase (5-LOX) inhibitors revealed no significant differences in their effects on normal and SAH (1 hour and 1 week). Phospholipase C (PLC) inhibitor (1-(6-((17beta-3-methoxyestra-1,3,5(10)-trien-17yl)amino)hexyl)-1H-pyrrole-2,5,-dione [U-73122]) slightly inhibited contraction of SAH (1 hour and 1 week) when compared to controls. Phospholipase A2 (PLA2) inhibitor (manoalide) and cytosolic PLA2 (cPLA2) inhibitor (arachidonyltrifluoromenthylketone [AACOCF3]) more strongly attenuated contraction in SAH (1 hour and 1 week) than in controls. Secreted PLA2 (sPLA2) inhibitor (indoxam), PLC inhibitor (2-nitro-4-carboxyphenyl N, N-diphenylcarbamate [NCDC]), and COX-2 inhibitors (nimesulide, (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indanone) [L-745337], and celecoxib) only slightly inhibited contraction of SAH (1 week) when compared to normal and SAH (1 hour). The calcium-independent PLA2 (iPLA2) inhibitor bromoenol lactone (BEL) showed greater inhibition of contraction in SAH (1 hour) when compared to normal and SAH (1 week). One week after exposure to SAH, PLC, sPLA2, and COX-2 activity were enhanced and cPLA2 activity was inhibited. One hour after exposure to SAH, PLC activity was enhanced and cPLA2 and iPLA2 activity was inhibited. Such changes of inflammatory arachidonic acid metabolites by smoking after SAH may play important roles in fatal cerebral circulatory disorders, suggesting important implications for the etiology and pathogenesis of SAH. Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.

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

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.

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

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.

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

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.

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

76 FR 70123 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2011-11-10

... Natural Gas Production Report. DATES: Comments must be filed by January 9, 2012. If you anticipate... the United States and the requirement for accurate and timely natural gas production information... disseminated through the EIA Natural Gas Monthly, Monthly Natural Gas Gross Production Report, and EIA Natural...

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.

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.

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.

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.

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.

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

Plant Products for Pharmacology: Application of Enzymes in Their Transformations

PubMed Central

Zarevúcka, Marie; Wimmer, Zdeněk

2008-01-01

Different plant products have been subjected to detailed investigations due to their increasing importance for improving human health. Plants are sources of many groups of natural products, of which large number of new compounds has already displayed their high impact in human medicine. This review deals with the natural products which may be found dissolved in lipid phase (phytosterols, vitamins etc.). Often subsequent convenient transformation of natural products may further improve the pharmacological properties of new potential medicaments based on natural products. To respect basic principles of sustainable and green procedures, enzymes are often employed as efficient natural catalysts in such plant product transformations. Transformations of lipids and other natural products under the conditions of enzyme catalysis show increasing importance in environmentally safe and sustainable production of pharmacologically important compounds. In this review, attention is focused on lipases, efficient and convenient biocatalysts for the enantio- and regioselective formation / hydrolysis of ester bond in a wide variety of both natural and unnatural substrates, including plant products, eg. plant oils and other natural lipid phase compounds. The application of enzymes for preparation of acylglycerols and transformation of other natural products provides big advantage in comparison with employing of conventional chemical methods: Increased selectivity, higher product purity and quality, energy conservation, elimination of heavy metal catalysts, and sustainability of the employed processes, which are catalyzed by enzymes. Two general procedures are used in the transformation of lipid-like natural products: (a) Hydrolysis/alcoholysis of triacylglycerols and (b) esterification of glycerol. The reactions can be performed under conventional conditions or in supercritical fluids/ionic liquids. Enzyme-catalyzed reactions in supercritical fluids combine the advantages of biocatalysts (substrate specificity under mild reaction conditions) and supercritical fluids (high mass-transfer rate, easy separation of reaction products from the solvent, environmental benefits based on excluding organic solvents from the production process). PMID:19330086

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.

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 consists of crude or partially fractionated mixtures, the library contents should be profiled to identify the known components present - a process known as dereplication. The use of mass spectrometry and HPLC-mass spectrometry together with spectral databases is a powerful tool in the chemometric profiling of bio-sources for natural product production. High throughput, high sensitivity flow NMR is an emerging tool in this area as well. Whether by cell based or biomolecular target based assays, screening of natural product extract libraries continues to furnish novel lead molecules for further drug development, despite challenges in the analysis and prioritization of natural products hits. Spectroscopic techniques are now being used to directly screen natural product and synthetic libraries. Mass spectrometry in the form of methods such as ESI-ICRFTMS, and FACS-MS as well as NMR methods such as SAR by NMR and STD-NMR have been utilized to effectively screen molecular libraries. Overall, emerging advances in mass spectrometry, NMR and other technologies are making it possible to overcome the challenges encountered in screening natural products libraries in today's drug discovery environment. As we apply these technologies and develop them even further, we can look forward to increased impact of natural products in the HTS based drug discovery.

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.

Seed production in the first eight years and frequency of natural selfing in a simulated jack pine seedling seed orchard

Treesearch

Thomas D. Rudolph

1977-01-01

Seed production and percent of natural selfing were determined in an 8 x 8-foot, 1200-tree plantation. Actual seed production was determined through age 6; production through age 8 was projected based on first-year cone counts at age 7. The percent of natural self-pollination, production of seedlings from natural selfing, and percent of selfs that were lethal were...

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

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.

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

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.

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...

Linking neuroethology to the chemical biology of natural products: interactions between cone snails and their fish prey, a case study.

PubMed

Olivera, Baldomero M; Raghuraman, Shrinivasan; Schmidt, Eric W; Safavi-Hemami, Helena

2017-09-01

From a biological perspective, a natural product can be defined as a compound evolved by an organism for chemical interactions with another organism including prey, predator, competitor, pathogen, symbiont or host. Natural products hold tremendous potential as drug leads and have been extensively studied by chemists and biochemists in the pharmaceutical industry. However, the biological purpose for which a natural product evolved is rarely addressed. By focusing on a well-studied group of natural products-venom components from predatory marine cone snails-this review provides a rationale for why a better understanding of the evolution, biology and biochemistry of natural products will facilitate both neuroscience and the potential for drug leads. The larger goal is to establish a new sub-discipline in the broader field of neuroethology that we refer to as "Chemical Neuroethology", linking the substantial work carried out by chemists on natural products with accelerating advances in neuroethology.

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 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

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.

Investigating Nature's Mysteries for Drug Development

Cancer.gov

More than half of the drugs approved to treat cancer come from a natural product or a natural product prototype. Scientists in NCI-Frederick's Natural Products Branch are exploring ways to harness chemicals produced by marine invertebrates, other animals, plants, and microbes for cancer drug discovery.

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.

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.

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.

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.

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 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.

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.

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.

30 CFR 260.123 - How do I measure natural gas production for a lease issued in a sale held after November 2000?

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 for a... Systems Royalty Suspension (rs) Leases § 260.123 How do I measure natural gas production for a lease issued in a sale held after November 2000? You must measure natural gas production subject to the royalty...

30 CFR 260.123 - How do I measure natural gas production for a lease issued in a sale held after November 2000?

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 for a... measure natural gas production for a lease issued in a sale held after November 2000? You must measure natural gas production subject to the royalty suspension volume for your lease as follows: 5.62 thousand...

Caryophyllene driven diversity in an one-pot rearrangement of oxidation and transanular reactions

NASA Astrophysics Data System (ADS)

Tang, Hao-Yu; Quan, Lu-Lu; Yu, Jie; Zhang, Qiang; Gao, Jin-Ming

2018-03-01

Diversity oriented synthesis starting from natural products is a newly coming strategy to build diverse skeletons to meet the demands of high throughput screening in drug development. Caryophyllene was being considered as an ideal starting point to build divers natural-like sesquiterpenes due to its rich sources and build-in reactivity. In this paper, six new natural-like products (2-7) were synthesized form the natural cryophyllene oxide via cascade oxidation and transannular reactions in a one-pot procedure. Their structures were elucidated by exhaustive spectra method including 2D NMR and X-ray diffraction. Of the products, compounds 6 and 7 possess very similar skeleton to natural products. Our findings demonstrated that one-pot cascade reactions on macrocyclic natural products is a concise strategy to create diverse natural-like skeletons.

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.

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

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 form 'activity cliffs'. In all, prioritization strategies for the NAA were proposed. Chemo-informatic profiling of NAA and CRAD have produced a wealth of information that may guide decisions and facilitate anti-malarial drug development from natural products. Articulation of the information provided within an interactive data-mining environment led to a prioritized list of NAA.

Discovery of New Compounds Active against Plasmodium falciparum by High Throughput Screening of Microbial Natural Products.

PubMed

Pérez-Moreno, Guiomar; Cantizani, Juan; Sánchez-Carrasco, Paula; Ruiz-Pérez, Luis Miguel; Martín, Jesús; El Aouad, Noureddine; Pérez-Victoria, Ignacio; Tormo, José Rubén; González-Menendez, Víctor; González, Ignacio; de Pedro, Nuria; Reyes, Fernando; Genilloud, Olga; Vicente, Francisca; González-Pacanowska, Dolores

2016-01-01

Due to the low structural diversity within the set of antimalarial drugs currently available in the clinic and the increasing number of cases of resistance, there is an urgent need to find new compounds with novel modes of action to treat the disease. Microbial natural products are characterized by their large diversity provided in terms of the chemical complexity of the compounds and the novelty of structures. Microbial natural products extracts have been underexplored in the search for new antiparasitic drugs and even more so in the discovery of new antimalarials. Our objective was to find new druggable natural products with antimalarial properties from the MEDINA natural products collection, one of the largest natural product libraries harboring more than 130,000 microbial extracts. In this work, we describe the optimization process and the results of a phenotypic high throughput screen (HTS) based on measurements of Plasmodium lactate dehydrogenase. A subset of more than 20,000 extracts from the MEDINA microbial products collection has been explored, leading to the discovery of 3 new compounds with antimalarial activity. In addition, we report on the novel antiplasmodial activity of 4 previously described natural products.

78 FR 15370 - Draft Guidance for Industry and Food and Drug Administration Staff: Recommendations for Labeling...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-03-11

... Product Container Is Not Made With Natural Rubber Latex.'' The purpose of this draft guidance is to make recommendations on the appropriate language to include in the labeling of a medical product to convey that natural... Products To Inform Users That the Product or Product Container Is Not Made With Natural Rubber Latex...

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 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.

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.

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

Tagging polyketides/non-ribosomal peptides with a clickable functionality and applications

PubMed Central

Zhu, Xuejun; Zhang, Wenjun

2015-01-01

Bioorthogonal chemistry has recently emerged to be one of the most powerful tools in drug discovery and chemical biology. The exploration of it has successfully advanced the field of natural product research. In this Perspective, we survey current strategies for the installation of chemical handles into the molecular scaffolds of several major classes of natural products, including polyketides (PKs), non-ribosomal peptides (NRPs), and their hybrids. By tagging these natural products with chemical handles and coupling them with subsequent bioorthogonal reactions, researchers have visualized and studied the mode of action of natural products, as well as synthesized derivatives with better pharmaceutical properties. We conclude this Perspective by considering two questions: is there a general way to synthesize tagged PKs/NRPs? Does natural product labeling have a broader impact in the field of natural product research beyond current known applications? PMID:25815285

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

Chemoprevention in gastrointestinal physiology and disease. Targeting the progression of cancer with natural products: a focus on gastrointestinal cancer.

PubMed

Khoogar, Roxane; Kim, Byung-Chang; Morris, Jay; Wargovich, Michael J

2016-05-01

The last decade has witnessed remarkable progress in the utilization of natural products for the prevention and treatment of human cancer. Many agents now in the pipeline for clinical trial testing have evolved from our understanding of how human nutritional patterns account for widespread differences in cancer risk. In this review, we have focused on many of these promising agents arguing that they may provide a new strategy for cancer control: natural products once thought to be only preventive in their mode of action now are being explored for efficacy in tandem with cancer therapeutics. Natural products may reduce off-target toxicity of therapeutics while making cancers more amenable to therapy. On the horizon is the use of certain natural products, in their own right, as mitigants of late-stage cancer, a new frontier for small-molecule natural product drug discovery. Copyright © 2016 the American Physiological Society.

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

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.

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.

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.

Hydrocarbon gas liquids production and related industrial development

EIA Publications

2016-01-01

Hydrocarbon gas liquids (HGL) are produced at refineries from crude oil and at natural gas processing plants from unprocessed natural gas. From 2010 to 2015, total HGL production increased by 42%. Natural gas processing plants accounted for all the increase, with recovered natural gas plant liquids (NGPL)—light hydrocarbon gases such as propane—rising by 58%, from 2.07 million barrels per day (b/d) in 2010 to 3.27 million b/d in 2015, while refinery output of HGL declined by 7%. The rapid increase in NGPL output was the result of rapid growth in natural gas production, as production shifted to tight gas and shale gas resources, and as producers targeted formations likely to yield natural gas with high liquids content. Annual Energy Outlook 2016 results suggest varying rates of future NGPL production growth, depending on relative crude oil and natural gas prices.

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

[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.

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.

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

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

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 from marine organisms with neuroprotective activity in the experimental models of Alzheimer's disease, Parkinson's disease and ischemic brain stroke: their molecular targets and action mechanisms.

PubMed

Choi, Dong-Young; Choi, Hyukjae

2015-02-01

Continuous increases in the incidence of neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), and brain stroke demand the urgent development of therapeutics. Marine organisms are well-known producers of natural products with diverse structures and pharmacological activities. Therefore, researchers have endeavored to identify marine natural products with neuroprotective effects. In this regard, this review summarizes therapeutic targets for AD, PD, and ischemic brain stroke and marine natural products with pharmacological activities on the targets according to taxonomies of marine organisms. Furthermore, several marine natural products on the clinical trials for the treatment of neurological disorders are discussed.

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.

75 FR 20271 - Oil and Gas and Sulphur Operations in the Outer Continental Shelf-Oil and Gas Production...

Federal Register 2010, 2011, 2012, 2013, 2014

2010-04-19

... amending the regulations regarding oil and natural gas production requirements. This is a complete rewrite... flaring natural gas, to ensure appropriate development of these natural resources. The final rule eliminates most restrictions on production rates and clarifies limits on the amount of natural gas that can...

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders.

PubMed

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), c aenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders.

Quantitative and Systems Pharmacology 3. Network-Based Identification of New Targets for Natural Products Enables Potential Uses in Aging-Associated Disorders

PubMed Central

Fang, Jiansong; Gao, Li; Ma, Huili; Wu, Qihui; Wu, Tian; Wu, Jun; Wang, Qi; Cheng, Feixiong

2017-01-01

Aging that refers the accumulation of genetic and physiology changes in cells and tissues over a lifetime has been shown a high risk of developing various complex diseases, such as neurodegenerative disease, cardiovascular disease and cancer. Over the past several decades, natural products have been demonstrated as anti-aging interveners via extending lifespan and preventing aging-associated disorders. In this study, we developed an integrated systems pharmacology infrastructure to uncover new indications for aging-associated disorders by natural products. Specifically, we incorporated 411 high-quality aging-associated human genes or human-orthologous genes from mus musculus (MM), saccharomyces cerevisiae (SC), caenorhabditis elegans (CE), and drosophila melanogaster (DM). We constructed a global drug-target network of natural products by integrating both experimental and computationally predicted drug-target interactions (DTI). We further built the statistical network models for identification of new anti-aging indications of natural products through integration of the curated aging-associated genes and drug-target network of natural products. High accuracy was achieved on the network models. We showcased several network-predicted anti-aging indications of four typical natural products (caffeic acid, metformin, myricetin, and resveratrol) with new mechanism-of-actions. In summary, this study offers a powerful systems pharmacology infrastructure to identify natural products for treatment of aging-associated disorders. PMID:29093681

30 CFR 256.40 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... products means natural gas liquid products including the following: ethane, propane, butane, pentane... resulting from the removal of natural gas liquids and nonhydrocarbon gases. (3) Of liquefied petroleum products means the volume of natural gas liquids produced from reservoir gas and liquefied at surface...

30 CFR 556.40 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... products means natural gas liquid products including the following: ethane, propane, butane, pentane... resulting from the removal of natural gas liquids and nonhydrocarbon gases. (3) Of liquefied petroleum products mean the volume of natural gas liquids produced from reservoir gas and liquefied at surface...

30 CFR 556.40 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... products means natural gas liquid products including the following: ethane, propane, butane, pentane... resulting from the removal of natural gas liquids and nonhydrocarbon gases. (3) Of liquefied petroleum products mean the volume of natural gas liquids produced from reservoir gas and liquefied at surface...

30 CFR 556.40 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... products means natural gas liquid products including the following: ethane, propane, butane, pentane... resulting from the removal of natural gas liquids and nonhydrocarbon gases. (3) Of liquefied petroleum products mean the volume of natural gas liquids produced from reservoir gas and liquefied at surface...

Focus: who reaps the benefits of biodiversity?

PubMed Central

Karasov, C

2001-01-01

The search for wild plant and animal products of potential value to medicine, agriculture, and other uses has been going on for hundreds, possibly thousands, of years. Many commonly prescribed medicines in the United States include ingredients derived from natural products, and roughly 80% of the world's people rely on natural products for their primary medical needs. Until the past decade, all of these natural products were collected without compensating the source countries. But the rules of collecting changed in 1992 with the establishment of the Convention on Biological Diversity, which offers financial compensation for natural products and seeks to conserve biological diversity, use natural products sustainably, and fairly share products made from gene stocks. Questions remain, however, as to how to share the benefits of biodiversity equitably, as well as whether the lack of both U.S. support for the agreement and enforceability render the convention impotent. PMID:11748021

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.

Database for Rapid Dereplication of Known Natural Products Using Data from MS and Fast NMR Experiments.

PubMed

Zani, Carlos L; Carroll, Anthony R

2017-06-23

The discovery of novel and/or new bioactive natural products from biota sources is often confounded by the reisolation of known natural products. Dereplication strategies that involve the analysis of NMR and MS spectroscopic data to infer structural features present in purified natural products in combination with database searches of these substructures provide an efficient method to rapidly identify known natural products. Unfortunately this strategy has been hampered by the lack of publically available and comprehensive natural product databases and open source cheminformatics tools. A new platform, DEREP-NP, has been developed to help solve this problem. DEREP-NP uses the open source cheminformatics program DataWarrior to generate a database containing counts of 65 structural fragments present in 229 358 natural product structures derived from plants, animals, and microorganisms, published before 2013 and freely available in the nonproprietary Universal Natural Products Database (UNPD). By counting the number of times one or more of these structural features occurs in an unknown compound, as deduced from the analysis of its NMR ( 1 H, HSQC, and/or HMBC) and/or MS data, matching structures carrying the same numeric combination of searched structural features can be retrieved from the database. Confirmation that the matching structure is the same compound can then be verified through literature comparison of spectroscopic data. This methodology can be applied to both purified natural products and fractions containing a small number of individual compounds that are often generated as screening libraries. The utility of DEREP-NP has been verified through the analysis of spectra derived from compounds (and fractions containing two or three compounds) isolated from plant, marine invertebrate, and fungal sources. DEREP-NP is freely available at https://github.com/clzani/DEREP-NP and will help to streamline the natural product discovery process.

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

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

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

Molecular approaches towards development of purified natural products and their structurally known derivatives as efficient anti-cancer drugs: current trends.

PubMed

Saha, Santu Kumar; Khuda-Bukhsh, Anisur Rahman

2013-08-15

Several natural products and their derivatives, either in purified or structurally identified form, exhibit immense pharmacological and biological properties, some of them showing considerable anticancer potential. Although the molecular mechanisms of action of some of these products are yet to be elucidated, extensive research in this area continues to generate new data that are clinically exploitable. Recent advancement in molecular biology, high throughput screening, biomarker identifications, target selection and genomic approaches have enabled us to understand salient interactions of natural products and their derivatives with cancer cells vis-à-vis normal cells. In this review we highlight the recent approaches and application of innovative technologies made to improve quality as well as efficiency of structurally identified natural products and their derivatives, particularly in small molecular forms capable of being used in "targeted therapies" in oncology. These products preferentially involve multiple mechanistic pathways and overcome chemo-resistance in tumor types with cumulative action. We also mention briefly a few physico-chemical features that compare natural products with drugs in recent natural product discovery approaches. We further report here a few purified natural products as examples that provide molecular interventions in cancer therapeutics to give the reader a glimpse of the current trends of approach for discovering useful anticancer drugs. © 2013 Elsevier B.V. All rights reserved.

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.

15 CFR Supplement No. 1 to Part 754 - Petroleum and Petroleum Products

Code of Federal Regulations, 2012 CFR

2012-01-01

... more than 125 seconds. 2711.11.0000 Natural gas, methane and mixtures thereof (including liquefied... Petroleum Reserves Production Act. 2 Natural gas and liquefied natural gas (LNG), and synthetic natural gas...

15 CFR Supplement No. 1 to Part 754 - Petroleum and Petroleum Products

Code of Federal Regulations, 2014 CFR

2014-01-01

... more than 125 seconds. 2711.11.0000 Natural gas, methane and mixtures thereof (including liquefied... Petroleum Reserves Production Act. 2 Natural gas and liquefied natural gas (LNG), and synthetic natural gas...

15 CFR Supplement No. 1 to Part 754 - Petroleum and Petroleum Products

Code of Federal Regulations, 2011 CFR

2011-01-01

... more than 125 seconds. 2711.11.0000 Natural gas, methane and mixtures thereof (including liquefied... Petroleum Reserves Production Act. 2 Natural gas and liquefied natural gas (LNG), and synthetic natural gas...

15 CFR Supplement No. 1 to Part 754 - Petroleum and Petroleum Products

Code of Federal Regulations, 2010 CFR

2010-01-01

... more than 125 seconds. 2711.11.0000 Natural gas, methane and mixtures thereof (including liquefied... Petroleum Reserves Production Act. 2 Natural gas and liquefied natural gas (LNG), and synthetic natural gas...

15 CFR Supplement No. 1 to Part 754 - Petroleum and Petroleum Products

Code of Federal Regulations, 2013 CFR

2013-01-01

... more than 125 seconds. 2711.11.0000 Natural gas, methane and mixtures thereof (including liquefied... Petroleum Reserves Production Act. 2 Natural gas and liquefied natural gas (LNG), and synthetic natural gas...

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 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.

Role of natural gas in meeting an electric sector emissions ...

EPA Pesticide Factsheets

With advances in natural gas extraction technologies, there is an increase in availability of domestic natural gas, and natural gas is gaining a larger share of use as a fuel in electricity production. At the power plant, natural gas is a cleaner burning fuel than coal, but uncertainties exist in the amount of methane leakage occurring upstream in the extraction and production of natural gas. At high leakage levels, these methane emissions could outweigh the benefits of switching from coal to natural gas. This analysis uses the MARKAL linear optimization model to compare the carbon emissions profiles and system-wide global warming potential of the U.S. energy system over a series of model runs in which the power sector is asked to meet a specific CO2 reduction target and the availability of natural gas changes. Scenarios are run with a range of upstream methane emission leakage rates from natural gas production. While the total CO2 emissions are reduced in most scenarios, total greenhouse gas emissions show an increase or no change when both natural gas availability and methane emissions from natural gas production are high. Article presents summary of results from an analyses of natural gas resource availability and power sector emissions reduction strategies under different estimates of methane leakage rates during natural gas extraction and production. This was study was undertaken as part of the Energy Modeling Forum Study #31:

"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.

Mimicking/extracting structure and functions of natural products: synthetic approaches that address unexplored needs in chemical biology.

PubMed

Hirai, Go

2015-04-01

Natural products are often attractive and challenging targets for synthetic chemists, and many have interesting biological activities. However, synthetic chemists need to be more than simply suppliers of compounds to biologists. Therefore, we have been seeking ways to actively apply organic synthetic methods to chemical biology studies of natural products and their activities. In this personal review, I would like to introduce our work on the development of new biologically active compounds inspired by, or extracted from, the structures of natural products, focusing on enhancement of functional activity and specificity and overcoming various drawbacks of the parent natural products. Copyright © 2014 The Chemical Society of Japan and Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

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.

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.

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.

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 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.

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.

Evaluation of Point-of-Care Resources for Dietary Supplement Information.

PubMed

Montgomery, Ashley E; Beckett, Robert D; Montagano, Kaitlin J; Kutom, Samah

2018-01-01

To evaluate 6 tertiary, point-of-care drug information resources' dietary supplement content. This was a cross-sectional evaluation of Lexicomp Natural Products Database, Micromedex Alternative Medicine, Clinical Pharmacology, Natural Medicines, The Review of Natural Products, and Handbook of Nonprescription Drugs. Each resource was evaluated for scope, completeness, consistency, and ease of use. For a sample of 66 supplements, scope scores ranged from 69.7% (Micromedex) to 100% (Natural Medicines). Completeness scores were high considering uses, dose, adverse effects, and mechanism (85.7% to 100%). Overall completeness scores ranged from 82.5% ( Handbook of Nonprescription Drugs) to 100% (Clinical Pharmacology, Natural Medicines, The Review of Natural Products). Consistency scores ranged from 0% ( Handbook of Nonprescription Drugs) to 100% (Natural Medicines, The Review of Natural Products). Mean time to locate and gather information was similar among groups. Resources were similar for completeness and ease of use. Scope and consistency varied depending on the resource.

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

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.

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.

Silencing of tryptamine biosynthesis for production of nonnatural alkaloids in plant culture.

PubMed

Runguphan, Weerawat; Maresh, Justin J; O'Connor, Sarah E

2009-08-18

Natural products have long served as both a source and inspiration for pharmaceuticals. Modifying the structure of a natural product often improves the biological activity of the compound. Metabolic engineering strategies to ferment "unnatural" products have been enormously successful in microbial organisms. However, despite the importance of plant derived natural products, metabolic engineering strategies to yield unnatural products from complex, lengthy plant pathways have not been widely explored. Here, we show that RNA mediated suppression of tryptamine biosynthesis in Catharanthus roseus hairy root culture eliminates all production of monoterpene indole alkaloids, a class of natural products derived from two starting substrates, tryptamine and secologanin. To exploit this chemically silent background, we introduced an unnatural tryptamine analog to the production media and demonstrated that the silenced plant culture could produce a variety of novel products derived from this unnatural starting substrate. The novel alkaloids were not contaminated by the presence of the natural alkaloids normally present in C. roseus. Suppression of tryptamine biosynthesis therefore did not appear to adversely affect expression of downstream biosynthetic enzymes. Targeted suppression of substrate biosynthesis therefore appears to be a viable strategy for programming a plant alkaloid pathway to more effectively produce desirable unnatural products. Moreover, although tryptamine is widely found among plants, this silenced line demonstrates that tryptamine does not play an essential role in growth or development in C. roseus root culture. Silencing the biosynthesis of an early starting substrate enhances our ability to harness the rich diversity of plant based natural products.

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 ...

40 CFR 98.393 - Calculating GHG emissions.

Code of Federal Regulations, 2010 CFR

2010-07-01

... from each individual petroleum product and natural gas liquid using Equation MM-1 of this section... of each petroleum product or natural gas liquid “i” (metric tons). Producti = Annual volume of... only includes products ex refinery gate. For natural gas liquids, volumes shall reflect the individual...

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.

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.

New Kid on the Block: LmbU Expands the Repertoire of Specialized Metabolic Regulators in Streptomyces.

PubMed

Ju, Kou-San; Zhang, Xiafei; Elliot, Marie A

2018-01-15

Streptomyces has an extensive natural product repertoire, including most of the naturally derived antibiotics. Understanding the control of natural product biosynthesis is central to antibiotic discovery and production optimization. Here, Hou et al. (J. Bacteriol. 200:00447-17, 2018, https://doi.org/10.1128/JB.00447-17) report the identification and characterization of a novel regulator-LmbU-that functions primarily as an activator of lincomycin production in Streptomyces lincolnensis Importantly, members of this new regulator family are associated with natural product biosynthetic clusters throughout the streptomycetes and their actinomycete relatives. Copyright © 2017 American Society for Microbiology.

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.

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.

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.

New Synthetic Methods for Hypericum Natural Products

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

Jeon, Insik

Organic chemistry has served as a solid foundation for interdisciplinary research areas, such as molecular biology and medicinal chemistry. An understanding of the biological activities and structural elucidations of natural products can lead to the development of clinically valuable therapeutic options. The advancements of modern synthetic methodologies allow for more elaborate and concise natural product syntheses. The theme of this study centers on the synthesis of natural products with particularly challenging structures and interesting biological activities. The synthetic expertise developed here will be applicable to analog syntheses and to other research problems.

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry

PubMed Central

2018-01-01

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain. PMID:29436819

Fragment-Based Screening of a Natural Product Library against 62 Potential Malaria Drug Targets Employing Native Mass Spectrometry.

PubMed

Vu, Hoan; Pedro, Liliana; Mak, Tin; McCormick, Brendan; Rowley, Jessica; Liu, Miaomiao; Di Capua, Angela; Williams-Noonan, Billy; Pham, Ngoc B; Pouwer, Rebecca; Nguyen, Bao; Andrews, Katherine T; Skinner-Adams, Tina; Kim, Jessica; Hol, Wim G J; Hui, Raymond; Crowther, Gregory J; Van Voorhis, Wesley C; Quinn, Ronald J

2018-04-13

Natural products are well known for their biological relevance, high degree of three-dimensionality, and access to areas of largely unexplored chemical space. To shape our understanding of the interaction between natural products and protein targets in the postgenomic era, we have used native mass spectrometry to investigate 62 potential protein targets for malaria using a natural-product-based fragment library. We reveal here 96 low-molecular-weight natural products identified as binding partners of 32 of the putative malarial targets. Seventy-nine (79) fragments have direct growth inhibition on Plasmodium falciparum at concentrations that are promising for the development of fragment hits against these protein targets. This adds a fragment library to the published HTS active libraries in the public domain.

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.

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.

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.

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

40 CFR Table Mm-1 to Subpart Mm of... - Default Factors for Petroleum Products and Natural Gas Liquids 1 2

Code of Federal Regulations, 2013 CFR

2013-07-01

... and Natural Gas Liquids 1 2 MM Table MM-1 to Subpart MM of Part 98 Protection of Environment... Factors for Petroleum Products and Natural Gas Liquids 1 2 Products Column A: density(metric tons/bbl... Natural Gas Liquids Aviation Gasoline 0.1120 85.00 0.3490 Special Naphthas 0.1222 84.76 0.3798 Lubricants...

40 CFR Table Mm-1 to Subpart Mm of... - Default Factors for Petroleum Products and Natural Gas Liquids 1 2

Code of Federal Regulations, 2014 CFR

2014-07-01

... and Natural Gas Liquids 1 2 MM Table MM-1 to Subpart MM of Part 98 Protection of Environment... Factors for Petroleum Products and Natural Gas Liquids 1 2 Products Column A: density(metric tons/bbl... Natural Gas Liquids Aviation Gasoline 0.1120 85.00 0.3490 Special Naphthas 0.1222 84.76 0.3798 Lubricants...

40 CFR Table Mm-1 to Subpart Mm of... - Default Factors for Petroleum Products and Natural Gas Liquids 1 2

Code of Federal Regulations, 2012 CFR

2012-07-01

... and Natural Gas Liquids 1 2 MM Table MM-1 to Subpart MM of Part 98 Protection of Environment... Factors for Petroleum Products and Natural Gas Liquids 1 2 Products Column A: density(metric tons/bbl... Natural Gas Liquids Aviation Gasoline 0.1120 85.00 0.3490 Special Naphthas 0.1222 84.76 0.3798 Lubricants...

40 CFR Table Mm-1 to Subpart Mm of... - Default Factors for Petroleum Products and Natural Gas Liquids 1 2

Code of Federal Regulations, 2011 CFR

2011-07-01

... and Natural Gas Liquids 1 2 MM Table MM-1 to Subpart MM of Part 98 Protection of Environment... Factors for Petroleum Products and Natural Gas Liquids 1 2 Products Column A: density(metric tons/bbl... Natural Gas Liquids Aviation Gasoline 0.1120 85.00 0.3490 Special Naphthas 0.1222 84.76 0.3798 Lubricants...

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.

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

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.

Legendary Chemical Aphrodisiacs.

ERIC Educational Resources Information Center

Waddell, Thomas G.; And Others

1980-01-01

Presents a survey of the literature and a summary of information regarding aphrodisiacs. Chemical compounds are discussed as groups of plant natural products, animal natural products, and synthetic products. (CS)

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

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 (Madin-Darby canine kidney type II) and the probe substrate estrone 3-sulfate, IC 50s 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. Nobiletin was the most potent (IC 50 , 3.7 μm); 6',7'-dihydroxybergamottin, naringin, naringenin and tangeretin were moderately potent (IC 50 , 20-50 μm); and bergamottin and hesperidin were the least potent (IC 50 , >300 μm) OATP2B1 inhibitors. Intestinal absorption simulations based on physiochemical properties were used to determine the ratios of unbound concentration to IC 50 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. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

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.

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.

Exploring the decision to disclose the use of natural products among outpatients: a mixed-method study

PubMed Central

2013-01-01

Background There is little understanding of the reasons for the limited communication between patients and conventional healthcare professionals regarding patients’ use of complementary and alternative medicine (CAM). The purpose of this study is to explore the predictors of outpatients’ decision to disclose their use of natural products to conventional healthcare professionals. Methods A mixed method design was used. Quantitative data were obtained through a survey and qualitative data were obtained from semi-structured interviews. A total of 257 outpatients who fulfilled the criteria of having used natural products prior to the interview were recruited for this study. Subsequently, 39 patients of those who completed the survey were further selected to take part in an in-depth qualitative interview. Results Predictors of the decision to disclose the use of natural products to conventional healthcare professionals included age, frequency of clinic visits, knowledge of the natural products and the attitude towards the benefits of CAM use. The themes that emerged from the qualitative data included safeness of the natural products, consulting alternative sources of information, apprehension regarding the development of negative relationships with healthcare professionals and reactions from the healthcare professionals. Conclusions Understanding the factors and reasons affecting patients’ decision as to whether to disclose their use of natural products provides an opportunity for conventional healthcare professionals to communicate better with patients. It is important to encourage patients to disclose their use of natural products in order to provide responsible health care as well as increasing patient safety regarding medication usage. PMID:24245611

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.

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.

Antagonism of Human Formyl Peptide Receptor 1 with Natural Compounds and their Synthetic Derivatives

PubMed Central

Schepetkin, Igor A.; Khlebnikov, Andrei I.; Kirpotina, Liliya N.; Quinn, Mark T.

2015-01-01

Formyl peptide receptor 1 (FPR1) regulates a wide variety of neutrophil functional responses and plays an important role in inflammation and the pathogenesis of various diseases. To date, a variety of natural and synthetic molecules have been identified as FPR1 ligands. Here, we review current knowledge on natural products and natural product-inspired small-molecules reported to antagonize and/or inhibit the FPR1-mediated responses. Based on this literature, additional screening of selected commercially available natural compounds for their ability to inhibit fMLF-induced Ca2+ mobilization in human neutrophils and FPR1 transfected HL-60 cells, and pharmacophore modeling, natural products with potential as FPR1 antagonists are considered and discussed in this review. The identification and characterization of natural products that antagonize FPR1 activity may have potential for the development of novel therapeutics to limit or alter the outcome of inflammatory processes. PMID:26382576

UPLC-MS-ELSD-PDA as a powerful dereplication tool to facilitate compound identification from small molecule natural product libraries

USDA-ARS?s Scientific Manuscript database

Generation of natural product libraries containing column fractions, each with only a few small molecules, by a high throughput, automated fractionation system has made it possible to implement an improved dereplication strategy for selection and prioritization of hits in a natural product discovery...

Ghana Country Analysis Brief

EIA Publications

2016-01-01

Ghana is a small oil and natural gas producer in West Africa. Oil and natural gas production are both expected to increase within the next five years with the start of new offshore projects. Ghana exports its crude oil production to international markets, while the country’s natural gas production is used to fuel its domestic power plants.

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.

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

USDA-ARS?s Scientific Manuscript database

Although natural products have been a particularly rich source of human medicines, the rate at which new molecules are being discovered is declining precipitously. Based on the large number of natural product biosynthetic genes in microbial genomes, many have suggested “genome mining” as an approach...

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

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.

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.

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.

Simultaneous structure-activity studies and arming of natural products by C-H amination reveal cellular targets of eupalmerin acetate.

PubMed

Li, Jing; Cisar, Justin S; Zhou, Cong-Ying; Vera, Brunilda; Williams, Howard; Rodríguez, Abimael D; Cravatt, Benjamin F; Romo, Daniel

2013-06-01

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C-H amination reactions developed by Du Bois to carry out simultaneous structure-activity relationship studies and arming (alkynylation) of natural products at 'unfunctionalized' positions. Allylic and benzylic C-H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C-H amination-oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these-the marine-derived anticancer diterpene, eupalmerin acetate-quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action.

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

Simultaneous structure-activity studies and arming of natural products by C-H amination reveal cellular targets of eupalmerin acetate

NASA Astrophysics Data System (ADS)

Li, Jing; Cisar, Justin S.; Zhou, Cong-Ying; Vera, Brunilda; Williams, Howard; Rodríguez, Abimael D.; Cravatt, Benjamin F.; Romo, Daniel

2013-06-01

Natural products have a venerable history of, and enduring potential for the discovery of useful biological activity. To fully exploit this, the development of chemical methodology that can functionalize unique sites within these complex structures is highly desirable. Here, we describe the use of rhodium(II)-catalysed C-H amination reactions developed by Du Bois to carry out simultaneous structure-activity relationship studies and arming (alkynylation) of natural products at ‘unfunctionalized’ positions. Allylic and benzylic C-H bonds in the natural products undergo amination while olefins undergo aziridination, and tertiary amine-containing natural products are converted to amidines by a C-H amination-oxidation sequence or to hydrazine sulfamate zwitterions by an unusual N-amination. The alkynylated derivatives are ready for conversion into cellular probes that can be used for mechanism-of-action studies. Chemo- and site-selectivity was studied with a diverse library of natural products. For one of these—the marine-derived anticancer diterpene, eupalmerin acetate—quantitative proteome profiling led to the identification of several protein targets in HL-60 cells, suggesting a polypharmacological mode of action.

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.

Naturally good: Front-of-package claims as message cues.

PubMed

Skubisz, Christine

2017-01-01

Excess bodyweight is a significant public health problem in the United States, increasing the risk of adverse health conditions including hypertension, diabetes, heart disease, stroke, and cancer. Americans are consuming more calories than their bodies need each day and making purchasing decisions using heuristic cues, rather than caloric information. A recent trend in food and beverage labeling is the placement of a natural claim on a product's package. Unfortunately, the United States has not established clear requirements for natural claims and manufacturers are using this term liberally. Using models of information processing as a framework, the goal of this study was to predict the effects of natural claims on message processing and evaluations. It was predicted that natural claims would be perceived as heuristics for healthfulness. A 6 (product) x 2 (claim) experimental design was carried out. Support for the prediction that natural labeled products are evaluated as more healthful was found. Despite the fact that natural products contained the same number of calories as their regular counterparts, participants estimated that natural products contained 18% fewer calories. Implications of these findings for food labeling and public health are discussed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Characterizing the emission implications of future natural gas production and use in the U.S. and Rocky Mountain region: A scenario-based energy system modeling approach

NASA Astrophysics Data System (ADS)

McLeod, Jeffrey

The recent increase in U.S. natural gas production made possible through advancements in extraction techniques including hydraulic fracturing has transformed the U.S. energy supply landscape while raising questions regarding the balance of environmental impacts associated with natural gas production and use. Impact areas at issue include emissions of methane and criteria pollutants from natural gas production, alongside changes in emissions from increased use of natural gas in place of coal for electricity generation. In the Rocky Mountain region, these impact areas have been subject to additional scrutiny due to the high level of regional oil and gas production activity and concerns over its links to air quality. Here, the MARKAL (MArket ALlocation) least-cost energy system optimization model in conjunction with the EPA-MARKAL nine-region database has been used to characterize future regional and national emissions of CO 2, CH4, VOC, and NOx attributed to natural gas production and use in several sectors of the economy. The analysis is informed by comparing and contrasting a base case, business-as-usual scenario with scenarios featuring variations in future natural gas supply characteristics, constraints affecting the electricity generation mix, carbon emission reduction strategies and increased demand for natural gas in the transportation sector. Emission trends and their associated sensitivities are identified and contrasted between the Rocky Mountain region and the U.S. as a whole. The modeling results of this study illustrate the resilience of the short term greenhouse gas emission benefits associated with fuel switching from coal to gas in the electric sector, but also call attention to the long term implications of increasing natural gas production and use for emissions of methane and VOCs, especially in the Rocky Mountain region. This analysis can help to inform the broader discussion of the potential environmental impacts of future natural gas production and use by illustrating links between relevant economic and environmental variables.

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

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.

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.

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.

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 other basin using a top-down methodology, and may be indicative of some characteristics of the basin that make sources from the north-eastern Marcellus region unique.

Synthesis and Demonstration of the Biological Relevance of sp3 -rich Scaffolds Distantly Related to Natural Product Frameworks.

PubMed

Foley, Daniel J; Craven, Philip G E; Collins, Patrick M; Doveston, Richard G; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank; Marsden, Stephen P; Nelson, Adam

2017-10-26

The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A "top-down" synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp 3 -rich scaffolds. The scaffolds have local natural product-like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high-throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

40 CFR 98.403 - Calculating GHG emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Natural Gas and Natural Gas Liquids § 98.403... natural gas processing plants from local production, received as a liquid and vaporized for delivery, or... local production, or natural gas that was received as a liquid, vaporized and delivered, and any other...

A High-Throughput Assay for Screening of Natural Products that Enhanced Tumoricidal Activity of NK Cells.

PubMed

Gong, Chenyuan; Ni, Zhongya; Yao, Chao; Zhu, Xiaowen; Ni, Lulu; Wang, Lixin; Zhu, Shiguo

2015-01-01

Recently, immunotherapy has shown a lot of promise in cancer treatment and different immune cell types are involved in this endeavor. Among different immune cell populations, NK cells are also an important component in unleashing the therapeutic activity of immune cells. Therefore, in order to enhance the tumoricidal activity of NK cells, identification of new small-molecule natural products is important. Despite the availability of different screening methods for identification of natural products, a simple, economic and high-throughput method is lacking. Hence, in this study, we have developed a high-throughput assay for screening and indentifying natural products that can enhance NK cell-mediated killing of cancer cells. We expanded human NK cell population from human peripheral blood mononuclear cells (PBMCs) by culturing these PBMCs with membrane-bound IL-21 and CD137L engineered K562 cells. Next, expanded NK cells were co-cultured with non-small cell lung cancer (NSCLC) cells with or without natural products and after 24 h of co-culturing, harvested supernatants were analyzed for IFN-γ secretions by ELISA method. We screened 502 natural products and identified that 28 candidates has the potential to induce IFN-γ secretion by NK cells to varying degrees. Among the 28 natural product candidates, we further confirmed and analyzed the potential of one molecule, andrographolide. It actually increased IFN-γ secretion by NK cells and enhanced NK cell-mediated killing of NSCLC cells. Our results demonstrated that this IFN-γ based high-throughput assay for screening of natural products for NK cell tumoricidal activity is a simple, economic and reliable method.

Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases.

PubMed

Bulaj, Grzegorz; Ahern, Margaret M; Kuhn, Alexis; Judkins, Zachary S; Bowen, Randy C; Chen, Yizhe

2016-01-01

Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products, and their integration with self-care, music and mHealth, expands precision/personalized medicine strategies for chronic diseases via pharmacological-behavioral combination therapies.

Marine Microbial Secondary Metabolites: Pathways, Evolution and Physiological Roles.

PubMed

Giordano, Daniela; Coppola, Daniela; Russo, Roberta; Denaro, Renata; Giuliano, Laura; Lauro, Federico M; di Prisco, Guido; Verde, Cinzia

2015-01-01

Microbes produce a huge array of secondary metabolites endowed with important ecological functions. These molecules, which can be catalogued as natural products, have long been exploited in medical fields as antibiotics, anticancer and anti-infective agents. Recent years have seen considerable advances in elucidating natural-product biosynthesis and many drugs used today are natural products or natural-product derivatives. The major contribution to recent knowledge came from application of genomics to secondary metabolism and was facilitated by all relevant genes being organised in a contiguous DNA segment known as gene cluster. Clustering of genes regulating biosynthesis in bacteria is virtually universal. Modular gene clusters can be mixed and matched during evolution to generate structural diversity in natural products. Biosynthesis of many natural products requires the participation of complex molecular machines known as polyketide synthases and non-ribosomal peptide synthetases. Discovery of new evolutionary links between the polyketide synthase and fatty acid synthase pathways may help to understand the selective advantages that led to evolution of secondary-metabolite biosynthesis within bacteria. Secondary metabolites confer selective advantages, either as antibiotics or by providing a chemical language that allows communication among species, with other organisms and their environment. Herewith, we discuss these aspects focusing on the most clinically relevant bioactive molecules, the thiotemplated modular systems that include polyketide synthases, non-ribosomal peptide synthetases and fatty acid synthases. We begin by describing the evolutionary and physiological role of marine natural products, their structural/functional features, mechanisms of action and biosynthesis, then turn to genomic and metagenomic approaches, highlighting how the growing body of information on microbial natural products can be used to address fundamental problems in environmental evolution and biotechnology. © 2015 Elsevier Ltd. All rights reserved.

Sales of Fossil Fuels Produced from Federal and Indian Lands, FY 2003 through FY 2014

EIA Publications

2015-01-01

The U.S. Energy Information Administration estimates that total sales of fossil fuels produced from Federal and Indian Lands increased in fiscal year 2014 compared to fiscal year 2013. Production of crude oil increased 7%, natural gas production declined 7%, natural gas plant liquids production increased by 8%, and coal production increased slightly. Detailed tables and maps of production, by State, are contained in the report. EIA’s estimates are based on data provided by the U.S. Department of the Interior’s Office of Natural Resources Revenue.

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.

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.

Elaborating the role of natural products-induced autophagy in cancer treatment: achievements and artifacts in the state of the art.

PubMed

Wang, Ning; Feng, Yibin

2015-01-01

Autophagy is a homeostatic process that is highly conserved across different types of mammalian cells. Autophagy is able to relieve tumor cell from nutrient and oxidative stress during the rapid expansion of cancer. Excessive and sustained autophagy may lead to cell death and tumor shrinkage. It was shown in literature that many anticancer natural compounds and extracts could initiate autophagy in tumor cells. As summarized in this review, the tumor suppressive action of natural products-induced autophagy may lead to cell senescence, provoke apoptosis-independent cell death, and complement apoptotic cell death by robust or target-specific mechanisms. In some cases, natural products-induced autophagy could protect tumor cells from apoptotic death. Technical variations in detecting autophagy affect data quality, and study focus should be made on elaborating the role of autophagy in deciding cell fate. In vivo study monitoring of autophagy in cancer treatment is expected to be the future direction. The clinical-relevant action of autophagy-inducing natural products should be highlighted in future study. As natural products are an important resource in discovery of lead compound of anticancer drug, study on the role of autophagy in tumor suppressive effect of natural products continues to be necessary and emerging.

Accessing Nature’s diversity through metabolic engineering and synthetic biology

PubMed Central

King, Jason R.; Edgar, Steven; Qiao, Kangjian; Stephanopoulos, Gregory

2016-01-01

In this perspective, we highlight recent examples and trends in metabolic engineering and synthetic biology that demonstrate the synthetic potential of enzyme and pathway engineering for natural product discovery. In doing so, we introduce natural paradigms of secondary metabolism whereby simple carbon substrates are combined into complex molecules through “scaffold diversification”, and subsequent “derivatization” of these scaffolds is used to synthesize distinct complex natural products. We provide examples in which modern pathway engineering efforts including combinatorial biosynthesis and biological retrosynthesis can be coupled to directed enzyme evolution and rational enzyme engineering to allow access to the “privileged” chemical space of natural products in industry-proven microbes. Finally, we forecast the potential to produce natural product-like discovery platforms in biological systems that are amenable to single-step discovery, validation, and synthesis for streamlined discovery and production of biologically active agents. PMID:27081481

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

Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction.

PubMed

Woerly, Eric M; Roy, Jahnabi; Burke, Martin D

2014-06-01

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin b-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Synthesis of most polyene natural product motifs using just 12 building blocks and one coupling reaction

NASA Astrophysics Data System (ADS)

Woerly, Eric M.; Roy, Jahnabi; Burke, Martin D.

2014-06-01

The inherent modularity of polypeptides, oligonucleotides and oligosaccharides has been harnessed to achieve generalized synthesis platforms. Importantly, like these other targets, most small-molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled both the synthesis of a wide range of polyene frameworks that covered all of this natural-product chemical space and the first total syntheses of the polyene natural products asnipyrone B, physarigin A and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach to making small molecules in the laboratory.

Natural Products and Supplements for Geriatric Depression and Cognitive Disorders: An Evaluation of the Research

PubMed Central

Varteresian, Taya; Lavretsky, Helen

2014-01-01

Numerous geriatric patients are using Complementary and Alternative Medicine (CAM) for late-life mood and cognitive disorders. Natural products and supplements are a common CAM intervention which have risks and benefits of which patients should be appropriately advised. The data for omega-3 fatty acids, ginkgo biloba, SAMe, St John’s wort, B Vitamins and Vitamin D, huperzine, caprylidene and coconut oil will be evaluated. Since the evidence basis for natural products and supplements is limited, especially for the geriatric population. Studies involving the general adult population are included to infer effects in the aging population. Despite the data available, more rigorous studies with larger sample sizes over longer periods of time are still needed. Regardless of a physician’s preference to recommend various natural supplements and products, a physician could protect their patients by having an understanding of the side effects and indications for various natural products. PMID:24912606

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

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.

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.

Constructing a Spatially Resolved Methane Emission Inventory of Natural Gas Production and Distribution over Contiguous United States

NASA Astrophysics Data System (ADS)

Li, X.; Omara, M.; Adams, P. J.; Presto, A. A.

2017-12-01

Methane is the second most powerful greenhouse gas after Carbon Dioxide. The natural gas production and distribution accounts for 23% of the total anthropogenic methane emissions in the United States. The boost of natural gas production in U.S. in recent years poses a potential concern of increased methane emissions from natural gas production and distribution. The Emission Database for Global Atmospheric Research (Edgar) v4.2 and the EPA Greenhouse Gas Inventory (GHGI) are currently the most commonly used methane emission inventories. However, recent studies suggested that both Edgar v4.2 and the EPA GHGI largely underestimated the methane emission from natural gas production and distribution in U.S. constrained by both ground and satellite measurements. In this work, we built a gridded (0.1° Latitude ×0.1° Longitude) methane emission inventory of natural gas production and distribution over the contiguous U.S. using emission factors measured by our mobile lab in the Marcellus Shale, the Denver-Julesburg Basin, and the Uintah Basin, and emission factors reported from other recent field studies for other natural gas production regions. The activity data (well location and count) are mostly obtained from the Drillinginfo, the EPA Greenhouse Gas Reporting Program (GHGRP) and the U.S. Energy Information Administration (EIA). Results show that the methane emission from natural gas production and distribution estimated by our inventory is about 20% higher than the EPA GHGI, and in some major natural gas production regions, methane emissions estimated by the EPA GHGI are significantly lower than our inventory. For example, in the Marcellus Shale, our estimated annual methane emission in 2015 is 600 Gg higher than the EPA GHGI. We also ran the GEOS-Chem methane simulation to estimate the methane concentration in the atmosphere with our built inventory, the EPA GHGI and the Edgar v4.2 over the nested North American Domain. These simulation results showed differences in some major gas production regions. The simulated methane concentrations will be compared with the GOSAT satellite data to explore whether our built inventory could potentially improve the prediction of regional methane concentrations in the atmosphere.

30 CFR 1206.362 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.362 Section 1206.362 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.106 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.106 Section 1206.106 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.362 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.362 Section 1206.362 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.106 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.106 Section 1206.106 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.362 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.362 Section 1206.362 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.106 - What are my responsibilities to place production into marketable condition and to market production?

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false What are my responsibilities to place production into marketable condition and to market production? 1206.106 Section 1206.106 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

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.

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 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

Immobilized magnetic beads-based multi-target affinity selection coupled with HPLC-MS for screening active compounds from traditional Chinese medicine and natural products.

PubMed

Chen, Yaqi; Chen, Zhui; Wang, Yi

2015-01-01

Screening and identifying active compounds from traditional Chinese medicine (TCM) and other natural products plays an important role in drug discovery. Here, we describe a magnetic beads-based multi-target affinity selection-mass spectrometry approach for screening bioactive compounds from natural products. Key steps and parameters including activation of magnetic beads, enzyme/protein immobilization, characterization of functional magnetic beads, screening and identifying active compounds from a complex mixture by LC/MS, are illustrated. The proposed approach is rapid and efficient in screening and identification of bioactive compounds from complex natural products.

Direct Capture and Heterologous Expression of Salinispora Natural Product Genes for the Biosynthesis of Enterocin

PubMed Central

2015-01-01

Heterologous expression of secondary metabolic pathways is a promising approach for the discovery and characterization of bioactive natural products. Herein we report the first heterologous expression of a natural product from the model marine actinomycete genus Salinispora. Using the recently developed method of yeast-mediated transformation-associated recombination for natural product gene clusters, we captured a type II polyketide synthase pathway from Salinispora pacifica with high homology to the enterocin pathway from Streptomyces maritimus and successfully produced enterocin in two different Streptomyces host strains. This result paves the way for the systematic interrogation of Salinispora’s promising secondary metabolome. PMID:25382643

Direct capture and heterologous expression of Salinispora natural product genes for the biosynthesis of enterocin.

PubMed

Bonet, Bailey; Teufel, Robin; Crüsemann, Max; Ziemert, Nadine; Moore, Bradley S

2015-03-27

Heterologous expression of secondary metabolic pathways is a promising approach for the discovery and characterization of bioactive natural products. Herein we report the first heterologous expression of a natural product from the model marine actinomycete genus Salinispora. Using the recently developed method of yeast-mediated transformation-associated recombination for natural product gene clusters, we captured a type II polyketide synthase pathway from Salinispora pacifica with high homology to the enterocin pathway from Streptomyces maritimus and successfully produced enterocin in two different Streptomyces host strains. This result paves the way for the systematic interrogation of Salinispora's promising secondary metabolome.

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.

Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases

PubMed Central

Gul, Waseem; Hamann, Mark T.

2016-01-01

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities. PMID:16236327

Potential of Natural Products in the Inhibition of Adipogenesis through Regulation of PPARγ Expression and/or Its Transcriptional Activity.

PubMed

Feng, Shi; Reuss, Laura; Wang, Yu

2016-09-23

Obesity is a global health problem characterized as an increase in the mass of adipose tissue. Adipogenesis is one of the key pathways that increases the mass of adipose tissue, by which preadipocytes mature into adipocytes through cell differentiation. Peroxisome proliferator-activated receptor γ (PPARγ), the chief regulator of adipogenesis, has been acutely investigated as a molecular target for natural products in the development of anti-obesity treatments. In this review, the regulation of PPARγ expression by natural products through inhibition of CCAAT/enhancer-binding protein β (C/EBPβ) and the farnesoid X receptor (FXR), increased expression of GATA-2 and GATA-3 and activation of the Wnt/β-catenin pathway were analyzed. Furthermore, the regulation of PPARγ transcriptional activity associated with natural products through the antagonism of PPARγ and activation of Sirtuin 1 (Sirt1) and AMP-activated protein kinase (AMPK) were discussed. Lastly, regulation of mitogen-activated protein kinase (MAPK) by natural products, which might regulate both PPARγ expression and PPARγ transcriptional activity, was summarized. Understanding the role natural products play, as well as the mechanisms behind their regulation of PPARγ activity is critical for future research into their therapeutic potential for fighting obesity.

Radiation processing of natural polymers: The IAEA contribution

NASA Astrophysics Data System (ADS)

Haji-Saeid, Mohammad; Safrany, Agnes; Sampa, Maria Helena de O.; Ramamoorthy, Natesan

2010-03-01

Radiation processing offers a clean and additive-free method for preparation of value-added novel materials based on renewable, non-toxic, and biodegradable natural polymers. Crosslinked natural polymers can be used as hydrogel wound dressings, face cleaning cosmetic masks, adsorbents of toxins, and non-bedsore mats; while low molecular weight products show antibiotic, antioxidant, and plant-growth promoting properties. Recognizing the potential benefits that radiation technology can offer for processing of natural polymers into useful products, the IAEA implemented a coordinated research project (CRP) on "Development of Radiation-processed products of Natural Polymers for application in Agriculture, Healthcare, Industry and Environment". This CRP was launched at the end of 2007 with participation of 16 MS to help connecting radiation technology and end-users to derive enhanced benefits from these new value-added products of radiation-processed natural materials. In this paper the results of activities in participating MS related to this work will be presented.

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.

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.

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-Candida compounds from plants and organisms but also to carried out details on molecules from already known anti-Candida compounds and to more elucidate mechanisms of action. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Drilling Productivity Report

EIA Publications

2017-01-01

Energy Information Administration’s (EIA) new Drilling Productivity Report (DPR) takes a fresh look at oil and natural gas production, starting with an assessment of how and where drilling for hydrocarbons is taking place. The DPR uses recent data on the total number of drilling rigs in operation along with estimates of drilling productivity and estimated changes in production from existing oil and natural gas wells to provide estimated changes in oil and natural gas production for six key fields. EIA's approach does not distinguish between oil-directed rigs and gas-directed rigs because once a well is completed it may produce both oil and gas; more than half of the wells produce both.

Hepatoprotective natural triterpenoids.

PubMed

Xu, Guo-Bo; Xiao, Yao-Hua; Zhang, Qing-Yan; Zhou, Meng; Liao, Shang-Gao

2018-02-10

Liver diseases are one of the leading causes of death in the world. In spite of tremendous advances in modern drug research, effective and safe hepatoprotective agents are still in urgent demand. Natural products are undoubtedly valuable sources for drug leads. A number of natural triterpenoids were reported to possess pronounced hepatoprotective effects, and triterpenoids have become one of the most important classes of natural products for hepatoprotective agents. However, the significance of natural triterpenoids has been underestimated in the hepatoprotective drug discovery, with only very limited triterpenoids being covered in the reviews of hepatoprotective natural products. In this paper, ca 350 natural triterpenoids with reported hepatoprotective effects in ca 120 references between 1975 and 2016 will be reviewed, and the structure-activity relationships of certain types of natural triterpenoids, if available, will be discussed. Patents are not included. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Emissions implications of future natural gas production and use in the U.S. and in the Rocky Mountain region.

PubMed

McLeod, Jeffrey D; Brinkman, Gregory L; Milford, Jana B

2014-11-18

Enhanced prospects for natural gas production raise questions about the balance of impacts on air quality, as increased emissions from production activities are considered alongside the reductions expected when natural gas is burned in place of other fossil fuels. This study explores how trends in natural gas production over the coming decades might affect emissions of greenhouse gases (GHG), volatile organic compounds (VOCs) and nitrogen oxides (NOx) for the United States and its Rocky Mountain region. The MARKAL (MARKet ALlocation) energy system optimization model is used with the U.S. Environmental Protection Agency's nine-region database to compare scenarios for natural gas supply and demand, constraints on the electricity generation mix, and GHG emissions fees. Through 2050, total energy system GHG emissions show little response to natural gas supply assumptions, due to offsetting changes across sectors. Policy-driven constraints or emissions fees are needed to achieve net reductions. In most scenarios, wind is a less expensive source of new electricity supplies in the Rocky Mountain region than natural gas. U.S. NOx emissions decline in all the scenarios considered. Increased VOC emissions from natural gas production offset part of the anticipated reductions from the transportation sector, especially in the Rocky Mountain region.

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.

10 CFR 221.11 - Natural gas and ethane.

Code of Federal Regulations, 2010 CFR

2010-01-01

... 10 Energy 3 2010-01-01 2010-01-01 false Natural gas and ethane. 221.11 Section 221.11 Energy DEPARTMENT OF ENERGY OIL PRIORITY SUPPLY OF CRUDE OIL AND PETROLEUM PRODUCTS TO THE DEPARTMENT OF DEFENSE UNDER THE DEFENSE PRODUCTION ACT Exclusions § 221.11 Natural gas and ethane. The supply of natural gas...

10 CFR 221.11 - Natural gas and ethane.

Code of Federal Regulations, 2011 CFR

2011-01-01

... 10 Energy 3 2011-01-01 2011-01-01 false Natural gas and ethane. 221.11 Section 221.11 Energy DEPARTMENT OF ENERGY OIL PRIORITY SUPPLY OF CRUDE OIL AND PETROLEUM PRODUCTS TO THE DEPARTMENT OF DEFENSE UNDER THE DEFENSE PRODUCTION ACT Exclusions § 221.11 Natural gas and ethane. The supply of natural gas...

Biomass production efficiency controlled by management in temperate and boreal ecosystems

NASA Astrophysics Data System (ADS)

Campioli, M.; Vicca, S.; Luyssaert, S.; Bilcke, J.; Ceschia, E.; Chapin, F. S., III; Ciais, P.; Fernández-Martínez, M.; Malhi, Y.; Obersteiner, M.; Olefeldt, D.; Papale, D.; Piao, S. L.; Peñuelas, J.; Sullivan, P. F.; Wang, X.; Zenone, T.; Janssens, I. A.

2015-11-01

Plants acquire carbon through photosynthesis to sustain biomass production, autotrophic respiration and production of non-structural compounds for multiple purposes. The fraction of photosynthetic production used for biomass production, the biomass production efficiency, is a key determinant of the conversion of solar energy to biomass. In forest ecosystems, biomass production efficiency was suggested to be related to site fertility. Here we present a database of biomass production efficiency from 131 sites compiled from individual studies using harvest, biometric, eddy covariance, or process-based model estimates of production. The database is global, but dominated by data from Europe and North America. We show that instead of site fertility, ecosystem management is the key factor that controls biomass production efficiency in terrestrial ecosystems. In addition, in natural forests, grasslands, tundra, boreal peatlands and marshes, biomass production efficiency is independent of vegetation, environmental and climatic drivers. This similarity of biomass production efficiency across natural ecosystem types suggests that the ratio of biomass production to gross primary productivity is constant across natural ecosystems. We suggest that plant adaptation results in similar growth efficiency in high- and low-fertility natural systems, but that nutrient influxes under managed conditions favour a shift to carbon investment from the belowground flux of non-structural compounds to aboveground biomass.

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.

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.

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.

How to translate a bioassay into a screening assay for natural products: general considerations and implementation of antimicrobial screens.

PubMed

Fallarero, Adyary; Hanski, Leena; Vuorela, Pia

2014-09-01

Natural product sources have been a valuable provider of molecular diversity in many drug discovery programs and several therapeutically important drugs have been isolated from these. However, the screening of such materials can be very complicated due to the fact that they contain a complex mixture of secondary metabolites, but also the purified natural compounds exert a challenge for bioactivity screening. Success in identifying new therapeutics using in vitro bioassays is largely dependent upon the proper design, validation, and implementation of the screening assay. In this review, we discuss some aspects which are of significant concern when screening natural products in a microtiter plate-based format, being partly applicable to other assay formats as well, such as validation parameters, layouts for assay protocols, and common interferences caused by natural products samples, as well as various troubleshooting strategies. Examples from the field of natural product drug discovery of antibacterial compounds are discussed, and contributions from the realm of academic screenings are highlighted. Georg Thieme Verlag KG Stuttgart · New York.

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.

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.

Impact of continuous flow chemistry in the synthesis of natural products and active pharmaceutical ingredients.

PubMed

Souza, Juliana M DE; Galaverna, Renan; Souza, Aline A N DE; Brocksom, Timothy J; Pastre, Julio C; Souza, Rodrigo O M A DE; Oliveira, Kleber T DE

2018-01-01

We present a comprehensive review of the advent and impact of continuous flow chemistry with regard to the synthesis of natural products and drugs, important pharmaceutical products and definitely responsible for a revolution in modern healthcare. We detail the beginnings of modern drugs and the large scale batch mode of production, both chemical and microbiological. The introduction of modern continuous flow chemistry is then presented, both as a technological tool for enabling organic chemistry, and as a fundamental research endeavor. This part details the syntheses of bioactive natural products and commercial drugs.

A Generalization of the Formula for the Triangular Number of the Sum and Product of Natural Numbers

ERIC Educational Resources Information Center

Asiru, M. A.

2008-01-01

This note generalizes the formula for the triangular number of the sum and product of two natural numbers to similar results for the triangular number of the sum and product of "r" natural numbers. The formula is applied to derive formula for the sum of an odd and an even number of consecutive triangular numbers.

Natural Product Total Synthesis in the Organic Laboratory: Total Synthesis of Caffeic Acid Phenethyl Ester (CAPE), a Potent 5-Lipoxygenase Inhibitor from Honeybee Hives

ERIC Educational Resources Information Center

Touaibia, Mohamed; Guay, Michel

2011-01-01

Natural products play a critical role in modern organic synthesis and learning synthetic techniques is an important component of the organic laboratory experience. In addition to traditional one-step organic synthesis laboratories, a multistep natural product synthesis is an interesting experiment to challenge students. The proposed three-step…

40 CFR 49.140 - Introduction.

Code of Federal Regulations, 2013 CFR

2013-07-01

...: AIR QUALITY PLANNING AND MANAGEMENT General Federal Implementation Plan Provisions Federal Implementation Plan for Oil and Natural Gas Production Facilities, Fort Berthold Indian Reservation (mandan..., production operations, and storage operations at existing, new and modified oil and natural gas production...

40 CFR 49.140 - Introduction.

Code of Federal Regulations, 2014 CFR

2014-07-01

...: AIR QUALITY PLANNING AND MANAGEMENT General Federal Implementation Plan Provisions Federal Implementation Plan for Oil and Natural Gas Production Facilities, Fort Berthold Indian Reservation (mandan..., production operations, and storage operations at existing, new and modified oil and natural gas production...

Natural Products as Sources of New Drugs over the 30 Years from 1981 to 2010†

PubMed Central

Newman, David J.; Cragg, Gordon M.

2013-01-01

This review is an updated and expanded version of the three prior reviews that were published in this journal in 1997, 2003 and 2007. In the case of all approved therapeutic agents, the time frame has been extended to cover the 30 years from January 1st 1981 to December 31st 2010 for all diseases world-wide, and from 1950 (earliest so far identified) to December 2010 for all approved antitumor drugs world-wide. We have continued to utilize our secondary subdivision of a “natural product mimic” or “NM” to join the original primary divisions, and have added a new designation “natural product botanical” or “NB” to cover those botanical “defined mixtures” that have now been recognized as drug entities by the FDA and similar organizations. From the data presented, the utility of natural products as sources of novel structures, but not necessarily the final drug entity, is still alive and well. Thus, in the area of cancer, over the time frame from around the 1940s to date, of the 175 small molecules, 131 or 74.8% are other than “S” (synthetic), with 85 or 48.6% actually being either natural products or directly derived there from. 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. Although combinatorial chemistry techniques have succeeded as methods of optimizing structures, and have been used very successfully in the optimization of many recently approved agents, we are only able to identify only one de novo combinatorial compound approved as a drug in this 30-year time frame. 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 we consider that this area of natural product research should be expanded significantly. PMID:22316239

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

Controlling Air Pollution from the Oil and Natural Gas Industry

EPA Pesticide Factsheets

EPA regulations for the oil and natural gas industry help combat climate change and reduce air pollution that harms public health. EPA’s regulations apply to oil production, and the production, process, transmission and storage of natural gas.

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.

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. All rights reserved.

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 prioritization pipeline proves to be efficient. Implementation of this approach in drug discovery programs based on natural extract screening should speed up and rationalize the isolation of bioactive natural products.

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.

Marine actinobacteria associated with marine organisms and their potentials in producing pharmaceutical natural products.

PubMed

Valliappan, Karuppiah; Sun, Wei; Li, Zhiyong

2014-09-01

Actinobacteria are ubiquitous in the marine environment, playing an important ecological role in the recycling of refractory biomaterials and producing novel natural products with pharmic applications. Actinobacteria have been detected or isolated from the marine creatures such as sponges, corals, mollusks, ascidians, seaweeds, and seagrass. Marine organism-associated actinobacterial 16S rRNA gene sequences, i.e., 3,003 sequences, deposited in the NCBI database clearly revealed enormous numbers of actinobacteria associated with marine organisms. For example, RDP classification of these sequences showed that 112 and 62 actinobacterial genera were associated with the sponges and corals, respectively. In most cases, it is expected that these actinobacteria protect the host against pathogens by producing bioactive compounds. Natural products investigation and functional gene screening of the actinobacteria associated with the marine organisms revealed that they can synthesize numerous natural products including polyketides, isoprenoids, phenazines, peptides, indolocarbazoles, sterols, and others. These compounds showed anticancer, antimicrobial, antiparasitic, neurological, antioxidant, and anti-HIV activities. Therefore, marine organism-associated actinobacteria represent an important resource for marine drugs. It is an upcoming field of research to search for novel actinobacteria and pharmaceutical natural products from actinobacteria associated with the marine organisms. In this review, we attempt to summarize the present knowledge on the diversity and natural products production of actinobacteria associated with the marine organisms, based on the publications from 1991 to 2013.

40 CFR 49.4161 - Introduction.

Code of Federal Regulations, 2014 CFR

2014-07-01

...: AIR QUALITY PLANNING AND MANAGEMENT Implementation Plans for Tribes-Region VIII Federal Implementation Plan for Oil and Natural Gas Well Production Facilities; Fort Berthold Indian Reservation (mandan..., production operations, and storage operations at existing, new and modified oil and natural gas production...

40 CFR 49.4161 - Introduction.

Code of Federal Regulations, 2013 CFR

2013-07-01

...: AIR QUALITY PLANNING AND MANAGEMENT Implementation Plans for Tribes-Region VIII Federal Implementation Plan for Oil and Natural Gas Well Production Facilities; Fort Berthold Indian Reservation (mandan..., production operations, and storage operations at existing, new and modified oil and natural gas production...

30 CFR 256.40 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... interest. (g) Liquefied petroleum products means natural gas liquid products including the following... liquids and nonhydrocarbon gases. (3) Of liquefied petroleum products means the volume of natural gas liquids produced from reservoir gas and liquefied at surface separators, field facilities, or gas...

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.

Methods of refining natural oils, and methods of producing fuel compositions

DOEpatents

Firth, Bruce E.; Kirk, Sharon E.

2015-10-27

A method of refining a natural oil includes: (a) providing a feedstock that includes a natural oil; (b) reacting the feedstock in the presence of a metathesis catalyst to form a metathesized product that includes olefins and esters; (c) passivating residual metathesis catalyst with an agent that comprises nitric acid; (d) separating the olefins in the metathesized product from the esters in the metathesized product; and (e) transesterifying the esters in the presence of an alcohol to form a transesterified product and/or hydrogenating the olefins to form a fully or partially saturated hydrogenated product. Methods for suppressing isomerization of olefin metathesis products produced in a metathesis reaction, and methods of producing fuel compositions are described.

Plants and other natural products used in the management of oral infections and improvement of oral health.

PubMed

Chinsembu, Kazhila C

2016-02-01

Challenges of resistance to synthetic antimicrobials have opened new vistas in the search for natural products. This article rigorously reviews plants and other natural products used in oral health: Punica granatum L. (pomegranate), Matricaria recutita L. (chamomile), Camellia sinensis (L.) Kuntze (green tea), chewing sticks made from Diospyros mespiliformis Hochst. ex A.D.C., Diospyros lycioides Desf., and Salvadora persica L. (miswak), honey and propolis from the manuka tree (Leptospermum scoparium J.R. Forst. & G. Forst.), rhein from Rheum rhabarbarum L. (rhubarb), dried fruits of Vitis vinifera L. (raisins), essential oils, probiotics and mushrooms. Further, the review highlights plants from Africa, Asia, Brazil, Mexico, Europe, and the Middle East. Some of the plants' antimicrobial properties and chemical principles have been elucidated. While the use of natural products for oral health is prominent in resource-poor settings, antimicrobial testing is mainly conducted in the following countries (in decreasing order of magnitude): India, South Africa, Brazil, Japan, France, Egypt, Iran, Mexico, Kenya, Switzerland, Nigeria, Australia, Uganda, and the United Kingdom. While the review exposes a dire gap for more studies on clinical efficacy and toxicity, the following emerging trend was noted: basic research on plants for oral health is mainly done in Brazil, Europe and Australia. Brazil, China, India and New Zealand generally conduct value addition of natural products for fortification of toothpastes. African countries focus on bioprospecting and primary production of raw plants and other natural products with antimicrobial efficacies. The Middle East and Egypt predominantly research on plants used as chewing sticks. More research and funding are needed in the field of natural products for oral health, especially in Africa where oral diseases are fuelled by human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Copyright © 2015 Elsevier B.V. All rights reserved.

Effects of pH changes in water-based solvents to isolate antibacterial activated extracts of natural products

NASA Astrophysics Data System (ADS)

Buang, Yohanes; Suwari, Ola, Antonius R. B.

2017-12-01

Effects of pH changes in solvents on isolation of antibacterial activities of natural product extracts were conducted in the present study. Sarang semut (M. pendens) tubers as the model material for the study was considered to be the strategic resource of natural products based on its biochemical and therapeutical effects. The water with pH 5, 7, 9, and 13 was used as the solvents. The antibacterial activities of the resulted extracts indicated that higher the working pH, higher activities of the resulted extracts. The extent activities of the resulted extracts followed the increasing pH of the maceration system. The study also found that higher pH of the working solvent, higher the amounts of the antibacterial extracts isolated from the sample matrix of the natural product. The higher pH of the water solvents plays essential roles to promote the antibacterial activities of the natural product extracts from M. pendens tubers.

Plant metabolic clusters - from genetics to genomics.

PubMed

Nützmann, Hans-Wilhelm; Huang, Ancheng; Osbourn, Anne

2016-08-01

Contents 771 I. 771 II. 772 III. 780 IV. 781 V. 786 786 References 786 SUMMARY: Plant natural products are of great value for agriculture, medicine and a wide range of other industrial applications. The discovery of new plant natural product pathways is currently being revolutionized by two key developments. First, breakthroughs in sequencing technology and reduced cost of sequencing are accelerating the ability to find enzymes and pathways for the biosynthesis of new natural products by identifying the underlying genes. Second, there are now multiple examples in which the genes encoding certain natural product pathways have been found to be grouped together in biosynthetic gene clusters within plant genomes. These advances are now making it possible to develop strategies for systematically mining multiple plant genomes for the discovery of new enzymes, pathways and chemistries. Increased knowledge of the features of plant metabolic gene clusters - architecture, regulation and assembly - will be instrumental in expediting natural product discovery. This review summarizes progress in this area. © 2016 The Authors. New Phytologist © 2016 New Phytologist Trust.

Late-stage chemoselective functional-group manipulation of bioactive natural products with super-electrophilic silylium ions

NASA Astrophysics Data System (ADS)

Bender, Trandon A.; Payne, Philippa R.; Gagné, Michel R.

2018-01-01

The selective (and controllable) modification of complex molecules with disparate functional groups (for example, natural products) is a long-standing challenge that has been addressed using catalysts tuned to perform singular transformations (for example, C-H hydroxylation). A method whereby reactions with diverse functional groups within a single natural product are feasible depending on which catalyst or reagent is chosen would widen the possible structures one could obtain. Fluoroarylborane catalysts can heterolytically split Si-H bonds to yield an oxophilic silylium (R3Si+) equivalent along with a reducing (H-) equivalent. Together, these reactive intermediates enable the reduction of multiple functional groups. Exogenous phosphine Lewis bases further modify the catalyst speciation and attenuate aggressive silylium ions for the selective modification of complex natural products. Manipulation of the catalyst, silane reagent and the reaction conditions provides experimental control over which site is modified (and how). Applying this catalytic method to complex bioactive compounds (natural products or drugs) provides a powerful tool for studying structure-activity relationships.

Strategies for dereplication of natural compounds using high-resolution tandem mass spectrometry.

PubMed

Kind, Tobias; Fiehn, Oliver

2017-09-01

Complete structural elucidation of natural products is commonly performed by nuclear magnetic resonance spectroscopy (NMR), but annotating compounds to most likely structures using high-resolution tandem mass spectrometry is a faster and feasible first step. The CASMI contest 2016 (Critical Assessment of Small Molecule Identification) provided spectra of eighteen compounds for the best manual structure identification in the natural products category. High resolution precursor and tandem mass spectra (MS/MS) were available to characterize the compounds. We used the Seven Golden Rules, Sirius2 and MS-FINDER software for determination of molecular formulas, and then we queried the formulas in different natural product databases including DNP, UNPD, ChemSpider and REAXYS to obtain molecular structures. We used different in-silico fragmentation tools including CFM-ID, CSI:FingerID and MS-FINDER to rank these compounds. Additional neutral losses and product ion peaks were manually investigated. This manual and time consuming approach allowed for the correct dereplication of thirteen of the eighteen natural products.

Synthesis and Demonstration of the Biological Relevance of sp3‐rich Scaffolds Distantly Related to Natural Product Frameworks

PubMed Central

Foley, Daniel J.; Craven, Philip G. E.; Collins, Patrick M.; Doveston, Richard G.; Aimon, Anthony; Talon, Romain; Churcher, Ian; von Delft, Frank

2017-01-01

Abstract The productive exploration of chemical space is an enduring challenge in chemical biology and medicinal chemistry. Natural products are biologically relevant, and their frameworks have facilitated chemical tool and drug discovery. A “top‐down” synthetic approach is described that enabled a range of complex bridged intermediates to be converted with high step efficiency into 26 diverse sp3‐rich scaffolds. The scaffolds have local natural product‐like features, but are only distantly related to specific natural product frameworks. To assess biological relevance, a set of 52 fragments was prepared, and screened by high‐throughput crystallography against three targets from two protein families (ATAD2, BRD1 and JMJD2D). In each case, 3D fragment hits were identified that would serve as distinctive starting points for ligand discovery. This demonstrates that frameworks that are distantly related to natural products can facilitate discovery of new biologically relevant regions within chemical space. PMID:28983993

Synthesis of most polyene natural product motifs using just twelve building blocks and one coupling reaction

PubMed Central

Woerly, Eric M.; Roy, Jahnabi; Burke, Martin D.

2014-01-01

The inherent modularity of polypeptides, oligonucleotides, and oligosaccharides has been harnessed to achieve generalized building block-based synthesis platforms. Importantly, like these other targets, most small molecule natural products are biosynthesized via iterative coupling of bifunctional building blocks. This suggests that many small molecules also possess inherent modularity commensurate with systematic building block-based construction. Supporting this hypothesis, here we report that the polyene motifs found in >75% of all known polyene natural products can be synthesized using just 12 building blocks and one coupling reaction. Using the same general retrosynthetic algorithm and reaction conditions, this platform enabled the synthesis of a wide range of polyene frameworks covering all of this natural product chemical space, and first total syntheses of the polyene natural products asnipyrone B, physarigin A, and neurosporaxanthin β-D-glucopyranoside. Collectively, these results suggest the potential for a more generalized approach for making small molecules in the laboratory. PMID:24848233

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.

Comprehensive separation of secondary metabolites in natural products by high-speed counter-current chromatography using a three-phase solvent system.

PubMed

Yanagida, Akio; Yamakawa, Yutaka; Noji, Ryoko; Oda, Ako; Shindo, Heisaburo; Ito, Yoichiro; Shibusawa, Yoichi

2007-06-01

High-speed counter-current chromatography (HSCCC) using the three-phase solvent system n-hexane-methyl acetate-acetonitrile-water at a volume ratio of 4:4:3:4 was applied to the comprehensive separation of secondary metabolites in several natural product extracts. A wide variety of secondary metabolites in each natural product was effectively extracted with the three-phase solvent system, and the filtered extract was directly submitted to the HSCCC separation using the same three-phase system. In the HSCCC profiles of crude natural drugs listed in the Japanese Pharmacopoeia, several physiologically active compounds were clearly separated from other components in the extracts. The HSCCC profiles of several tea products, each manufactured by a different process, clearly showed their compositional difference in main compounds such as catechins, caffeine, and pigments. These HSCCC profiles also provide useful information about hydrophobic diversity of whole components present in each natural product.

Diversity and abundance of phosphonate biosynthetic genes in nature

USDA-ARS?s Scientific Manuscript database

Phosphonates, molecules containing direct C-P bonds, comprise a structurally diverse class of natural products with interesting and useful biological properties. Although their synthesis in protozoa was discovered more than fifty years ago, the extent and diversity of phosphonate production in natur...

Divergent Total Syntheses of Rhodomyrtosones A and B

PubMed Central

Gervais, Anais; Lazarski, Kiel E.; Porco, John A.

2015-01-01

Herein, we report total syntheses of the tetramethyldihydroxanthene natural product rhodomyrtosone B and the related bis-furan β-triketone natural product rhodomyrtosone A. Nickel-(II)-catalyzed 1,4-conjugate addition of an α-alkylidene-β-dicarbonyl substrate was developed to access the congener rhodomyrtosone B, and oxygenation of the same monoalkylidene derivative followed by cyclization was employed to obtain the bis-furan natural product rhodomyrtosone A. PMID:26351970

Russian Oil and Natural Gas: Strategic Culture and Security Implications of European Dependence

DTIC Science & Technology

2007-12-01

Russia receives from consumption of oil and natural gas exports to Europe on their Gross National Product and economic growth for the future. By...Gross National Product and economic growth for the future. By understanding Russia’s strategic culture and the interdependence of European demand and...EXPORTS ...............66 1. Oil and Natural Gas Reserves and Production ..68 2. Exports to Europe ............................71 3. Revenues

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

PubMed

Isgut, Monica; Rao, Mukkavilli; Yang, Chunhua; Subrahmanyam, Vangala; Rida, Padmashree C G; Aneja, Ritu

2018-03-01

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs. © 2017 Wiley Periodicals, Inc.

Stereodivergent Synthesis of 1,3-Syn-Polyol Natural Product for Stereochemical-Based Structure Activity Relationship Studies

NASA Astrophysics Data System (ADS)

Zheng, Jiamin

The 1,3-syn-diol functionality is very common in many natural products. An important class containing this moiety are the 1,3-syn-polyol/pyranone natural products, which have been isolated from a variety of plant sources, and possess biological activities like plant growth inhibition as well as antifeedant, antifungal, antibacterial, and antitumor properties. The feature of this class is a 6-membered lactone where the lactoe oxygen is part of a 1,3-syn-diol motif. To pursue the 1,3-syn-polyol/pyranone natural products, an iterative hydration of polyene strategy was utilized to provide the 1,3- syn-diol functionality, and asymmetric synthetic strategies were explored to form the requisite stereochemistry. The versatility of the asymmetric approach was demonstrated in the synthesis of eupatorium pyranone and also in an ongoing project aimed at the synthesis of SIA7248. As an outgrowth of our work on the total syntheses of 1,3-syn -polyol natural products inspired a stereo-divergent synthesis of 1,3-syn-polyol natural products and their analogs for stereochemical-based structure-activity relationship (SSAR) studies. To identify the key structural factors important for the anticancer activity of the 1,3-syn-polyol/pyranones, a stereo-divergent 16-member library of pyranone/polyol congeners was designed, synthesized and tested with variations in both stereochemistry and numbers of polyol repeat units. Having access to stereochemical isomers of the biologically active natural products allowed us to design experiments that help illustrate their mechanisms of action.

Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases

PubMed Central

Bulaj, Grzegorz; Ahern, Margaret M.; Kuhn, Alexis; Judkins, Zachary S.; Bowen, Randy C.; Chen, Yizhe

2016-01-01

Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products, and their integration with self-care, music and mHealth, expands precision/personalized medicine strategies for chronic diseases via pharmacological-behavioral combination therapies. PMID:27262323

Emissions of CH4 from natural gas production in the United States using aircraft-based observations (Invited)

NASA Astrophysics Data System (ADS)

Sweeney, C.; Ryerson, T. B.; Karion, A.; Peischl, J.; Petron, G.; Schnell, R. C.; Tsai, T.; Crosson, E.; Rella, C.; Trainer, M.; Frost, G. J.; Hardesty, R. M.; Montzka, S. A.; Dlugokencky, E. J.; Tans, P. P.

2013-12-01

New extraction technologies are making natural gas from shale and tight sand gas reservoirs in the United States (US) more accessible. As a result, the US has become the largest producer of natural gas in the world. This growth in natural gas production may result in increased leakage of methane, a potent greenhouse gas, offsetting the climate benefits of natural gas relative to other fossil fuels. Methane emissions from natural gas production are not well quantified because of the large variety of potential sources, the variability in production and operating practices, the uneven distribution of emitters, and a lack of verification of emission inventories with direct atmospheric measurements. Researchers at the NOAA Earth System Research Laboratory (ESRL) have used simple mass balance approaches to estimate emissions of CH4 from several natural gas and oil plays across the US. We will summarize the results of the available aircraft and ground-based atmospheric emissions estimates to better understand the spatial and temporal distribution of these emissions in the US.

Emissions of CH4 from natural gas production in the United States using aircraft-based observations

NASA Astrophysics Data System (ADS)

Sweeney, Colm; Karion, Anna; Petron, Gabrielle; Ryerson, Thomas; Peischl, Jeff; Trainer, Michael; Rella, Chris; Hardesty, Michael; Crosson, Eric; Montzka, Stephen; Tans, Pieter; Shepson, Paul; Kort, Eric

2014-05-01

New extraction technologies are making natural gas from shale and tight sand gas reservoirs in the United States (US) more accessible. As a result, the US has become the largest producer of natural gas in the world. This growth in natural gas production may result in increased leakage of methane, a potent greenhouse gas, offsetting the climate benefits of natural gas relative to other fossil fuels. Methane emissions from natural gas production are not well quantified because of the large variety of potential sources, the variability in production and operating practices, the uneven distribution of emitters, and a lack of verification of emission inventories with direct atmospheric measurements. Researchers at the NOAA Earth System Research Laboratory (ESRL) have used simple mass balance approaches in combination with isotopes and light alkanes to estimate emissions of CH4 from several natural gas and oil plays across the US. We will summarize the results of the available aircraft and ground-based atmospheric emissions estimates to better understand the spatial and temporal distribution of these emissions in the US.

Chiral thiazoline and thiazole building blocks for the synthesis of peptide-derived natural products.

PubMed

Just-Baringo, Xavier; Albericio, Fernando; Alvarez, Mercedes

2014-01-01

Thiazoline and thiazole heterocycles are privileged motifs found in numerous peptide-derived natural products of biological interest. During the last decades, the synthesis of optically pure building blocks has been addressed by numerous groups, which have developed a plethora of strategies to that end. Efficient and reliable methodologies that are compatible with the intricate and capricious architectures of natural products are a must to further develop their science. Structure confirmation, structure-activity relationship studies and industrial production are fields of paramount importance that require these robust methodologies in order to successfully bring natural products into the clinic. Today's chemist toolbox is assorted with many powerful methods for chiral thiazoline and thiazole synthesis. Ranging from biomimetic approaches to stereoselective alkylations, one is likely to find a suitable method for their needs.

HSQC-TOCSY Fingerprinting for Prioritization of Polyketide- and Peptide-Producing Microbial Isolates.

PubMed

Buedenbender, Larissa; Habener, Leesa J; Grkovic, Tanja; Kurtböke, D İpek; Duffy, Sandra; Avery, Vicky M; Carroll, Anthony R

2018-04-27

Microbial products are a promising source for drug leads as a result of their unique structural diversity. However, reisolation of already known natural products significantly hampers the discovery process, and it is therefore important to incorporate effective microbial isolate selection and dereplication protocols early in microbial natural product studies. We have developed a systematic approach for prioritization of microbial isolates for natural product discovery based on heteronuclear single-quantum correlation-total correlation spectroscopy (HSQC-TOCSY) nuclear magnetic resonance profiles in combination with antiplasmodial activity of extracts. The HSQC-TOCSY experiments allowed for unfractionated microbial extracts containing polyketide and peptidic natural products to be rapidly identified. Here, we highlight how this approach was used to prioritize extracts derived from a library of 119 ascidian-associated actinomycetes that possess a higher potential to produce bioactive polyketides and peptides.

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.

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.

50 CFR 29.21-9 - Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid or...

Code of Federal Regulations, 2013 CFR

2013-10-01

... transportation of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom... Regulations § 29.21-9 Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid... of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom...

50 CFR 29.21-9 - Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid or...

Code of Federal Regulations, 2012 CFR

2012-10-01

... transportation of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom... Regulations § 29.21-9 Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid... of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom...

50 CFR 29.21-9 - Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid or...

Code of Federal Regulations, 2014 CFR

2014-10-01

... transportation of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom... Regulations § 29.21-9 Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid... of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom...

50 CFR 29.21-9 - Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid or...

Code of Federal Regulations, 2010 CFR

2010-10-01

... transportation of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom... Regulations § 29.21-9 Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid... of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom...

50 CFR 29.21-9 - Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid or...

Code of Federal Regulations, 2011 CFR

2011-10-01

... transportation of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom... Regulations § 29.21-9 Rights-of-way for pipelines for the transportation of oil, natural gas, synthetic liquid... of oil, natural gas, synthetic liquid or gaseous fuels, or any refined product produced therefrom...

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...

Producing Seed Crops to Naturally Regenerate Southern Pines

Treesearch

James P. Barnett; Ronald O. Haugen

1995-01-01

The biological processes that affect seed production in natural southern pine are documented, and information that will allow foresters to manipulate stands in a manner to improve and predict seed production is provided. As a result, natural regeneration should become a more reliable technique.

46 CFR 68.55 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-10-01

...) or a tank vessel that is a liquefied natural gas carrier that— (i) Was delivered by the builder of... means— (1) Oil, petroleum products, petrochemicals, or liquefied natural gas cargo that is beneficially...) Oil, petroleum products, petrochemicals, or liquefied natural gas cargo not beneficially owned by the...

Majors' Shift to Natural Gas, The

EIA Publications

2001-01-01

The Majors' Shift to Natural Gas investigates the factors that have guided the United States' major energy producers' growth in U.S. natural gas production relative to oil production. The analysis draws heavily on financial and operating data from the Energy Information Administration's Financial Reporting System (FRS)

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 Origin Lycopene and Its "Green" Downstream Processing.

PubMed

Papaioannou, Emmanouil H; Liakopoulou-Kyriakides, Maria; Karabelas, Anastasios J

2016-01-01

Lycopene is an abundant natural carotenoid pigment with several biological functions (well-known for its antioxidant properties) which is under intensive investigation in recent years. Lycopene chemistry, its natural distribution, bioavailability, biological significance, and toxicological effects are briefly outlined in the first part of this review. The second, major part, deals with various modern downstream processing techniques, which are assessed in order to identify promising approaches for the recovery of lycopene and of similar lipophilic compounds. Natural lycopene is synthesized in plants and by microorganisms, with main representatives of these two categories (for industrial production) tomato and its by-products and the fungus Blakeslea trispora, respectively. Currently, there is a great deal of effort to develop efficient downstream processing for large scale production of natural-origin lycopene, with trends strongly indicating the necessity for "green" and mild extraction conditions. In this review, emphasis is placed on final product safety and ecofriendly processing, which are expected to totally dominate in the field of natural-origin lycopene extraction and purification.

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.

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

Diverted organic synthesis (DOS): accessing a new, natural product inspired, neurotrophically active scaffold through an intramolecular Pauson-Khand reaction.

PubMed

Mehta, Goverdhan; Samineni, Ramesh; Srihari, Pabbaraja; Reddy, R Gajendra; Chakravarty, Sumana

2012-09-14

Drawing inspiration from the impressive neurotrophic activity exhibited by the natural product paecilomycine A, we have designed a new natural product-like scaffold employing an intramolecular Pauson-Khand reaction. Several compounds based on the new designer scaffold exhibited promising neurotrophic activity and are worthy of further biological evaluation. Our findings also highlight the importance of a DOS strategy in creating useful therapeutical leads.

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

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

Contemporary Strategies for the Synthesis of Tetrahydropyran Derivatives: Application to Total Synthesis of Neopeltolide, a Marine Macrolide Natural Product

PubMed Central

Fuwa, Haruhiko

2016-01-01

Tetrahydropyrans are structural motifs that are abundantly present in a range of biologically important marine natural products. As such, significant efforts have been paid to the development of efficient and versatile methods for the synthesis of tetrahydropyran derivatives. Neopeltolide, a potent antiproliferative marine natural product, has been an attractive target compound for synthetic chemists because of its complex structure comprised of a 14-membered macrolactone embedded with a tetrahydropyran ring, and twenty total and formal syntheses of this natural product have been reported so far. This review summarizes the total and formal syntheses of neopeltolide and its analogues, highlighting the synthetic strategies exploited for constructing the tetrahydropyran ring. PMID:27023567

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

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

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.

The biology and chemistry of the zoanthamine alkaloids.

PubMed

Behenna, Douglas C; Stockdill, Jennifer L; Stoltz, Brian M

2008-01-01

Marine natural products have long played an important role in natural products chemistry and drug discovery. Mirroring the rich variety and complicated interactions of the marine environment, the substances isolated from sea creatures tend to be incredibly diverse in both molecular structure and biological activity. The natural products isolated from the polyps of marine zoanthids are no exception. The zoanthamine alkaloids, the first of which were isolated over 20 years ago, are of particular interest to the synthetic community because they feature a novel structural framework and exhibit a broad range of biological activities. In this Review, we summarize the major contributions to understanding the zoanthamine natural products with regard to their isolation and structure determination, as well as studies on their biological activity and total synthesis.

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

Synthesis, characterization and wound healing imitation of Fe3O4 magnetic nanoparticle grafted by natural products

NASA Astrophysics Data System (ADS)

Pala, Sravan Kumar

This research focused on the study of the core-shelled magnetic nanomaterials derived from a colloidal chemistry. The goals are four-fold: (1) synthesis of Fe3O4MNMs using colloidal chemistry. The Fe 3O4 MNMs were then grafted with extracts derived from natural products, namely Olecraceavar italica (broccoli), Boletus edulis (mushroom)and Solanum lycopersicum (tomato);(2)characterization of natural products by chromatography and mass spectrometry;(3) characterization of MNMs to determine their crystallinity, morphological and elemental composition by the state-of-the-art instruments; and (4) biological evaluation using Gram-negative and Gram-positive bacteria. The approach provides advantages to precisely control the composition and homogeneity. The second advantage of the colloidal chemistry is its user friendliness and feasibility. Due to the nature of the natural products, the compatibility of MNM is anticipated to be enhanced.In this chapter, the nanomaterials will be discussed from four perspectives,§1.1 Nanotechnology (§1.1), §1.2 Synthesis of nanomaterials; §1.3 The natural product extract,; §1.4 Characterization of nanomaterials; and §1.5Biological application of nanomaterials.Fig. 1 summarized the overarching goals of this study.

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.

40 CFR 49.147 - Notification and reporting requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... FEDERAL ASSISTANCE INDIAN COUNTRY: AIR QUALITY PLANNING AND MANAGEMENT General Federal Implementation Plan Provisions Federal Implementation Plan for Oil and Natural Gas Production Facilities, Fort Berthold Indian... after the first date of production for the first oil and natural gas well at each oil and natural gas...

40 CFR 49.147 - Notification and reporting requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... FEDERAL ASSISTANCE INDIAN COUNTRY: AIR QUALITY PLANNING AND MANAGEMENT General Federal Implementation Plan Provisions Federal Implementation Plan for Oil and Natural Gas Production Facilities, Fort Berthold Indian... after the first date of production for the first oil and natural gas well at each oil and natural gas...

7 CFR 766.52 - Eligibility.

Code of Federal Regulations, 2012 CFR

2012-01-01

... borrower's actual production, income and expense records for the year the natural disaster occurred; (ii... expenses incurred because of the natural disaster. (5) For the next production cycle, the borrower must... special servicing action under this part to the loan since the natural disaster occurred. (5) For any loan...

7 CFR 766.52 - Eligibility.

Code of Federal Regulations, 2011 CFR

2011-01-01

... borrower's actual production, income and expense records for the year the natural disaster occurred; (ii... expenses incurred because of the natural disaster. (5) For the next production cycle, the borrower must... special servicing action under this part to the loan since the natural disaster occurred. (5) For any loan...

7 CFR 766.52 - Eligibility.

Code of Federal Regulations, 2014 CFR

2014-01-01

... borrower's actual production, income and expense records for the year the natural disaster occurred; (ii... expenses incurred because of the natural disaster. (5) For the next production cycle, the borrower must... special servicing action under this part to the loan since the natural disaster occurred. (5) For any loan...

7 CFR 766.52 - Eligibility.

Code of Federal Regulations, 2010 CFR

2010-01-01

... borrower's actual production, income and expense records for the year the natural disaster occurred; (ii... expenses incurred because of the natural disaster. (5) For the next production cycle, the borrower must... special servicing action under this part to the loan since the natural disaster occurred. (5) For any loan...

7 CFR 766.52 - Eligibility.

Code of Federal Regulations, 2013 CFR

2013-01-01

... borrower's actual production, income and expense records for the year the natural disaster occurred; (ii... expenses incurred because of the natural disaster. (5) For the next production cycle, the borrower must... special servicing action under this part to the loan since the natural disaster occurred. (5) For any loan...

40 CFR 98.397 - Records that must be retained.

Code of Federal Regulations, 2014 CFR

2014-07-01

..., natural gas liquids, and biomass, reporters shall maintain metering, gauging, and other records normally... petroleum products, natural gas liquids, biomass, and feedstocks reported under this subpart. (d) Reporters... carbon share for any petroleum product or natural gas liquid for which CO2 emissions were calculated...

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.

Macrocyclic drugs and synthetic methodologies toward macrocycles

PubMed Central

Yu, Xufen; Sun, Dianqing

2015-01-01

Macrocyclic scaffolds are commonly found in bioactive natural products and pharmaceutical molecules. So far, a large number of macrocyclic natural products have been isolated and synthesized. The construction of macrocycles is generally considered as a crucial and challenging step in the synthesis of macrocyclic natural products. Over the last several decades, numerous efforts have been undertaken toward the synthesis of complex naturally occurring macrocycles and great progresses have been made to advance the field of total synthesis. The commonly used synthetic methodologies toward macrocyclization include macrolactonization, macrolactamization, transition metal-catalyzed cross coupling, ring-closing metathesis, and click reaction, among others. Selected recent examples of macrocyclic synthesis of natural products and druglike macrocycles with significant biological relevance are highlighted in each class. The primary goal of this review is to summarize currently used macrocyclic drugs, highlight the therapeutic potential of this underexplored drug class and outline the general synthetic methodologies for the synthesis of macrocycles. PMID:23708234

Methane emissions estimate from airborne measurements over a western United States natural gas field

NASA Astrophysics Data System (ADS)

Karion, Anna; Sweeney, Colm; PéTron, Gabrielle; Frost, Gregory; Michael Hardesty, R.; Kofler, Jonathan; Miller, Ben R.; Newberger, Tim; Wolter, Sonja; Banta, Robert; Brewer, Alan; Dlugokencky, Ed; Lang, Patricia; Montzka, Stephen A.; Schnell, Russell; Tans, Pieter; Trainer, Michael; Zamora, Robert; Conley, Stephen

2013-08-01

(CH4) emissions from natural gas production are not well quantified and have the potential to offset the climate benefits of natural gas over other fossil fuels. We use atmospheric measurements in a mass balance approach to estimate CH4 emissions of 55 ± 15 × 103 kg h-1 from a natural gas and oil production field in Uintah County, Utah, on 1 day: 3 February 2012. This emission rate corresponds to 6.2%-11.7% (1σ) of average hourly natural gas production in Uintah County in the month of February. This study demonstrates the mass balance technique as a valuable tool for estimating emissions from oil and gas production regions and illustrates the need for further atmospheric measurements to determine the representativeness of our single-day estimate and to better assess inventories of CH4 emissions.

Enriching the biological space of natural products and charting drug metabolites, through real time biotransformation monitoring: The NMR tube bioreactor.

PubMed

Chatzikonstantinou, Alexandra V; Chatziathanasiadou, Maria V; Ravera, Enrico; Fragai, Marco; Parigi, Giacomo; Gerothanassis, Ioannis P; Luchinat, Claudio; Stamatis, Haralambos; Tzakos, Andreas G

2018-01-01

Natural products offer a wide range of biological activities, but they are not easily integrated in the drug discovery pipeline, because of their inherent scaffold intricacy and the associated complexity in their synthetic chemistry. Enzymes may be used to perform regioselective and stereoselective incorporation of functional groups in the natural product core, avoiding harsh reaction conditions, several protection/deprotection and purification steps. Herein, we developed a three step protocol carried out inside an NMR-tube. 1st-step: STD-NMR was used to predict the: i) capacity of natural products as enzyme substrates and ii) possible regioselectivity of the biotransformations. 2nd-step: The real-time formation of multiple-biotransformation products in the NMR-tube bioreactor was monitored in-situ. 3rd-step: STD-NMR was applied in the mixture of the biotransformed products to screen ligands for protein targets. Herein, we developed a simple and time-effective process, the "NMR-tube bioreactor", that is able to: (i) predict which component of a mixture of natural products can be enzymatically transformed, (ii) monitor in situ the transformation efficacy and regioselectivity in crude extracts and multiple substrate biotransformations without fractionation and (iii) simultaneously screen for interactions of the biotransformation products with pharmaceutical protein targets. We have developed a green, time-, and cost-effective process that provide a simple route from natural products to lead compounds for drug discovery. This process can speed up the most crucial steps in the early drug discovery process, and reduce the chemical manipulations usually involved in the pipeline, improving the environmental compatibility. Copyright © 2017 Elsevier B.V. All rights reserved.

30 CFR 1206.55 - What are my responsibilities to place production into marketable condition and to market the...

Code of Federal Regulations, 2012 CFR

2012-07-01

... 30 Mineral Resources 3 2012-07-01 2012-07-01 false What are my responsibilities to place production into marketable condition and to market the production? 1206.55 Section 1206.55 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.55 - What are my responsibilities to place production into marketable condition and to market the...

Code of Federal Regulations, 2013 CFR

2013-07-01

... 30 Mineral Resources 3 2013-07-01 2013-07-01 false What are my responsibilities to place production into marketable condition and to market the production? 1206.55 Section 1206.55 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

30 CFR 1206.55 - What are my responsibilities to place production into marketable condition and to market the...

Code of Federal Regulations, 2014 CFR

2014-07-01

... 30 Mineral Resources 3 2014-07-01 2014-07-01 false What are my responsibilities to place production into marketable condition and to market the production? 1206.55 Section 1206.55 Mineral Resources OFFICE OF NATURAL RESOURCES REVENUE, DEPARTMENT OF THE INTERIOR NATURAL RESOURCES REVENUE PRODUCT...

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.

Identification of ω-N-Methyl-4-hydroxytryptamine (Norpsilocin) as a Psilocybe Natural Product.

PubMed

Lenz, Claudius; Wick, Jonas; Hoffmeister, Dirk

2017-10-27

We report the identification of ω-N-methyl-4-hydroxytryptamine (norpsilocin, 1) from the carpophores of the hallucinogenic mushroom Psilocybe cubensis. The structure was elucidated by 1D and 2D NMR spectroscopy and high-resolution mass spectrometry. Norpsilocin has not previously been reported as a natural product. It likely represents the actual psychotropic agent liberated from its 4-phosphate ester derivative, the known natural product baeocystin. We further present a simple and artifact-free extraction method that prevents dephosphorylation and therefore helps reflect the naturally occurring metabolic profile of Psilocybe mushrooms in subsequent analyses.

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.

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.

Biomimicry as a basis for drug discovery.

PubMed

Kolb, V M

1998-01-01

Selected works are discussed which clearly demonstrate that mimicking various aspects of the process by which natural products evolved is becoming a powerful tool in contemporary drug discovery. Natural products are an established and rich source of drugs. The term "natural product" is often used synonymously with "secondary metabolite." Knowledge of genetics and molecular evolution helps us understand how biosynthesis of many classes of secondary metabolites evolved. One proposed hypothesis is termed "inventive evolution." It invokes duplication of genes, and mutation of the gene copies, among other genetic events. The modified duplicate genes, per se or in conjunction with other genetic events, may give rise to new enzymes, which, in turn, may generate new products, some of which may be selected for. Steps of the inventive evolution can be mimicked in several ways for purpose of drug discovery. For example, libraries of chemical compounds of any imaginable structure may be produced by combinatorial synthesis. Out of these libraries new active compounds can be selected. In another example, genetic system can be manipulated to produce modified natural products ("unnatural natural products"), from which new drugs can be selected. In some instances, similar natural products turn up in species that are not direct descendants of each other. This is presumably due to a horizontal gene transfer. The mechanism of this inter-species gene transfer can be mimicked in therapeutic gene delivery. Mimicking specifics or principles of chemical evolution including experimental and test-tube evolution also provides leads for new drug discovery.

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.

How to boost marine fungal research: A first step towards a multidisciplinary approach by combining molecular fungal ecology and natural products chemistry.

PubMed

Reich, Marlis; Labes, Antje

2017-12-01

Marine fungi have attracted attention in recent years due to increased appreciation of their functional role in ecosystems and as important sources of new natural products. The concomitant development of various "omic" technologies has boosted fungal research in the fields of biodiversity, physiological ecology and natural product biosynthesis. Each of these research areas has its own research agenda, scientific language and quality standards, which have so far hindered an interdisciplinary exchange. Inter- and transdisciplinary interactions are, however, vital for: (i) a detailed understanding of the ecological role of marine fungi, (ii) unlocking their hidden potential for natural product discovery, and (iii) designing access routes for biotechnological production. In this review and opinion paper, we describe the two different "worlds" of marine fungal natural product chemists and marine fungal molecular ecologists. The individual scientific approaches and tools employed are summarised and explained, and enriched with a first common glossary. We propose a strategy to find a multidisciplinary approach towards a comprehensive view on marine fungi and their chemical potential. Copyright © 2017 The Authors. Published by 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...

Importance of Low Permeability Natural Gas Reservoirs (released in AEO2010)

EIA Publications

2010-01-01

Production from low-permeability reservoirs, including shale gas and tight gas, has become a major source of domestic natural gas supply. In 2008, low-permeability reservoirs accounted for about 40% of natural gas production and about 35% of natural gas consumption in the United States. Permeability is a measure of the rate at which liquids and gases can move through rock. Low-permeability natural gas reservoirs encompass the shale, sandstone, and carbonate formations whose natural permeability is roughly 0.1 millidarcies or below. (Permeability is measured in darcies.)

Biosynthetic Pathway for the Epipolythiodioxopiperazine Acetylaranotin in Aspergillus terreus Revealed by Genome-based Deletion Analysis

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

Guo, Chun-Jun; Yeh, Hsu-Hua; Chiang, Yi Ming

2013-04-15

Abstract Epipolythiodioxopiperazines (ETPs) are a class of fungal secondary metabolites derived from cyclic peptides. Acetylaranotin belongs to one structural subgroup of ETPs characterized by the presence of a seven-membered dihydrooxepine ring. Defining the genes involved in acetylaranotin biosynthesis should provide a means to increase production of these compounds and facilitate the engineering of second-generation molecules. The filamentous fungus Aspergillus terreus produces acetylaranotin and related natural products. Using targeted gene deletions, we have identified a cluster of 9 genes including one nonribosomal peptide synthase gene, ataP, that is required for acetylaranotin biosynthesis. Chemical analysis of the wild type and mutant strainsmore » enabled us to isolate seventeen natural products that are either intermediates in the normal biosynthetic pathway or shunt products that are produced when the pathway is interrupted through mutation. Nine of the compounds identified in this study are novel natural products. Our data allow us to propose a complete biosynthetic pathway for acetylaranotin and related natural products.« less

Spontaneously Reported Adverse Reactions for Herbal Medicinal Products and Natural Remedies in Sweden 2007-15: Report from the Medical Products Agency.

PubMed

Svedlund, Erika; Larsson, Maria; Hägerkvist, Robert

2017-06-01

In relation to the extensive use of herbal medicinal products in self-care, the safety information is limited and there is a need for improvement. This study describes spontaneously reported adverse reactions related to herbal medicinal products and natural remedies in Sweden. To evaluate the characteristics and frequency of adverse events recorded by the Swedish Medical Products Agency, where herbal medicinal products and natural remedies were suspected as causative agents. Adverse drug reactions reported to the Swedish Medical Product Agency during 2007-15 related to approved herbal medicinal products or natural remedies were included and analysed in the retrospective study. Reports had been assessed for causality when they were lodged and only reports that had been assessed as at least possible were included in the study. In total, 116 reports (concerning 259 adverse reactions) related to herbal medicinal products or natural remedies were found in the Swedish national pharmacovigilance database. The active ingredients most frequently suspected during the study period were black cohosh rhizome (15 reports), purple coneflower herb (14 reports) and a combination of extracts of pollen (13 reports). Adverse reactions related to skin and subcutaneous tissue were the most commonly reported reactions. No previously unknown safety problems have been discovered in the present study. This finding could be explained by a thorough pre-approval assessment of medicinal products and the fact that most herbal preparations in medicinal products have been in clinical use for many years (for traditional herbal medicinal products, the requirements are ≥30 years), i.e. adverse reactions are acknowledged and assessed before approval.

77 FR 15395 - Notice Pursuant to the National Cooperative Research and Production Act of 1993-Cooperative...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-15

... Production Act of 1993--Cooperative Research Group on Mechanical Stratigraphy and Natural Deformation in... Research Group on Mechanical Stratigraphy and Natural Deformation in Eagle Ford Formation and Equivalent... Eagle Ford's planned activity is to understand mechanical stratigraphy and natural deformation in Eagle...

Natural and anthropogenic rates of soil erosion

USDA-ARS?s Scientific Manuscript database

Regions of land that are brought into crop production from native vegetation typically undergo a period of soil erosion instability, and long term erosion rates are greater than for natural lands as long as the land continues being used for crop production. Average rates of soil erosion under natur...

40 CFR 98.396 - Data reporting requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... natural gas liquid listed in table MM-1 of this subpart that enters the refinery to be further refined or... standard method or other industry standard practice used. For natural gas liquids, quantity shall reflect the individual components of the product. (2) For each petroleum product or natural gas liquid listed...

40 CFR 98.396 - Data reporting requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... natural gas liquid listed in table MM-1 of this subpart that enters the refinery to be further refined or... standard method or other industry standard practice used. For natural gas liquids, quantity shall reflect the individual components of the product. (2) For each petroleum product or natural gas liquid listed...

40 CFR 98.393 - Calculating GHG emissions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... emissions from each individual petroleum product and natural gas liquid using Equation MM-1 of this section... of each petroleum product or natural gas liquid “i” (metric tons). Producti = Annual volume of... reported under § 98.396(a)(1). For natural gas liquids, volumes shall reflect the individual components of...

40 CFR 98.396 - Data reporting requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... natural gas liquid listed in table MM-1 of this subpart that enters the refinery to be further refined or... standard method or other industry standard practice used. For natural gas liquids, quantity shall reflect the individual components of the product. (2) For each petroleum product or natural gas liquid listed...

40 CFR 98.393 - Calculating GHG emissions.

Code of Federal Regulations, 2014 CFR

2014-07-01

... emissions from each individual petroleum product and natural gas liquid using Equation MM-1 of this section... of each petroleum product or natural gas liquid “i” (metric tons). Producti = Annual volume of... reported under § 98.396(a)(2). For natural gas liquids, volumes shall reflect the individual components of...

40 CFR 98.396 - Data reporting requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... natural gas liquid listed in table MM-1 of this subpart that enters the refinery to be further refined or... standard method or other industry standard practice used. For natural gas liquids, quantity shall reflect the individual components of the product. (2) For each petroleum product or natural gas liquid listed...

40 CFR 98.393 - Calculating GHG emissions.

Code of Federal Regulations, 2012 CFR

2012-07-01

... emissions from each individual petroleum product and natural gas liquid using Equation MM-1 of this section... of each petroleum product or natural gas liquid “i” (metric tons). Producti = Annual volume of... reported under § 98.396(a)(1). For natural gas liquids, volumes shall reflect the individual components of...

40 CFR 98.393 - Calculating GHG emissions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... emissions from each individual petroleum product and natural gas liquid using Equation MM-1 of this section... of each petroleum product or natural gas liquid “i” (metric tons). Producti = Annual volume of... reported under § 98.396(a)(1). For natural gas liquids, volumes shall reflect the individual components of...

Prospecting for new bacterial metabolites: a glossary of approaches for inducing, activating and upregulating the biosynthesis of bacterial cryptic or silent natural products.

PubMed

Zarins-Tutt, Joseph Scott; Barberi, Tania Triscari; Gao, Hong; Mearns-Spragg, Andrew; Zhang, Lixin; Newman, David J; Goss, Rebecca Jane Miriam

2016-01-01

Covering: up to 2015. Over the centuries, microbial secondary metabolites have played a central role in the treatment of human diseases and have revolutionised the pharmaceutical industry. With the increasing number of sequenced microbial genomes revealing a plethora of novel biosynthetic genes, natural product drug discovery is entering an exciting second golden age. Here, we provide a concise overview as an introductory guide to the main methods employed to unlock or up-regulate these so called 'cryptic', 'silent' and 'orphan' gene clusters, and increase the production of the encoded natural product. With a predominant focus on bacterial natural products we will discuss the importance of the bioinformatics approach for genome mining, the use of first different and simple culturing techniques and then the application of genetic engineering to unlock the microbial treasure trove.

An analysis of the sponge Acanthostrongylophora igens’ microbiome yields an actinomycete that produces the natural product manzamine A

PubMed Central

Waters, Amanda L.; Peraud, Olivier; Kasanah, Noer; Sims, James W.; Kothalawala, Nuwan; Anderson, Matthew A.; Abbas, Samuel H.; Rao, Karumanchi V.; Jupally, Vijay R.; Kelly, Michelle; Dass, Amala; Hill, Russell T.; Hamann, Mark T.

2016-01-01

Sponges have generated significant interest as a source of bioactive and elaborate secondary metabolites that hold promise for the development of novel therapeutics for the control of an array of human diseases. However, research and development of marine natural products can often be hampered by the difficulty associated with obtaining a stable and sustainable production source. Herein we report the first successful characterization and utilization of the microbiome of a marine invertebrate to identify a sustainable production source for an important natural product scaffold. Through molecular-microbial community analysis, optimization of fermentation conditions and MALDI-MS imaging, we provide the first report of a sponge-associated bacterium (Micromonospora sp.) that produces the manzamine class of antimalarials from the Indo-Pacific sponge Acanthostrongylophora ingens (Thiele, 1899) (Class Demospongiae, Order Haplosclerida, Family Petrosiidae). These findings suggest that a general strategy of analysis of the macroorganism’s microbiome could significantly transform the field of natural products drug discovery by gaining access to not only novel drug leads, but the potential for sustainable production sources and biosynthetic genes at the same time. PMID:27785452

Synthetic biology approaches for the production of plant metabolites in unicellular organisms.

PubMed

Moses, Tessa; Mehrshahi, Payam; Smith, Alison G; Goossens, Alain

2017-07-10

Synthetic biology is the repurposing of biological systems for novel objectives and applications. Through the co-ordinated and balanced expression of genes, both native and those introduced from other organisms, resources within an industrial chassis can be siphoned for the commercial production of high-value commodities. This developing interdisciplinary field has the potential to revolutionize natural product discovery from higher plants, by providing a diverse array of tools, technologies, and strategies for exploring the large chemically complex space of plant natural products using unicellular organisms. In this review, we emphasize the key features that influence the generation of biorefineries and highlight technologies and strategic solutions that can be used to overcome engineering pitfalls with rational design. Also presented is a succinct guide to assist the selection of unicellular chassis most suited for the engineering and subsequent production of the desired natural product, in order to meet the global demand for plant natural products in a safe and sustainable manner. © The Author 2017. Published by Oxford University Press on behalf of the Society for Experimental Biology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Hierarchical virtual screening of the dual MMP-2/HDAC-6 inhibitors from natural products based on pharmacophore models and molecular docking.

PubMed

Wang, Yijun; Yang, Limei; Hou, Jiaying; Zou, Qing; Gao, Qi; Yao, Wenhui; Yao, Qizheng; Zhang, Ji

2018-02-12

The dual-target inhibitors tend to improve the response rate in treating tumors, comparing with the single-target inhibitors. Matrix metalloproteinase-2 (MMP-2) and histone deacetylase-6 (HDAC-6) are attractive targets for cancer therapy. In this study, the hierarchical virtual screening of dual MMP-2/HDAC-6 inhibitors from natural products is investigated. The pharmacophore model of MMP-2 inhibitors is built based on ligands, but the pharmacophore model of HDAC-6 inhibitors is built based on the experimental crystal structures of multiple receptor-ligand complexes. The reliability of these two pharmacophore models is validated subsequently. The hierarchical virtual screening, combining these two different pharmacophore models of MMP-2 and HDAC-6 inhibitors with molecular docking, is carried out to identify the dual MMP-2/HDAC-6 inhibitors from a database of natural products. The four potential dual MMP-2/HDAC-6 inhibitors of natural products, STOCK1 N-46177, STOCK1 N-52245, STOCK1 N-55477, and STOCK1 N-69706, are found. The studies of binding modes show that the screened four natural products can simultaneously well bind with the MMP-2 and HDAC-6 active sites by different kinds of interactions, to inhibit the MMP-2 and HDAC-6 activities. In addition, the ADMET properties of screened four natural products are assessed. These found dual MMP-2/HDAC-6 inhibitors of natural products could serve as the lead compounds for designing the new dual MMP-2/HDAC-6 inhibitors having higher biological activities by carrying out structural modifications and optimizations in the future studies.

Biodiversity as a source of anticancer drugs.

PubMed

Tan, G; Gyllenhaal, C; Soejarto, D D

2006-03-01

Natural Products have been the most significant source of drugs and drug leads in history. Their dominant role in cancer chemotherapeutics is clear with about 74% of anticancer compounds being either natural products, or natural product-derived. The biodiversity of the world provides a resource of unlimited structural diversity for bioprospecting by international drug discovery programs such as the ICBGs and NCDDGs, the latter focusing exclusively on anticancer compounds. However, many sources of natural products remain largely untapped. Technology is gradually overcoming the traditional difficulties encountered in natural products research by improving access to biodiverse resources, and ensuring the compatibility of samples with high throughput procedures. However, the acquisition of predictive biodiversity remains challenging. Plant and organism species may be selected on the basis of potentially useful phytochemical composition by consulting ethnopharmacological, chemosystematic, and ecological information. On the conservation/political front, the Convention on Biological Diversity (CBD) is allaying the anxiety surrounding the notion of biopiracy, which has defeated many attempts to discover and develop new natural products for human benefit. As it becomes increasingly evident and important, the CBD fosters cooperation and adaptation to new regulations and collaborative research agreements with source countries. Even as the past inadequacies of combinatorial chemistry are being analyzed, the intrinsic value of natural products as a source of drug leads is being increasingly appreciated. Their rich structural and stereochemical characteristics make them valuable as templates for exploring novel molecular diversity with the aim of synthesizing lead generation libraries with greater biological relevance. This will ensure an ample supply of starting materials for screening against the multitude of potentially "druggable" targets uncovered by genomics technologies. Far from being mutually exclusive, biodiversity and genomics should be the driving force of drug discovery in the 21st century.

Ecological Roles and Biological Activities of Specialized Metabolites from the Genus Nicotiana.

PubMed

Jassbi, Amir Reza; Zare, Somayeh; Asadollahi, Mojtaba; Schuman, Meredith C

2017-10-11

Species of Nicotiana grow naturally in different parts of the world and have long been used both medicinally and recreationally by human societies. More recently in our history, Nicotiana tabacum has attracted interest as one of the most economically important industrial crops. Nicotiana species are frequently investigated for their bioactive natural products, and the ecological role of their specialized metabolites in responses to abiotic stress or biotic stress factors like pathogens and herbivores. The interest of tobacco companies in genetic information as well as the success of a few wild tobacco species as experimental model organisms have resulted in growing knowledge about the molecular biology and ecology of these plants and functional studies of the plant's natural products. Although a large number of reviews and books on biologically active natural products already exists, mostly from N. tabacum, we focus our attention on the ecological roles and biological activity of natural products, versus products from cured and processed material, in this Review. The studied compounds include alkaloids, aromatic compounds, flavonoids, volatiles, sesquiterpenoids, diterpenes alcohols, and sugar esters from trichomes of the plants, and recently characterized acyclic hydroxygeranyllinalool diterpene glycosides (HGL-DTGs). In this Review (1800s-2017), we describe the above-mentioned classes of natural products, emphasizing their biological activities and functions as they have been determined either in bioassay-guided purification approaches or in bioassays with plants in which the expression of specific biosynthetic genes has been genetically manipulated. Additionally, a review on the history, taxonomy, ecology, and medicinal application of different Nicotiana species growing around the globe presented in this Review may be of interest for pharmacognosists, natural products, and ecological chemists.

Natural products induce a G protein-mediated calcium pathway activating p53 in cancer cells

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

Ginkel, Paul R. van; Yan, Michael B.; Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison, WI 53792

Paclitaxel, etoposide, vincristine and doxorubicin are examples of natural products being used as chemotherapeutics but with adverse side effects that limit their therapeutic window. Natural products derived from plants and having low toxicity, such as quercetin, resveratrol, epigallocatechin gallate and piceatannol, have been shown to inhibit tumor cell growth both in vitro and in pre-clinical models of cancer, but their mechanisms of action have not been fully elucidated, thus restricting their use as prototypes for developing synthetic analogs with improved anti-cancer properties. We and others have demonstrated that one of the earliest and consistent events upon exposure of tumor cellsmore » to these less toxic natural products is a rise in cytoplasmic calcium, activating several pro-apoptotic pathways. We describe here a G protein/inositol 1,4,5-trisphosphate pathway (InsP3) in MDA-MB-231 human breast cancer cells that mediates between these less toxic natural products and the release of calcium from the endoplasmic reticulum. Further, we demonstrate that this elevation of intracellular calcium modulates p53 activity and the subsequent transcription of several pro-apoptotic genes encoding PIG8, CD95, PIDD, TP53INP, RRM2B, Noxa, p21 and PUMA. We conclude from our findings that less toxic natural products likely bind to a G protein coupled receptor that activates a G protein-mediated and calcium-dependent pathway resulting selectively in tumor cell death. - Highlights: • Natural products having low toxicity increase cytoplasmic calcium in cancer cells. • A G-protein/IP{sub 3} pathway mediates the release of calcium from the ER. • The elevation of intracellular calcium modulates p53 activity. • p53 and other Ca{sup 2+}-dependent pro-apoptotic pathways inhibit cancer cell growth.« less

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes.

PubMed

Ju, Kou-San; Gao, Jiangtao; Doroghazi, James R; Wang, Kwo-Kwang A; Thibodeaux, Christopher J; Li, Steven; Metzger, Emily; Fudala, John; Su, Joleen; Zhang, Jun Kai; Lee, Jaeheon; Cioni, Joel P; Evans, Bradley S; Hirota, Ryuichi; Labeda, David P; van der Donk, Wilfred A; Metcalf, William W

2015-09-29

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed "genome mining" as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N(5)-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products.

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.

Discovery of phosphonic acid natural products by mining the genomes of 10,000 actinomycetes

PubMed Central

Ju, Kou-San; Gao, Jiangtao; Doroghazi, James R.; Wang, Kwo-Kwang A.; Thibodeaux, Christopher J.; Li, Steven; Metzger, Emily; Fudala, John; Su, Joleen; Zhang, Jun Kai; Lee, Jaeheon; Cioni, Joel P.; Evans, Bradley S.; Hirota, Ryuichi; Labeda, David P.; van der Donk, Wilfred A.; Metcalf, William W.

2015-01-01

Although natural products have been a particularly rich source of human medicines, activity-based screening results in a very high rate of rediscovery of known molecules. Based on the large number of natural product biosynthetic genes in microbial genomes, many have proposed “genome mining” as an alternative approach for discovery efforts; however, this idea has yet to be performed experimentally on a large scale. Here, we demonstrate the feasibility of large-scale, high-throughput genome mining by screening a collection of over 10,000 actinomycetes for the genetic potential to make phosphonic acids, a class of natural products with diverse and useful bioactivities. Genome sequencing identified a diverse collection of phosphonate biosynthetic gene clusters within 278 strains. These clusters were classified into 64 distinct groups, of which 55 are likely to direct the synthesis of unknown compounds. Characterization of strains within five of these groups resulted in the discovery of a new archetypical pathway for phosphonate biosynthesis, the first (to our knowledge) dedicated pathway for H-phosphinates, and 11 previously undescribed phosphonic acid natural products. Among these compounds are argolaphos, a broad-spectrum antibacterial phosphonopeptide composed of aminomethylphosphonate in peptide linkage to a rare amino acid N5-hydroxyarginine; valinophos, an N-acetyl l-Val ester of 2,3-dihydroxypropylphosphonate; and phosphonocystoximate, an unusual thiohydroximate-containing molecule representing a new chemotype of sulfur-containing phosphonate natural products. Analysis of the genome sequences from the remaining strains suggests that the majority of the phosphonate biosynthetic repertoire of Actinobacteria has been captured at the gene level. This dereplicated strain collection now provides a reservoir of numerous, as yet undiscovered, phosphonate natural products. PMID:26324907

Optimization of a natural medium for cellulase by a marine Aspergillus niger using response surface methodology.

PubMed

Xue, Dong-Sheng; Chen, Hui-Yin; Lin, Dong-Qiang; Guan, Yi-Xin; Yao, Shan-Jing

2012-08-01

The components of a natural medium were optimized to produce cellulase from a marine Aspergillus niger under solid state fermentation conditions by response surface methodology. Eichhornia crassipes and natural seawater were used as a major substrate and a source of mineral salts, respectively. Mineral salts of natural seawater could increase cellulase production. Raw corn cob and raw rice straw showed a significant positive effect on cellulase production. The optimum natural medium consisted of 76.9 % E. crassipes (w/w), 8.9 % raw corn cob (w/w), 3.5 % raw rice straw (w/w), 10.7 % raw wheat bran (w/w), and natural seawater (2.33 times the weight of the dry substrates). Incubation for 96 h in the natural medium increased the biomass to the maximum. The cellulase production was 17.80 U/g the dry weight of substrates after incubation for 144 h. The natural medium avoided supplying chemicals and pretreating substrates. It is promising for future practical fermentation of environment-friendly producing cellulase.

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.

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

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.

Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy

PubMed Central

Ahn, James; Ahn, Hyung Seok; Cheong, Jae Hoon; dela Peña, Ike

2016-01-01

Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a “safer” approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments. PMID:26966583

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

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.

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27 CFR 24.197 - Production by fermentation.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Production by fermentation... fermentation. In producing special natural wine by fermentation, flavoring materials may be added before or during fermentation. Special natural wine produced by fermentation may be ameliorated in the same manner...

27 CFR 24.197 - Production by fermentation.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Production by fermentation... fermentation. In producing special natural wine by fermentation, flavoring materials may be added before or during fermentation. Special natural wine produced by fermentation may be ameliorated in the same manner...

27 CFR 24.197 - Production by fermentation.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Production by fermentation... fermentation. In producing special natural wine by fermentation, flavoring materials may be added before or during fermentation. Special natural wine produced by fermentation may be ameliorated in the same manner...

27 CFR 24.197 - Production by fermentation.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Production by fermentation... fermentation. In producing special natural wine by fermentation, flavoring materials may be added before or during fermentation. Special natural wine produced by fermentation may be ameliorated in the same manner...

27 CFR 24.197 - Production by fermentation.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Production by fermentation... fermentation. In producing special natural wine by fermentation, flavoring materials may be added before or during fermentation. Special natural wine produced by fermentation may be ameliorated in the same manner...

Using Functional Signature Ontology (FUSION) to Identify Mechanisms of Action for Natural Products

PubMed Central

Potts, Malia B.; Kim, Hyun Seok; Fisher, Kurt W.; Hu, Youcai; Carrasco, Yazmin P.; Bulut, Gamze Betul; Ou, Yi-Hung; Herrera-Herrera, Mireya L.; Cubillos, Federico; Mendiratta, Saurabh; Xiao, Guanghua; Hofree, Matan; Ideker, Trey; Xie, Yang; Huang, Lily Jun-shen; Lewis, Robert E.; MacMillan, John B.; White, Michael A.

2014-01-01

A challenge for biomedical research is the development of pharmaceuticals that appropriately target disease mechanisms. Natural products can be a rich source of bioactive chemicals for medicinal applications but can act through unknown mechanisms and can be difficult to produce or obtain. To address these challenges, we developed a new marine-derived, renewable natural products resource and a method for linking bioactive derivatives of this library to the proteins and biological processes that they target in cells. We used cell-based screening and computational analysis to match gene expression signatures produced by natural products to those produced by siRNA and synthetic microRNA libraries. With this strategy, we matched proteins and microRNAs with diverse biological processes and also identified putative protein targets and mechanisms of action for several previously undescribed marine-derived natural products. We confirmed mechanistic relationships for selected short-interfering RNAs, microRNAs, and compounds with functional roles in autophagy, chemotaxis mediated by discoidin domain receptor 2, or activation of the kinase AKT. Thus, this approach may be an effective method for screening new drugs while simultaneously identifying their targets. PMID:24129700

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.

Investigating the Biosynthesis of Natural Products from Marine Proteobacteria: A Survey of Molecules and Strategies

PubMed Central

Timmermans, Marshall L.; Paudel, Yagya P.; Ross, Avena C.

2017-01-01

The phylum proteobacteria contains a wide array of Gram-negative marine bacteria. With recent advances in genomic sequencing, genome analysis, and analytical chemistry techniques, a whole host of information is being revealed about the primary and secondary metabolism of marine proteobacteria. This has led to the discovery of a growing number of medically relevant natural products, including novel leads for the treatment of multidrug-resistant Staphylococcus aureus (MRSA) and cancer. Of equal interest, marine proteobacteria produce natural products whose structure and biosynthetic mechanisms differ from those of their terrestrial and actinobacterial counterparts. Notable features of secondary metabolites produced by marine proteobacteria include halogenation, sulfur-containing heterocycles, non-ribosomal peptides, and polyketides with unusual biosynthetic logic. As advances are made in the technology associated with functional genomics, such as computational sequence analysis, targeted DNA manipulation, and heterologous expression, it has become easier to probe the mechanisms for natural product biosynthesis. This review will focus on genomics driven approaches to understanding the biosynthetic mechanisms for natural products produced by marine proteobacteria. PMID:28762997

The Role of Natural Products in Drug Discovery and Development against Neglected Tropical Diseases.

PubMed

Cheuka, Peter Mubanga; Mayoka, Godfrey; Mutai, Peggoty; Chibale, Kelly

2016-12-31

Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.

Systems Pharmacology-Based Discovery of Natural Products for Precision Oncology Through Targeting Cancer Mutated Genes.

PubMed

Fang, J; Cai, C; Wang, Q; Lin, P; Zhao, Z; Cheng, F

2017-03-01

Massive cancer genomics data have facilitated the rapid revolution of a novel oncology drug discovery paradigm through targeting clinically relevant driver genes or mutations for the development of precision oncology. Natural products with polypharmacological profiles have been demonstrated as promising agents for the development of novel cancer therapies. In this study, we developed an integrated systems pharmacology framework that facilitated identifying potential natural products that target mutated genes across 15 cancer types or subtypes in the realm of precision medicine. High performance was achieved for our systems pharmacology framework. In case studies, we computationally identified novel anticancer indications for several US Food and Drug Administration-approved or clinically investigational natural products (e.g., resveratrol, quercetin, genistein, and fisetin) through targeting significantly mutated genes in multiple cancer types. In summary, this study provides a powerful tool for the development of molecularly targeted cancer therapies through targeting the clinically actionable alterations by exploiting the systems pharmacology of natural products. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

[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.

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.

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.

Investigating the Biosynthesis of Natural Products from Marine Proteobacteria: A Survey of Molecules and Strategies.

PubMed

Timmermans, Marshall L; Paudel, Yagya P; Ross, Avena C

2017-08-01

The phylum proteobacteria contains a wide array of Gram-negative marine bacteria. With recent advances in genomic sequencing, genome analysis, and analytical chemistry techniques, a whole host of information is being revealed about the primary and secondary metabolism of marine proteobacteria. This has led to the discovery of a growing number of medically relevant natural products, including novel leads for the treatment of multidrug-resistant Staphylococcus aureus (MRSA) and cancer. Of equal interest, marine proteobacteria produce natural products whose structure and biosynthetic mechanisms differ from those of their terrestrial and actinobacterial counterparts. Notable features of secondary metabolites produced by marine proteobacteria include halogenation, sulfur-containing heterocycles, non-ribosomal peptides, and polyketides with unusual biosynthetic logic. As advances are made in the technology associated with functional genomics, such as computational sequence analysis, targeted DNA manipulation, and heterologous expression, it has become easier to probe the mechanisms for natural product biosynthesis. This review will focus on genomics driven approaches to understanding the biosynthetic mechanisms for natural products produced by marine proteobacteria.

Thiol-Based Probe for Electrophilic Natural Products Reveals That Most of the Ammosamides Are Artifacts.

PubMed

Reimer, Daniela; Hughes, Chambers C

2017-01-27

To date, 16 members of the ammosamide family of natural products have been discovered, and except for ammosamide D each of these metabolites is characterized by an unusual chlorinated pyrrolo[4,3,2-de]quinoline skeleton. Several ammosamides have been shown to inhibit quinone reductase 2, a flavoenzyme responsible for quelling toxic oxidative species in cells or for killing cancer cells outright. Treatment of the extract from an ammosamide-producing culture (Streptomyces strain CNR-698) with a thiol-based reagent designed to label electrophilic natural products produced an ammosamide C-thiol adduct. This observation led us to hypothesize, and then demonstrate through experimentation, that all of the other ammosamides are derived from ammosamide C via nonenzymatic processes involving exposure to nucleophiles, air, and light. Like many established electrophilic natural products, reaction with the thiol probe suggests that ammosamide C is itself an electrophilic natural product. Although ammosamide C did not show substantial cytotoxicity against cancer cells, its activity against a marine Bacillus bacterial strain may reflect its ecological role.

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

Diazo Reagents with Small Steric Footprints for Simultaneous Arming/SAR Studies of Alcohol-Containing Natural Products via O–H Insertion

PubMed Central

Chamni, Supakarn; He, Qing-Li; Dang, Yongjun; Bhat, Shridhar; Liu, Jun O.; Romo, Daniel

2011-01-01

Natural products are essential tools for basic cellular studies leading to the identification of medically relevant protein targets and the discovery of potential therapeutic leads. The development of methods that enable mild and selective derivatization of natural products continues to be of significant interest for mining their information-rich content. Herein, we describe novel diazo reagents for simultaneous arming and structure-activity relationship (SAR) studies of alcohol-containing natural products with a small steric footprint, namely an α-trifluoroethyl (HTFB) substituted reagent. The Rh(II)-catalyzed O–H insertion reaction of several natural products, including the potent translation inhibitor lactimidomycin, was investigated and useful reactivity and both chemo- and site (chemosite) selectivities were observed. Differential binding to the known protein targets of both FK506 and fumagillol was demonstrated, validating the advantage of the smaller steric footprint of trifluoroethyl derivatives. A p-azidophenyl diazo reagent is also described that will prove useful for photoaffinity labeling of low affinity small molecule protein receptors. PMID:21894934

Specificity in the interaction of natural products with their target proteins--a biochemical and structural insight.

PubMed

Venkatraman, Prasanna

2010-06-01

Natural products are an abundant source of anti cancer agents. They act as cytotoxic drugs, and inhibitors of apoptosis, transcription, cell proliferation and angiogenesis. While pathways targeted by natural products have been well studied, there is paucity of information about the in vivo molecular target/s of these compounds. This review summarizes some of the natural compounds for which the molecular targets, mechanism of action and structural basis of specificity have been well documented. These examples illustrate that 'off target' binding can be explained on the basis of diversity inherent to biomolecular interactions. There is enough evidence to suggest that natural compounds are potent and versatile warheads that can be optimized for a multi targeted therapeutic intervention in cancer.

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, which will be noted. Sub-critical water is finding increase use as an extraction/fractionation or reaction medium. The literature reports applications for the extraction spices, natural antioxidants (rosemary, anthocyanins, etc.), and herbal components (tea and coffee ingredients), Our studies and the literature provide adequate correlations of solute solubility in sub-critical water as well as models for the kinetics of extraction in this medium. Finally, the current state of critical fluid technology as applied to natural products and nutraceuticals will be assessed; noting specific processes, organizations, and products that exist.« less

Medicinal plants and natural products in amelioration of arsenic toxicity: a short review.

PubMed

Bhattacharya, Sanjib

2017-12-01

Chronic arsenic toxicity (arsenicosis) is considered a serious public health menace worldwide, as there is no specific, safe, and efficacious therapeutic management of arsenicosis. To collate the studies on medicinal plants and natural products with arsenic toxicity ameliorative effect, active pre-clinically and/or clinically. Literature survey was carried out by using Google, Scholar Google and Pub-Med. Only the scientific journal articles found on the internet for last two decades were considered. Minerals and semi-synthetic or synthetic analogs of natural products were excluded. Literature study revealed that 34 medicinal plants and 14 natural products exhibited significant protection from arsenic toxicity, mostly in preclinical trials and a few in clinical studies. This research could lead to development of a potentially useful agent in clinical management of arsenicosis in humans.

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

Natural Product Inspired Hsp90 N-Terminal Inhibitors for the Treatment of Cancer: From Bench to Bedside

PubMed Central

Blagg, Brian S. J.

2015-01-01

The 90 kDa heat shock proteins (Hsp90) are responsible for the conformational maturation of nascent polypeptides and the rematuration of denatured proteins. Proteins dependent upon Hsp90 are associated with all six hallmarks of cancer. Upon Hsp90 inhibition, protein substrates are degraded via the ubiquitin-proteasome pathway. Consequentially, inhibition of Hsp90 offers a therapeutic opportunity for the treatment of cancer. Natural product inhibitors of Hsp90 have been identified in vitro, which have served as leads for the development of more efficacious inhibitors and analogs that have entered clinical trials. This review highlights the development of natural product analogs, as well as the development of clinically important inhibitors that arose from natural products. PMID:26010985

Mother natural: Motivations and associations for consuming natural foods.

PubMed

Moscato, Emily M; Machin, Jane E

2018-02-01

Natural is perceived as innately positive and is a widely sought-after attribute in food products. The natural food industry continues to grow in response to rising consumer demand. This qualitative study explored mothers' motivations for purchasing and consuming natural food products for themselves and their families. Mothers are an important population because of their disproportionate influence on household food consumption. We employed participant photography and a series of three weekly focus groups to derive a rich understanding of the activities surrounding and motivations behind seeking natural in everyday buying decisions. Five major themes were identified. First, natural nurtures well-being: physical, psychological, social, and emotional health. Second, natural behaves "supernaturally," allowing positive attributes to be transmitted from the source to the recipient. Third, natural is associated with authenticity, providing a sense of trust, transparency, and control. Fourth, consuming natural reinforces the socially constructed idea of a good mother. Lastly, the preference for natural does not always translate into purchase; mothers face compromises because of conflicting priorities and resources. Understanding mothers' multiple motivations provides deeper insight into the attraction for natural products. The findings have application in positioning interventions for more nutritional eating and revising regulations on the food label natural. Copyright © 2017 Elsevier Ltd. All rights reserved.

Top-down Estimate of Methane Emissions from Natural Gas Production in Northeastern Pennsylvania Using Aircraft and Tower Observations

NASA Astrophysics Data System (ADS)

Barkley, Z.; Lauvaux, T.; Davis, K. J.; Deng, A.; Miles, N. L.; Richardson, S.; Martins, D. K.; Cao, Y.; Sweeney, C.; McKain, K.; Schwietzke, S.; Smith, M. L.; Kort, E. A.

2016-12-01

Leaks in natural gas infrastructure release 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 the energy's greenhouse footprint. This study presents two applications of inverse methodology for estimating regional emission rates from natural gas production and gathering facilities in northeastern Pennsylvania. First, we used the WRF-Chem mesoscale model at 3km resolution to simulate CH4 enhancements and compared them to observations obtained from a three-week flight campaign in May 2015 over the Marcellus shale region. Methane emission rates were adjusted to minimize the errors between aircraft observations and the model-simulated concentrations for each flight. Second, we present the first tower-based high resolution atmospheric inversion of CH4 emission rates from unconventional natural gas production activities. A year of continuous CH4 and calibrated δ13C isotope measurements were collected at four tower locations in northeastern Pennsylvania. The adjoint model used here combines a backward-in-time Lagrangian Particle Dispersion Model coupled with the WRF-Chem model at the same resolution. The prior for both optimization systems was compiled for major sources of CH4 within the Mid-Atlantic states, accounting for emissions from natural gas sources as well as emissions related to farming, waste management, coal, and other sources. Optimized natural gas emission rates are found to be 0.36% of total gas production, with a 2σ confidence interval between 0.27-0.45% of production. We present the results from the tower inversion over one year at 3km resolution providing additional information on spatial and temporal variability of emission rates from production and gathering facilities within the natural gas industry in comparison to flux estimates from the aircraft campaign.

Methods of refining natural oils and methods of producing fuel compositions

DOEpatents

Firth, Bruce E; Kirk, Sharon E; Gavaskar, Vasudeo S

2015-11-04

A method of refining a natural oil includes: (a) providing a feedstock that includes a natural oil; (b) reacting the feedstock in the presence of a metathesis catalyst to form a metathesized product that includes olefins and esters; (c) passivating residual metathesis catalyst with an agent selected from the group consisting of phosphorous acid, phosphinic acid, and a combination thereof; (d) separating the olefins in the metathesized product from the esters in the metathesized product; and (e) transesterifying the esters in the presence of an alcohol to form a transesterified product and/or hydrogenating the olefins to form a fully or partially saturated hydrogenated product. Methods for suppressing isomerization of olefin metathesis products produced in a metathesis reaction, and methods of producing fuel compositions are described.

75 FR 11148 - Agency Information Collection Activities: Proposed Collection; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-03-10

... Natural Gas Production Report. DATES: Comments must be filed by May 10, 2010. If you anticipate difficulty... the United States and the requirement for accurate and timely natural gas production information..., Reserves and Production Division, 1999 Bryan Street, Suite 1110, Dallas, Texas 75201-6801. To ensure...

Report: EPA Needs to Improve Air Emissions Data for the Oil and Natural Gas Production Sector

EPA Pesticide Factsheets

Report #13-P-0161, February 20, 2013. High levels of growth in the oil and natural gas (gas) production sector have underscored the need for EPA to gain a better understanding of emissions and potential risks from the production of oil and gas.

Measurement of VOCs Using Passive Sorbent Tubes Near Oil & Natural Gas Production Pads in Colorado and Texas

EPA Science Inventory

Improved understanding of near-source concentrations of volatile organic compounds (VOCs) and hazardous air pollutants (HAPs) around oil and natural gas production pads is important for several reasons. Production pads serve as the initial collection and storage location of produ...

40 CFR 98.394 - Monitoring and QA/QC requirements.

Code of Federal Regulations, 2011 CFR

2011-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.394 Monitoring and QA/QC requirements. (a) Determination of quantity. (1) The quantity of petroleum products, natural gas liquids, and... each petroleum product or natural gas liquid on any day of each calendar month of the reporting year in...

40 CFR 98.394 - Monitoring and QA/QC requirements.

Code of Federal Regulations, 2013 CFR

2013-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.394 Monitoring and QA/QC requirements. (a) Determination of quantity. (1) The quantity of petroleum products, natural gas liquids, and... each petroleum product or natural gas liquid on any day of each calendar month of the reporting year in...

40 CFR 98.394 - Monitoring and QA/QC requirements.

Code of Federal Regulations, 2012 CFR

2012-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.394 Monitoring and QA/QC requirements. (a) Determination of quantity. (1) The quantity of petroleum products, natural gas liquids, and... each petroleum product or natural gas liquid on any day of each calendar month of the reporting year in...

40 CFR 98.394 - Monitoring and QA/QC requirements.

Code of Federal Regulations, 2010 CFR

2010-07-01

... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.394 Monitoring and QA/QC requirements. (a) Determination of quantity. (1) The quantity of petroleum products, natural gas liquids... product or natural gas liquid on any day of each calendar month of the reporting year in which the...

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.

Natural Products as a Vital Source for the Discovery of Cancer Chemotherapeutic and Chemopreventive Agents

PubMed Central

Cragg, Gordon M.; Pezzuto, John M.

2016-01-01

Throughout history, natural products have played a dominant role in the treatment of human ailments. For example, the legendary discovery of penicillin transformed global existence. Presently, natural products comprise a large portion of current-day pharmaceutical agents, most notably in the area of cancer therapy. Examples include Taxol, vinblastine, and camptothecin. These structurally unique agents function by novel mechanisms of action; isolation from natural sources is the only plausible method that could have led to their discovery. In addition to terrestrial plants as sources for starting materials, the marine environment (e.g., ecteinascidin 743, halichondrin B, and dolastatins), microbes (e.g., bleomycin, doxorubicin, and staurosporin), and slime molds (e.g., epothilone B) have yielded remarkable cancer chemotherapeutic agents. Irrespective of these advances, cancer remains a leading cause of death worldwide. Undoubtedly, the prevention of human cancer is highly preferable to treatment. Cancer chemoprevention, the use of vaccines or pharmaceutical agents to inhibit, retard, or reverse the process of carcinogenesis, is another important approach for easing this formidable public health burden. Similar to cancer chemotherapeutic agents, natural products play an important role in this field. There are many examples, including dietary phytochemicals such as sulforaphane and phenethyl isothiocyanate (cruciferous vegetables) and resveratrol (grapes and grape products). Overall, natural product research is a powerful approach for discovering biologically active compounds with unique structures and mechanisms of action. Given the unfathomable diversity of nature, it is reasonable to suggest that chemical leads can be generated that are capable of interacting with most or possibly all therapeutic targets. PMID:26679767

Microcomputers in Agriculture. A Resource Guide for California Community College Faculty in Agriculture & Natural Resources. Update.

ERIC Educational Resources Information Center

California Community Colleges, Sacramento. Office of the Chancellor.

This resource guide contains descriptions of microcomputer programs that are suitable for use in community college courses in agriculture and natural resources. Product descriptions are organized according to the following subject areas: agricultural business, animal production, farm mechanics, farm management, forestry and natural resources,…

27 CFR 21.130 - Spike lavender oil, natural.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2012-04-01 2012-04-01 false Spike lavender oil, natural. 21.130 Section 21.130 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Denaturants § 21.130 Spike lavender oil, natural. (a) Alcohol content (as borneol). Not less than 30 percent...

27 CFR 21.130 - Spike lavender oil, natural.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2013-04-01 2013-04-01 false Spike lavender oil, natural. 21.130 Section 21.130 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Denaturants § 21.130 Spike lavender oil, natural. (a) Alcohol content (as borneol). Not less than 30 percent...

27 CFR 21.130 - Spike lavender oil, natural.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2014-04-01 2014-04-01 false Spike lavender oil, natural. 21.130 Section 21.130 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Denaturants § 21.130 Spike lavender oil, natural. (a) Alcohol content (as borneol). Not less than 30 percent...

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

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...

27 CFR 21.130 - Spike lavender oil, natural.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2011-04-01 2011-04-01 false Spike lavender oil, natural. 21.130 Section 21.130 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Denaturants § 21.130 Spike lavender oil, natural. (a) Alcohol content (as borneol). Not less than 30 percent...

27 CFR 21.130 - Spike lavender oil, natural.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 27 Alcohol, Tobacco Products and Firearms 1 2010-04-01 2010-04-01 false Spike lavender oil, natural. 21.130 Section 21.130 Alcohol, Tobacco Products and Firearms ALCOHOL AND TOBACCO TAX AND TRADE... Denaturants § 21.130 Spike lavender oil, natural. (a) Alcohol content (as borneol). Not less than 30 percent...

75 FR 71733 - Requirements for Measurement Facilities Used for the Royalty Valuation of Processed Natural Gas

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-24

... measurement of inlet production, residue gas, fuel gas, flare gas, condensate, natural gas liquids, or any... governing gas and liquid hydrocarbon production measurement. We have recently completed the first phase of... Requirements for Measurement Facilities Used for the Royalty Valuation of Processed Natural Gas AGENCY: Bureau...

40 CFR 98.396 - Data reporting requirements.

Code of Federal Regulations, 2014 CFR

2014-07-01

... product or natural gas liquid listed in Table MM-1 of this subpart that enters the refinery to be further...) [Reserved] (6) For each petroleum product and natural gas liquid (ex refinery gate) listed in Table MM-1 of this subpart, report the annual quantity in metric tons or barrels. For natural gas liquids, quantity...

40 CFR 98.2 - Who must report?

Code of Federal Regulations, 2010 CFR

2010-07-01

... products that is equivalent to 25,000 metric tons CO2e or more. (iii) Natural gas and natural gas liquids... or oxidation of the volume of petroleum products and natural gas liquids that are imported during the... GREENHOUSE GAS REPORTING General Provision § 98.2 Who must report? (a) The GHG reporting requirements and...

Life Cycle Water Consumption for Shale Gas and Conventional Natural Gas

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

Clark, Corrie E.; Horner, Robert M.; Harto, Christopher B.

2013-10-15

Shale gas production represents a large potential source of natural gas for the nation. The scale and rapid growth in shale gas development underscore the need to better understand its environmental implications, including water consumption. This study estimates the water consumed over the life cycle of conventional and shale gas production, accounting for the different stages of production and for flowback water reuse (in the case of shale gas). This study finds that shale gas consumes more water over its life cycle (13–37 L/GJ) than conventional natural gas consumes (9.3–9.6 L/GJ). However, when used as a transportation fuel, shale gasmore » consumes significantly less water than other transportation fuels. When used for electricity generation, the combustion of shale gas adds incrementally to the overall water consumption compared to conventional natural gas. The impact of fuel production, however, is small relative to that of power plant operations. The type of power plant where the natural gas is utilized is far more important than the source of the natural gas.« less

Life cycle water consumption for shale gas and conventional natural gas.

PubMed

Clark, Corrie E; Horner, Robert M; Harto, Christopher B

2013-10-15

Shale gas production represents a large potential source of natural gas for the nation. The scale and rapid growth in shale gas development underscore the need to better understand its environmental implications, including water consumption. This study estimates the water consumed over the life cycle of conventional and shale gas production, accounting for the different stages of production and for flowback water reuse (in the case of shale gas). This study finds that shale gas consumes more water over its life cycle (13-37 L/GJ) than conventional natural gas consumes (9.3-9.6 L/GJ). However, when used as a transportation fuel, shale gas consumes significantly less water than other transportation fuels. When used for electricity generation, the combustion of shale gas adds incrementally to the overall water consumption compared to conventional natural gas. The impact of fuel production, however, is small relative to that of power plant operations. The type of power plant where the natural gas is utilized is far more important than the source of the natural gas.

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.

Authenticity of raspberry flavor in food products using SPME-chiral-GC-MS.

PubMed

Hansen, Anne-Mette S; Frandsen, Henrik L; Fromberg, Arvid

2016-05-01

A fast and simple method for authenticating raspberry flavors from food products was developed. The two enantiomers of the compound (E)-α-ionone from raspberry flavor were separated on a chiral gas chromatographic column. Based on the ratio of these two enantiomers, the naturalness of a raspberry flavor can be evaluated due to the fact that a natural flavor will consist almost exclusively of the R enantiomer, while a chemical synthesis of the same compound will result in a racemic mixture. Twenty-seven food products containing raspberry flavors where investigated using SPME-chiral-GC-MS. We found raspberry jam, dried raspberries, and sodas declared to contain natural aroma all contained almost only R-(E)-α-ionone supporting the content of natural raspberry aroma. Six out of eight sweets tested did not indicate a content of natural aroma on the labeling which was in agreement with the almost equal distribution of the R and S isomer. Two products were labeled to contain natural raspberry flavors but were found to contain almost equal amounts of both enantiomers indicating a presence of synthetic raspberry flavors only. Additionally, two products that were labeled to contain both raspberry juice and flavor showed equal amounts of both enantiomers, indicating the presence of synthetic flavor.

Smell and Taste Disorders

MedlinePlus

... Information Drug Information, Search Drug Names, Generic and Brand Natural Products, Search Drug Interactions Pill Identifier Commonly ... Information Drug Information, Search Drug Names, Generic and Brand Natural Products, Search Drug Interactions Pill Identifier News & ...

Geographical and meteorological factors associated with isolation of Listeria species in New York State produce production and natural environments.

PubMed

Chapin, Travis K; Nightingale, Kendra K; Worobo, Randy W; Wiedmann, Martin; Strawn, Laura K

2014-11-01

Listeria species have been isolated from diverse environments, often at considerable prevalence, and are known to persist in food processing facilities. The presence of Listeria spp. has been suggested to be a marker for Listeria monocytogenes contamination. Therefore, a study was conducted to (i) determine the prevalence and diversity of Listeria spp. in produce production and natural environments and (ii) identify geographical and/or meteorological factors that affect the isolation of Listeria spp. in these environments. These data were also used to evaluate Listeria spp. as index organisms for L. monocytogenes in produce production environments. Environmental samples collected from produce production (n = 588) and natural (n = 734) environments in New York State were microbiologically analyzed to detect and isolate Listeria spp. The prevalence of Listeria spp. was approximately 33 and 34% for samples obtained from natural environments and produce production, respectively. Co-isolation of L. monocytogenes and at least one other species of Listeria in a given sample was recorded for 3 and 9% of samples from natural environments and produce production, respectively. Soil moisture and proximity to water and pastures were highly associated with isolation of Listeria spp. in produce production environments, while elevation, study site, and proximity to pastures were highly associated with isolation of Listeria spp. in natural environments, as determined by randomForest models. These data show that Listeria spp. were prevalent in both agricultural and nonagricultural environments and that geographical and meteorological factors associated with isolation of Listeria spp. were considerably different between the two environments.

Conversion of tropical lowland forest reduces nutrient return through litterfall, and alters nutrient use efficiency and seasonality of net primary production.

PubMed

Kotowska, Martyna M; Leuschner, Christoph; Triadiati, Triadiati; Hertel, Dietrich

2016-02-01

Tropical landscapes are not only rapidly transformed by ongoing land-use change, but are additionally confronted by increasing seasonal climate variation. There is an increasing demand for studies analyzing the effects and feedbacks on ecosystem functioning of large-scale conversions of tropical natural forest into intensively managed cash crop agriculture. We analyzed the seasonality of aboveground litterfall, fine root litter production, and aboveground woody biomass production (ANPP(woody)) in natural lowland forests, rubber agroforests under natural tree cover ("jungle rubber"), rubber and oil palm monocultures along a forest-to-agriculture transformation gradient in Sumatra. We hypothesized that the temporal fluctuation of litter production increases with increasing land-use intensity, while the associated nutrient fluxes and nutrient use efficiency (NUE) decrease. Indeed, the seasonal variation of aboveground litter production and ANPP(woody) increased from the natural forest to the plantations, while aboveground litterfall generally decreased. Nutrient return through aboveground litter was mostly highest in the natural forest; however, it was significantly lower only in rubber plantations. NUE of N, P and K was lowest in the oil palm plantations, with natural forest and the rubber systems showing comparably high values. Root litter production was generally lower than leaf litter production in all systems, while the root-to-leaf ratio of litter C flux increased along the land-use intensity gradient. Our results suggest that nutrient and C cycles are more directly affected by climate seasonality in species-poor agricultural systems than in species-rich forests, and therefore might be more susceptible to inter-annual climate fluctuation and climate change.

Prediction of the Passive Intestinal Absorption of Medicinal Plant Extract Constituents with the Parallel Artificial Membrane Permeability Assay (PAMPA).

PubMed

Petit, Charlotte; Bujard, Alban; Skalicka-Woźniak, Krystyna; Cretton, Sylvian; Houriet, Joëlle; Christen, Philippe; Carrupt, Pierre-Alain; Wolfender, Jean-Luc

2016-03-01

At the early drug discovery stage, the high-throughput parallel artificial membrane permeability assay is one of the most frequently used in vitro models to predict transcellular passive absorption. While thousands of new chemical entities have been screened with the parallel artificial membrane permeability assay, in general, permeation properties of natural products have been scarcely evaluated. In this study, the parallel artificial membrane permeability assay through a hexadecane membrane was used to predict the passive intestinal absorption of a representative set of frequently occurring natural products. Since natural products are usually ingested for medicinal use as components of complex extracts in traditional herbal preparations or as phytopharmaceuticals, the applicability of such an assay to study the constituents directly in medicinal crude plant extracts was further investigated. Three representative crude plant extracts with different natural product compositions were chosen for this study. The first extract was composed of furanocoumarins (Angelica archangelica), the second extract included alkaloids (Waltheria indica), and the third extract contained flavonoid glycosides (Pueraria montana var. lobata). For each medicinal plant, the effective passive permeability values Pe (cm/s) of the main natural products of interest were rapidly calculated thanks to a generic ultrahigh-pressure liquid chromatography-UV detection method and because Pe calculations do not require knowing precisely the concentration of each natural product within the extracts. The original parallel artificial membrane permeability assay through a hexadecane membrane was found to keep its predictive power when applied to constituents directly in crude plant extracts provided that higher quantities of the extract were initially loaded in the assay in order to ensure suitable detection of the individual constituents of the extracts. Such an approach is thus valuable for the high-throughput, cost-effective, and early evaluation of passive intestinal absorption of active principles in medicinal plants. In phytochemical studies, obtaining effective passive permeability values of pharmacologically active natural products is important to predict if natural products showing interesting activities in vitro may have a chance to reach their target in vivo. Georg Thieme Verlag KG Stuttgart · New York.

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).

Effects of natural products on several stages of the spore cycle of Clostridium difficile in vitro.

PubMed

Roshan, Niloufar; Riley, Thomas V; Hammer, Katherine A

2018-04-19

To investigate the effect of natural products on the spore cycle of C. difficile in vitro. Twenty-two natural products were investigated using four C. difficile strains. Effects on sporulation, determined using microscopy and a conventional spore recovery assay, showed that fresh onion bulb extract (6.3% v v -1 ) and coconut oil (8% v v -1 ) inhibited sporulation in all four isolates by 66-86% and 51-88%, respectively, compared to untreated controls. Fresh ginger rhizome extract (25% v v -1 ) was also inhibitory, although to a lesser extent. Using a standard spore germination and outgrowth assay, germination was unaffected by the 22 products, whereas outgrowth was significantly reduced by artichoke extract (18.8 mg ml -1 ), fresh onion bulb extract (25% v v -1 ), Leptospermum honeys (8% w v -1 ) and allicin (75 mg ml -1 ) (P < 0.01). Sporicidal activity, investigated using a standard plate recovery assay, was minimal. Three of the 22 natural products (13%) showed inhibitory effects on sporulation of C. difficile and six products (27%) reduced vegetative outgrowth of C. difficile. This study shows the potential of natural products to inhibit different stages of C. difficile sporulation and encourages further investigation in this field. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

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.

Enzymatic catalysis of the Diels-Alder reaction in the biosynthesis of natural products.

PubMed

Oikawa, Hideaki; Tokiwano, Tetsuo

2004-06-01

Recent studies on enzymes catalyzing the Diels- Alder reaction. often named "Diels-Alderases", clearlydemonstrated the involvement of this synthetically useful reaction in the biosynthesis of natural products.This review covers natural Diels-Alder type cycloadducts. synthetic efforts on the chemical feasibility ofthe biosynthctic Diels - Alder reaction and a brief history of studies on Diels-Alderases. In addition,reaction mechanisms of artificial and natural Diels--Alderases are discussed.

Nature reserves: Do they capture the full range of America's biological diversity?

USGS Publications Warehouse

Scott, J.M.; Davis, Frank W.; McGhie, R.G.; Wright, R.G.; Groves, C.; Estes, John

2001-01-01

Less than 6% of the coterminous United States is in nature reserves. Assessment of the occurrence of nature reserves across ranges of elevation and soil productivity classes indicates that nature reserves are most frequently found at higher elevations and on less productive soils. The distribution of plants and animals suggests that the greatest number of species is found at lower elevations. A preliminary assessment of the occurrence of mapped land cover types indicates that ???60% of mapped cover types have <10% of their area in nature reserves Land ownership patterns show that areas of lower elevation and more productive soils are most often privately owned and already extensively converted to urban and agricultural uses. Thus any effort to establish a system of nature reserves that captures the full geographical and ecological range of cover types and species must fully engage the private sector.

Transforming Beef By-products into Valuable Ingredients: Which Spell/Recipe to Use?

PubMed Central

Henchion, Maeve; McCarthy, Mary; O’Callaghan, Jim

2016-01-01

Satisfying the increasing global demand for protein results in challenges from a supply perspective. Increased use of animal proteins, through greater use of meat by-products, could form part of the solution, subject to consumer acceptance. This research investigates consumer evaluations of food products that incorporate ingredients derived from offals that have been produced through a range of food processing technologies. Using focus groups incorporating product stimuli representing various combinations of offals, processing, and carrier products, the research finds that the physical state and perceived naturalness of the ingredients influences acceptance. It also highlights the impact of life experiences, linked to demographic characteristics, on interpretations and evaluations of products and processes. Ideational influences, i.e., knowledge of the nature or origin of the substance, are reasons for rejecting some concepts, with misalignment between nature of processing and the product resulting in rejection of others. Lack of perceived necessity also results in rejection. Alignment of ingredients with existing culinary practices and routines, communication of potential sensory, or other benefits as well as naturalness are factors likely to promote acceptance, and generate repeat purchase, in some consumer segments. Trust in oversight that the products are safe is a prerequisite for acceptance in all cases. These findings have implications for pathways to increase sustainability of beef production and consumption through increased use of beef by-products. PMID:27965963

Vegetation Productivity in Natural vs. Cultivated Systems along Water Availability Gradients in the Dry Subtropics.

PubMed

Baldi, Germán; Texeira, Marcos; Murray, Francisco; Jobbágy, Esteban G

2016-01-01

The dry subtropics are subject to a rapid expansion of crops and pastures over vast areas of natural woodlands and savannas. In this paper, we explored the effect of this transformation on vegetation productivity (magnitude, and seasonal and long-term variability) along aridity gradients which span from semiarid to subhumid conditions, considering exclusively those areas with summer rains (>66%). Vegetation productivity was characterized with the proxy metric "Enhanced Vegetation Index" (EVI) (2000 to 2012 period), on 6186 natural and cultivated sampling points on five continents, and combined with a global climatology database by means of additive models for quantile regressions. Globally and regionally, cultivation amplified the seasonal and inter-annual variability of EVI without affecting its magnitude. Natural and cultivated systems maintained a similar and continuous increase of EVI with increasing water availability, yet achieved through contrasting ways. In natural systems, the productivity peak and the growing season length displayed concurrent steady increases with water availability, while in cultivated systems the productivity peak increased from semiarid to dry-subhumid conditions, and stabilized thereafter giving place to an increase in the growing season length towards wetter conditions. Our results help to understand and predict the ecological impacts of deforestation on vegetation productivity, a key ecosystem process linked to a broad range of services.

Natural Products: Key Prototypes to Drug Discovery Against Neglected Diseases Caused by Trypanosomatids.

PubMed

Varela, Marina Themoteo; Fernandes, Joao Paulo S

2018-04-30

Neglected tropical diseases are a group of infections caused by microorganisms and viruses that affect mainly poor regions of the world. In addition, most available drugs are associated with long periods of treatment and high toxicity which limits the application and patient compliance. Investment in research and development is not seen as an attractive deal by the pharmaceutical industry since the final product must ideally be cheap, not returning the amount invested. Natural products have always played an important source for bioactive compounds and are advantageous over synthetic compounds when considering the unique structural variety and biological activities. On the other hand, isolation difficulties and low yields, environmental impact and high cost usually limit their application as drug per se. In this review, the use of natural products as prototypes for the semi-synthesis or total synthesis, as well as natural products as promising hits are covered, specifically regarding compounds with activities against trypanosomatids such as Trypanosoma spp. and Leishmania spp. Selected reports from literature with this approach were retrieved. As summary, it can be concluded that natural products are an underestimated source for designing novel agents against these parasites. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

The use of natural and synthetic phospholipids as pharmaceutical excipients*

PubMed Central

van Hoogevest, Peter; Wendel, Armin

2014-01-01

In pharmaceutical formulations, phospholipids obtained from plant or animal sources and synthetic phospholipids are used. Natural phospholipids are purified from, e.g., soybeans or egg yolk using non-toxic solvent extraction and chromatographic procedures with low consumption of energy and minimum possible waste. Because of the use of validated purification procedures and sourcing of raw materials with consistent quality, the resulting products differing in phosphatidylcholine content possess an excellent batch to batch reproducibility with respect to phospholipid and fatty acid composition. The natural phospholipids are described in pharmacopeias and relevant regulatory guidance documentation of the Food and Drug Administration (FDA) and European Medicines Agency (EMA). Synthetic phospholipids with specific polar head group, fatty acid composition can be manufactured using various synthesis routes. Synthetic phospholipids with the natural stereochemical configuration are preferably synthesized from glycerophosphocholine (GPC), which is obtained from natural phospholipids, using acylation and enzyme catalyzed reactions. Synthetic phospholipids play compared to natural phospholipid (including hydrogenated phospholipids), as derived from the number of drug products containing synthetic phospholipids, a minor role. Only in a few pharmaceutical products synthetic phospholipids are used. Natural phospholipids are used in oral, dermal, and parenteral products including liposomes. Natural phospholipids instead of synthetic phospholipids should be selected as phospholipid excipients for formulation development, whenever possible, because natural phospholipids are derived from renewable sources and produced with more ecologically friendly processes and are available in larger scale at relatively low costs compared to synthetic phospholipids. Practical applications: For selection of phospholipid excipients for pharmaceutical formulations, natural phospholipids are preferred compared to synthetic phospholipids because they are available at large scale with reproducible quality at lower costs of goods. They are well accepted by regulatory authorities and are produced using less chemicals and solvents at higher yields. In order to avoid scale up problems during pharmaceutical development and production, natural phospholipid excipients instead of synthetic phospholipids should be selected whenever possible. PMID:25400504

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.

All Natural and Clean-Label Preservatives and Antimicrobial Agents Used during Poultry Processing and Packaging.

PubMed

Grant, Ar'quette; Parveen, Salina

2017-04-01

The poultry industry is faced with compounding pressures of maintaining product safety and wholesomeness while keeping up with consumer trends of all-natural foods and label accuracy. Consumers are increasingly demanding that their foods be minimally processed and contain compounds that are easily read and recognized, i.e., products must be clean labeled. The purpose of this review is to briefly describe several natural antimicrobial agents that can be incorporated into poultry processing. These compounds and their essential oils were included in this mini-review because they are generally recognized as safe by the U.S. Food and Drug Administration and are considered clean label: thyme extract, rosemary extract, garlic, and oregano. This list of natural antimicrobial agents by no means includes all of the options available to poultry processors. Rather, this review provides a brief glance at the potential these natural antimicrobial agents have in terms of reduced pathogenicity, increased shelf stability, and sensory acceptability through direct product application or as part of the product packaging.

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.

New and improved tools and methods for enhanced biosynthesis of natural products in microorganisms.

PubMed

Wang, Zhiqing; Cirino, Patrick C

2016-12-01

Engineering efficient biosynthesis of natural products in microorganisms requires optimizing gene expression levels to balance metabolite flux distributions and to minimize accumulation of toxic intermediates. Such metabolic optimization is challenged with identifying the right gene targets, and then determining and achieving appropriate gene expression levels. After decades of having a relatively limited set of gene regulation tools available, metabolic engineers are recently enjoying an ever-growing repertoire of more precise and tunable gene expression platforms. Here we review recent applications of natural and designed transcriptional and translational regulatory machinery for engineering biosynthesis of natural products in microorganisms. Customized trans-acting RNAs (sgRNA, asRNA and sRNA), along with appropriate accessory proteins, are allowing for unparalleled tuning of gene expression. Meanwhile metabolite-responsive transcription factors and riboswitches have been implemented in strain screening and evolution, and in dynamic gene regulation. Further refinements and expansions on these platform technologies will circumvent many long-term obstacles in natural products biosynthesis. Copyright © 2016 Elsevier Ltd. All rights reserved.

Functional Reconstitution of a Fungal Natural Product Gene Cluster by Advanced Genome Editing.

PubMed

Weber, Jakob; Valiante, Vito; Nødvig, Christina S; Mattern, Derek J; Slotkowski, Rebecca A; Mortensen, Uffe H; Brakhage, Axel A

2017-01-20

Filamentous fungi produce varieties of natural products even in a strain dependent manner. However, the genetic basis of chemical speciation between strains is still widely unknown. One example is trypacidin, a natural product of the opportunistic human pathogen Aspergillus fumigatus, which is not produced among different isolates. Combining computational analysis with targeted gene editing, we could link a single nucleotide insertion in the polyketide synthase of the trypacidin biosynthetic pathway and reconstitute its production in a nonproducing strain. Thus, we present a CRISPR/Cas9-based tool for advanced molecular genetic studies in filamentous fungi, exploiting selectable markers separated from the edited locus.

Food applications of natural antimicrobial compounds.

PubMed

Lucera, Annalisa; Costa, Cristina; Conte, Amalia; Del Nobile, Matteo A

2012-01-01

In agreement with the current trend of giving value to natural and renewable resources, the use of natural antimicrobial compounds, particularly in food and biomedical applications, becomes very frequent. The direct addition of natural compounds to food is the most common method of application, even if numerous efforts have been made to find alternative solutions to the aim of avoiding undesirable inactivation. Dipping, spraying, and coating treatment of food with active solutions are currently applied to product prior to packaging as valid options. The aim of the current work is to give an overview on the use of natural compounds in food sector. In particular, the review will gather numerous case-studies of meat, fish, dairy products, minimally processed fruit and vegetables, and cereal-based products where these compounds found application.

Food applications of natural antimicrobial compounds

PubMed Central

Lucera, Annalisa; Costa, Cristina; Conte, Amalia; Del Nobile, Matteo A.

2012-01-01

In agreement with the current trend of giving value to natural and renewable resources, the use of natural antimicrobial compounds, particularly in food and biomedical applications, becomes very frequent. The direct addition of natural compounds to food is the most common method of application, even if numerous efforts have been made to find alternative solutions to the aim of avoiding undesirable inactivation. Dipping, spraying, and coating treatment of food with active solutions are currently applied to product prior to packaging as valid options. The aim of the current work is to give an overview on the use of natural compounds in food sector. In particular, the review will gather numerous case-studies of meat, fish, dairy products, minimally processed fruit and vegetables, and cereal-based products where these compounds found application. PMID:23060862

Cyclic Sulfamidate Enabled Syntheses of Amino Acids, Peptides, Carbohydrates, and Natural Products

EPA Science Inventory

This article reviews the emergence of cyclic sulfamidates as versatile intermediatesfor the synthesis of unnatural amino acids, chalcogen peptides, modified sugars, drugs and drug candidates, and important natural products.

Alimentary hypokinesia

NASA Technical Reports Server (NTRS)

Petrovskiy, K. S.

1980-01-01

The problem of possible conservation of the natural activity of food products is discussed. The struggle for the preservation of the natural activity of food products is an important means of preventing the unfavorable consequences of long term hypokinesia.

10 CFR 625.2 - Definitions.

Code of Federal Regulations, 2012 CFR

2012-01-01

.... Petroleum means crude oil, residual fuel oil or any refined petroleum product (including any natural gas liquid and any natural gas liquid product) owned or contracted for by DOE and in storage in any permanent...

10 CFR 625.2 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-01-01

.... Petroleum means crude oil, residual fuel oil or any refined petroleum product (including any natural gas liquid and any natural gas liquid product) owned or contracted for by DOE and in storage in any permanent...

10 CFR 625.2 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-01-01

.... Petroleum means crude oil, residual fuel oil or any refined petroleum product (including any natural gas liquid and any natural gas liquid product) owned or contracted for by DOE and in storage in any permanent...

10 CFR 625.2 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-01-01

.... Petroleum means crude oil, residual fuel oil or any refined petroleum product (including any natural gas liquid and any natural gas liquid product) owned or contracted for by DOE and in storage in any permanent...

10 CFR 625.2 - Definitions.

Code of Federal Regulations, 2014 CFR

2014-01-01

.... Petroleum means crude oil, residual fuel oil or any refined petroleum product (including any natural gas liquid and any natural gas liquid product) owned or contracted for by DOE and in storage in any permanent...

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.

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.

Assessment of Pneumatic Controller Emission Measurements using a High Volume Sampler at the Oil and Natural Gas Production Pads in Utah

EPA Science Inventory

Oil and Natural Gas (ONG) production facilities have the potential to emit greenhouse gases such as methane (CH4) and other hydrocarbons (HCs) to the atmosphere. ONG production sites have multiple emission sources including storage tank venting, enclosed combustion devices, engin...

Alternative Fuels Data Center: Propane Production and Distribution

Science.gov Websites

produced from liquid components recovered during natural gas processing. These components include ethane & Incentives Propane Production and Distribution Propane is a by-product of natural gas processing distribution showing propane originating from three sources: 1) gas well and gas plant, 2) oil well and

40 CFR 98.390 - Definition of the source category.

Code of Federal Regulations, 2011 CFR

2011-07-01

... petroleum products and natural gas liquids as listed in Table MM-1 of this subpart. (a) A petroleum refinery... products or natural gas liquids as listed in Table MM-1 of this subpart. Any blender or refiner of refined... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.390 Definition of the...

40 CFR 98.390 - Definition of the source category.

Code of Federal Regulations, 2013 CFR

2013-07-01

... petroleum products and natural gas liquids as listed in Table MM-1 of this subpart. (a) A petroleum refinery... products or natural gas liquids as listed in Table MM-1 of this subpart. Any blender or refiner of refined... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.390 Definition of the...

40 CFR 98.390 - Definition of the source category.

Code of Federal Regulations, 2010 CFR

2010-07-01

... petroleum products and natural gas liquids as listed in Table MM-1 of this subpart. (a) A petroleum refinery... products or natural gas liquids as listed in Table MM-1 of this subpart. Any blender or refiner of refined... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.390 Definition of the...

40 CFR 98.390 - Definition of the source category.

Code of Federal Regulations, 2014 CFR

2014-07-01

... petroleum products and natural gas liquids as listed in Table MM-1 of this subpart. (a) A petroleum refinery... products or natural gas liquids as listed in Table MM-1 of this subpart. Any blender or refiner of refined... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.390 Definition of the...

40 CFR 98.390 - Definition of the source category.

Code of Federal Regulations, 2012 CFR

2012-07-01

... petroleum products and natural gas liquids as listed in Table MM-1 of this subpart. (a) A petroleum refinery... products or natural gas liquids as listed in Table MM-1 of this subpart. Any blender or refiner of refined... (CONTINUED) MANDATORY GREENHOUSE GAS REPORTING Suppliers of Petroleum Products § 98.390 Definition of the...

Organisms for biofuel production: natural bioresources and methodologies for improving their biosynthetic potentials.

PubMed

Hu, Guangrong; Ji, Shiqi; Yu, Yanchong; Wang, Shi'an; Zhou, Gongke; Li, Fuli

2015-01-01

In order to relieve the pressure of energy supply and environment contamination that humans are facing, there are now intensive worldwide efforts to explore natural bioresources for production of energy storage compounds, such as lipids, alcohols, hydrocarbons, and polysaccharides. Around the world, many plants have been evaluated and developed as feedstock for bioenergy production, among which several crops have successfully achieved industrialization. Microalgae are another group of photosynthetic autotroph of interest due to their superior growth rates, relatively high photosynthetic conversion efficiencies, and vast metabolic capabilities. Heterotrophic microorganisms, such as yeast and bacteria, can utilize carbohydrates from lignocellulosic biomass directly or after pretreatment and enzymatic hydrolysis to produce liquid biofuels such as ethanol and butanol. Although finding a suitable organism for biofuel production is not easy, many naturally occurring organisms with good traits have recently been obtained. This review mainly focuses on the new organism resources discovered in the last 5 years for production of transport fuels (biodiesel, gasoline, jet fuel, and alkanes) and hydrogen, and available methods to improve natural organisms as platforms for the production of biofuels.

Natural toxins for use in pest management.

PubMed

Duke, Stephen O; Cantrell, Charles L; Meepagala, Kumudini M; Wedge, David E; Tabanca, Nurhayat; Schrader, Kevin K

2010-08-01

Natural toxins are a source of new chemical classes of pesticides, as well as environmentally and toxicologically safer molecules than many of the currently used pesticides. Furthermore, they often have molecular target sites that are not exploited by currently marketed pesticides. There are highly successful products based on natural compounds in the major pesticide classes. These include the herbicide glufosinate (synthetic phosphinothricin), the spinosad insecticides, and the strobilurin fungicides. These and other examples of currently marketed natural product-based pesticides, as well as natural toxins that show promise as pesticides from our own research are discussed.

26 CFR 1.613A-5 - Election under section 613A(c)(4).

Code of Federal Regulations, 2011 CFR

2011-04-01

... TAX (CONTINUED) INCOME TAXES (CONTINUED) Natural Resources § 1.613A-5 Election under section 613A(c)(4... claim for credit or refund. The election allows the taxpayer to treat as his depletable natural gas... production, as well as primary production, but in determining the taxpayer's depletable natural gas quantity...

Competency Test Items for Applied Principles of Agribusiness and Natural Resources Occupations. Agricultural Production Component. A Report of Research.

ERIC Educational Resources Information Center

Cheek, Jimmy G.; McGhee, Max B.

An activity was undertaken to develop written criterion-referenced tests for the agricultural production component of Applied Principles of Agribusiness and Natural Resources Occupations. Intended for tenth grade students who have completed Fundamentals of Agribusiness and Natural Resources Occupations, applied principles were designed to consist…

Nonsteroidal anti-inflammatory drug activated gene-1 (NAG-1) modulators from natural products as anti-cancer agents

USDA-ARS?s Scientific Manuscript database

Natural products are rich source of gene modulators for prevention and treatment of cancer. In recent days, nonsteroidal anti-inflammatory drug (NSAID) activated gene-1 (NAG-1) has been focused as a new target of diverse cancers like colorectal, pancreatic, prostate, and breast. A variety of natural...

Activation of cryptic metabolite production through gene disruption: Dimethyl furan-2,4-dicarboxylate produced by Streptomyces sahachiroi.

PubMed

Simkhada, Dinesh; Zhang, Huitu; Mori, Shogo; Williams, Howard; Watanabe, Coran M H

2013-01-01

At least 65% of all small molecule drugs on the market today are natural products, however, re-isolation of previously identified and characterized compounds has become a serious impediment to the discovery of new bioactive natural products. Here, genetic knockout of an unusual non-ribosomal peptide synthetase (NRPS) C-PCP-C module, aziA2, is performed resulting in the accumulation of the secondary metabolite, dimethyl furan-2,4-dicarboxylate. The cryptic metabolite represents the first non-azinomycin related compound to be isolated and characterized from the soil bacterium, S. sahachiroi. The results from this study suggest that abolishing production of otherwise predominant natural products through genetic knockout may constitute a means to "activate" the production of novel secondary metabolites that would otherwise lay dormant within microbial genome sequences.

Nonwoven production from agricultural okra wastes and investigation of their thermal conductivities

NASA Astrophysics Data System (ADS)

Duman, M. N.; Kocak, E. D.; Merdan, N.; Mistik, I.

2017-10-01

Nowadays bio-based composite materials have been used in rising amounts and demanded widely in industrial uses, as they provide cost reduction and weight loss in the end use products. Agricultural cellulose based wastes can be a good alternative to synthetic fibers and can be used in natural fiber reinforced composite production, as there is a huge (more than 40 million tons) potential for natural cellulose production from agricultural wastes. Okra is one of the most grown vegetables around the world with stems left on the fields after harvest. When the similarity of mechanical properties of okra fibers with traditional bast fibers (flax, kenaf, hemp) are considered, from an economical and an environmental point of view this research emphasizes the potential of agricultural biomass for natural fiber production. In this study, okra stem wastes used for natural cellulosic fiber production and treated with 10% NaOH at 60°C for 10, 20, 30 and 40 minutes. By alkali treatment, decrease in fiber diameter and weight, and increase in tensile strength and elongation % have been observed. Nonwoven production has been done from both the fibers with and without surface treatments. Thermal conductivity properties of both nonwovens have been investigated.

Volatile organic compound emissions from unconventional natural gas production: Source signatures and air quality impacts

NASA Astrophysics Data System (ADS)

Swarthout, Robert F.

Advances in horizontal drilling and hydraulic fracturing over the past two decades have allowed access to previously unrecoverable reservoirs of natural gas and led to an increase in natural gas production. Intensive unconventional natural gas extraction has led to concerns about impacts on air quality. Unconventional natural gas production has the potential to emit vast quantities of volatile organic compounds (VOCs) into the atmosphere. Many VOCs can be toxic, can produce ground-level ozone or secondary organic aerosols, and can impact climate. This dissertation presents the results of experiments designed to validate VOC measurement techniques, to quantify VOC emission rates from natural gas sources, to identify source signatures specific to natural gas emissions, and to quantify the impacts of these emissions on potential ozone formation and human health. Measurement campaigns were conducted in two natural gas production regions: the Denver-Julesburg Basin in northeast Colorado and the Marcellus Shale region surrounding Pittsburgh, Pennsylvania. An informal measurement intercomparison validated the canister sampling methodology used throughout this dissertation for the measurement of oxygenated VOCs. Mixing ratios of many VOCs measured during both campaigns were similar to or higher than those observed in polluted cities. Fluxes of natural gas-associated VOCs in Colorado ranged from 1.5-3 times industry estimates. Similar emission ratios relative to propane were observed for C2-C6 alkanes in both regions, and an isopentane:n-pentane ratio ≈1 was identified as a unique tracer for natural gas emissions. Source apportionment estimates indicated that natural gas emissions were responsible for the majority of C2-C8 alkanes observed in each region, but accounted for a small proportion of alkenes and aromatic compounds. Natural gas emissions in both regions accounted for approximately 20% of hydroxyl radical reactivity, which could hinder federal ozone standard compliance in downwind cities. A health risk assessment showed no increase in cancer or chronic non-cancer risk at locations near natural gas wells in Pennsylvania, but the contribution of natural gas emissions to total risk was 3-6 times higher near wells. These results will assist policy makers, natural gas producers, and citizen stakeholders in crafting effective policies to control VOC emissions from natural gas production activities.

Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates

PubMed Central

Xiao, Zhiyan; Morris-Natschke, Susan L.; Lee, Kuo-Hsiung

2015-01-01

Natural products have made significant contribution to cancer chemotherapy over the past decades and remain an indispensable source of molecular and mechanistic diversity for anticancer drug discovery. More often than not, natural products may serve as leads for further drug development rather than as effective anticancer drugs by themselves. Generally, optimization of natural leads into anticancer drugs or drug candidates should not only address drug efficacy, but also improve ADMET profiles and chemical accessibility associated with the natural leads. Optimization strategies involve direct chemical manipulation of functional groups, structure-activity relationship-directed optimization and pharmacophore-oriented molecular design based on the natural templates. Both fundamental medicinal chemistry principles (e.g., bio-isosterism) and state-of-the-art computer-aided drug design techniques (e.g., structure-based design) can be applied to facilitate optimization efforts. In this review, the strategies to optimize natural leads to anticancer drugs or drug candidates are illustrated with examples and described according to their purposes. Furthermore, successful case studies on lead optimization of bioactive compounds performed in the Natural Products Research Laboratories at UNC are highlighted. PMID:26359649

Effects of plant diversity, community composition and environmental parameters on productivity in montane European grasslands.

PubMed

Kahmen, Ansgar; Perner, Jörg; Audorff, Volker; Weisser, Wolfgang; Buchmann, Nina

2005-02-01

In the past years, a number of studies have used experimental plant communities to test if biodiversity influences ecosystem functioning such as productivity. It has been argued, however, that the results achieved in experimental studies may have little predictive value for species loss in natural ecosystems. Studies in natural ecosystems have been equivocal, mainly because in natural ecosystems differences in diversity are often confounded with differences in land use history or abiotic parameters. In this study, we investigated the effect of plant diversity on ecosystem functioning in semi-natural grasslands. In an area of 10x20 km, we selected 78 sites and tested the effects of various measures of diversity and plant community composition on productivity. We separated the effects of plant diversity on ecosystem functioning from potentially confounding effects of community composition, management or environmental parameters, using multivariate statistical analyses. In the investigated grasslands, simple measures of biodiversity were insignificant predictors of productivity. However, plant community composition explained productivity very well (R2=0.31) and was a better predictor than environmental variables (soil and site characteristics) or management regime. Thus, complex measures such as community composition and structure are important drivers for ecosystem functions in semi-natural grasslands. Furthermore, our data show that it is difficult to extrapolate results from experimental studies to semi-natural ecosystems, although there is a need to investigate natural ecosystems to fully understand the relationship of biodiversity and ecosystem functioning.

Recreational drug discovery: natural products as lead structures for the synthesis of smart drugs.

PubMed

Appendino, Giovanni; Minassi, Alberto; Taglialatela-Scafati, Orazio

2014-07-01

Covering: up to December 2013. Over the past decade, there has been a growing transition in recreational drugs from natural materials (marijuana, hashish, opium), natural products (morphine, cocaine), or their simple derivatives (heroin), to synthetic agents more potent than their natural prototypes, which are sometimes less harmful in the short term, or that combine properties from different classes of recreational prototypes. These agents have been named smart drugs, and have become popular both for personal consumption and for collective intoxication at rave parties. The reasons for this transition are varied, but are mainly regulatory and commercial. New analogues of known illegal intoxicants are invisible to most forensic detection techniques, while the alleged natural status and the lack of avert acute toxicity make them appealing to a wide range of users. On the other hand, the advent of the internet has made possible the quick dispersal of information among users and the on-line purchase of these agents and/or the precursors for their synthesis. Unlike their natural products chemotypes (ephedrine, mescaline, cathinone, psilocybin, THC), most new drugs of abuse are largely unfamiliar to the organic chemistry community as well as to health care providers. To raise awareness of the growing plague of smart drugs we have surveyed, in a medicinal chemistry fashion, their development from natural products leads, their current methods of production, and the role that clandestine home laboratories and underground chemists have played in the surge of popularity of these drugs.

Environmental impact analysis of batik natural dyes using life cycle assessment

NASA Astrophysics Data System (ADS)

Rinawati, Dyah Ika; Sari, Diana Puspita; Purwanggono, Bambang; Hermawan, Andy Tri

2017-11-01

The use of natural dyes for batik dyeing is fewer than synthetic dyes because of its limitations in the application such complexity in manufacture and usage. For ease of use, natural dyes need to be processed into instant products. Extract of natural dyes are generally produced in liquid form that are less practical in long-term use. Dye powder obtained by drying the liquid extract using spray dryer. Production process of liquid natural dye is simpler and require less energy but need more energy for transporting. It is important to know which type of natural dyes should be produced based on their environmental impact. This research aim to compare environmental impact between liquid and powder natural dyes and also to find relative contribution of different stage in life cycle to total environmental impact. The appropriate method to analyze and compare the environmental impacts of powder and liquid natural dyes is Life Cycle Assessment (LCA). The "cradle to grave" approach used to assess environmental impact of powder and liquid natural dyes of Jalawe rind throughout production process of natural dyes, distribution and use of natural dyes for coloring batik. Results of this research show that powder natural dyes has lower environmental impacts than liquid natural dyes. It was found that distribution, mordanting and packaging of liquid dyes have big contribution to environmental impact.

Affinity Crystallography: A New Approach to Extracting High-Affinity Enzyme Inhibitors from Natural Extracts.

PubMed

Aguda, Adeleke H; Lavallee, Vincent; Cheng, Ping; Bott, Tina M; Meimetis, Labros G; Law, Simon; Nguyen, Nham T; Williams, David E; Kaleta, Jadwiga; Villanueva, Ivan; Davies, Julian; Andersen, Raymond J; Brayer, Gary D; Brömme, Dieter

2016-08-26

Natural products are an important source of novel drug scaffolds. The highly variable and unpredictable timelines associated with isolating novel compounds and elucidating their structures have led to the demise of exploring natural product extract libraries in drug discovery programs. Here we introduce affinity crystallography as a new methodology that significantly shortens the time of the hit to active structure cycle in bioactive natural product discovery research. This affinity crystallography approach is illustrated by using semipure fractions of an actinomycetes culture extract to isolate and identify a cathepsin K inhibitor and to compare the outcome with the traditional assay-guided purification/structural analysis approach. The traditional approach resulted in the identification of the known inhibitor antipain (1) and its new but lower potency dehydration product 2, while the affinity crystallography approach led to the identification of a new high-affinity inhibitor named lichostatinal (3). The structure and potency of lichostatinal (3) was verified by total synthesis and kinetic characterization. To the best of our knowledge, this is the first example of isolating and characterizing a potent enzyme inhibitor from a partially purified crude natural product extract using a protein crystallographic approach.

A renaissance in marine pharmacology: from preclinical curiosity to clinical reality.

PubMed

Glaser, Keith B; Mayer, Alejandro M S

2009-09-01

Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt (ziconotide, omega-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis) (trabectedin, ET-743) an antitumor agent scovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.

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.

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.

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.

Assessing the drug-likeness of lamellarins, a marine-derived natural product class with diverse oncological activities.

PubMed

Chittchang, Montakarn; Gleeson, M Paul; Ploypradith, Poonsakdi; Ruchirawat, Somsak

2010-06-01

Natural products currently represent an underutilized source of leads for the pharmaceutical industry, especially when one considers that almost 50% of all drugs were either derived from such sources or are very closely related. Lamellarins are a class of natural products with diverse biological activities and have entered into preclinical development for the treatment of multidrug-resistant tumors. Although these compounds demonstrated good cell penetration, as observed by their low microM activity in whole cell models, they have not been extensively profiled from a physicochemical point of view, and this is the goal of this study. For this study, we have determined the experimental logP values of a set of 25 lamellarins, given it is the single most important parameter in determining multiple ADMET parameters. We also discuss the relationship between this natural product class, natural product derivatives in development and on the market, oral marketed drugs, as well as drug molecules in development, using a range of physicochemical parameters in conjunction with principal components analysis (PCA). The impact of this systematic analysis on our ongoing medicinal chemistry strategy is also discussed. Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

75 FR 8318 - Agency Information Collection Activities: Submission for OMB Review; Comment Request

Federal Register 2010, 2011, 2012, 2013, 2014

2010-02-24

... and disposition of crude oil, petroleum products, and natural gas liquids. The data are published by..., blending plants, bulk terminals, crude oil and product pipelines, natural gas plant facilities, tankers...

Regional air quality impacts of increased natural gas production and use in Texas.

PubMed

Pacsi, Adam P; Alhajeri, Nawaf S; Zavala-Araiza, Daniel; Webster, Mort D; Allen, David T

2013-04-02

Natural gas use in electricity generation in Texas was estimated, for gas prices ranging from $1.89 to $7.74 per MMBTU, using an optimal power flow model. Hourly estimates of electricity generation, for individual electricity generation units, from the model were used to estimate spatially resolved hourly emissions from electricity generation. Emissions from natural gas production activities in the Barnett Shale region were also estimated, with emissions scaled up or down to match demand in electricity generation as natural gas prices changed. As natural gas use increased, emissions decreased from electricity generation and increased from natural gas production. Overall, NOx and SO2 emissions decreased, while VOC emissions increased as natural gas use increased. To assess the effects of these changes in emissions on ozone and particulate matter concentrations, spatially and temporally resolved emissions were used in a month-long photochemical modeling episode. Over the month-long photochemical modeling episode, decreases in natural gas prices typical of those experienced from 2006 to 2012 led to net regional decreases in ozone (0.2-0.7 ppb) and fine particulate matter (PM) (0.1-0.7 μg/m(3)). Changes in PM were predominantly due to changes in regional PM sulfate formation. Changes in regional PM and ozone formation are primarily due to decreases in emissions from electricity generation. Increases in emissions from increased natural gas production were offset by decreasing emissions from electricity generation for all the scenarios considered.

Natural antimicrobial/antioxidant agents in meat and poultry products as well as fruits and vegetables: A review.

PubMed

Aziz, Marya; Karboune, Salwa

2018-02-11

Synthetic preservatives are widely used by the food industry to control the growth of spoilage and pathogenic microorganisms and to inhibit the process of lipid oxidation extending the shelf-life, quality and safety of food products. However, consumer's preference for natural food additives and concern regarding the safety of synthetic preservatives prompted the food industry to look for natural alternatives. Natural antimicrobials, including plant extracts and their essential oils, enzymes, peptides, bacteriocins, bacteriophages, and fermented ingredients have all been shown to have the potential for use as alternatives to chemical antimicrobials. Some spices, herbs and other plant extracts were also reported to be strong antioxidants. The antimicrobial/antioxidant activities of some plant extracts and/or their essential oils are mainly due to the presence of some major bioactive compounds, including phenolic acids, terpenes, aldehydes, and flavonoids. The proposed mechanisms of action of these natural preservatives are reported. An overview of the research done on the direct incorporation of natural preservatives agents into meat and poultry products as well as fruit and vegetables to extend their shelf-life is presented. The development of edible packaging materials containing natural preservatives is growing and their applications in selected food products are also presented in this review.

Use of imagery and text that could convey reduced harm in American Spirit advertisements.

PubMed

Moran, Meghan Bridgid; Pierce, John P; Weiger, Caitlin; Cunningham, Mary C; Sargent, James D

2017-03-01

In 2015, the US Food and Drug Administration issued warning letters to three tobacco companies regarding use of the terms 'natural' and/or 'additive-free' to describe their products, as these terms inaccurately convey reduced harm. Yet, tobacco companies engage in a variety of alternate techniques to attempt to convey the same 'natural' (and thus reduced harm) message. It is critical to monitor these practices to inform regulatory action. To describe the marketing techniques used in Natural American Spirit (American Spirit) ads that could convey a natural and less harmful product image. Trained coders content analysed 142 American Spirit ads from 2012 to 2016. In addition to use of the terms 'natural' and 'additive-free', American Spirit ads engage in a variety of other linguistic and iconic techniques that could convey reduced harm, such as references to small, local or organic farming, eco-friendly practices, and plant, farming and other nature-related imagery. American Spirit ads use a wide range of marketing techniques to convey a natural product image, which could subsequently communicate reduced harm. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Marine Sponge Derived Natural Products between 2001 and 2010: Trends and Opportunities for Discovery of Bioactives

PubMed Central

Mehbub, Mohammad Ferdous; Lei, Jie; Franco, Christopher; Zhang, Wei

2014-01-01

Marine sponges belonging to the phylum Porifera (Metazoa), evolutionarily the oldest animals are the single best source of marine natural products. The present review presents a comprehensive overview of the source, taxonomy, country of origin or geographical position, chemical class, and biological activity of sponge-derived new natural products discovered between 2001 and 2010. The data has been analyzed with a view to gaining an outlook on the future trends and opportunities in the search for new compounds and their sources from marine sponges. PMID:25196730

The Vatican museum and the organic natural products. The Raphael's frescoes and the "Last Judgment" by Nicolò and Giovanni.

PubMed

Gabrielli, Nazzareno; Guiso, Marcella; Bianco, Armandodoriano

2017-05-25

In the second half of the 90s, alongside the restoration works of the Quattrocentisti (fifteenth century painters) in the Sistine Chapel, it also carried out the restoration of the frescoes of the Stanze di Raffaello. The results of scientific investigations conducted by the Scientific Research Laboratory of the Vatican Museums, previously presented in some assays of study, are summarised and presented in this letter to the Editor for the special issue of Natural Product Research: Natural Products in Cultural Heritage.

[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.

[Application of synthetic biology to sustainable utilization of Chinese materia medica resources].

PubMed

Huang, Lu-Qi; Gao, Wei; Zhou, Yong-Jin

2014-01-01

Bioactive natural products are the material bases of Chinese materia medica resources. With successful applications of synthetic biology strategies to the researches and productions of taxol, artemisinin and tanshinone, etc, the potential ability of synthetic biology in the sustainable utilization of Chinese materia medica resources has been attracted by many researchers. This paper reviews the development of synthetic biology, the opportunities of sustainable utilization of Chinese materia medica resources, and the progress of synthetic biology applied to the researches of bioactive natural products. Furthermore, this paper also analyzes how to apply synthetic biology to sustainable utilization of Chinese materia medica resources and what the crucial factors are. Production of bioactive natural products with synthetic biology strategies will become a significant approach for the sustainable utilization of Chinese materia medica resources.

Production traits of artificially and naturally hatched geese in intensive and free-range systems: I. Growth traits.

PubMed

Boz, M A; Sarica, M; Yamak, U S

2017-04-01

1. This study investigated the effect of incubation type and production system on geese growth traits. 2. A total of 216 geese were either naturally (114) or artificially (102) hatched and reared in intensive or free-range production systems (4 replicates each) until 18 weeks of age. 3. Weights of naturally hatched goslings (NHG) were significantly higher than artificially hatched goslings (AHG) at 2 weeks (644 vs. 536 g); however, weights of AHG were significantly higher than NHG at both 6 weeks (3245 vs. 3010 g) and 18 weeks (5212 vs. 4353 g). 4. AHG had better feed conversion ratios (FCRs) than NHG (6.21 vs. 6.46 at 18 weeks). Feed consumption of naturally hatched geese was found higher in first 4 weeks when compared to artificially hatched geese and artificially hatched geese consumed more feed than naturally hatched geese after 8 weeks. 5. Production system had insignificant effects on feed consumption, FCRs, viability and mutilation rates. 6. Slipped wings were more frequent in NHG than AHG (8.32% vs. 1.68% at 6 weeks; 23.84% vs. 5.12% between 7 and 18 weeks) and in free-range production when compared to intensive production (17.88% vs. 11.08% over the course of the production period). 7. The study results indicate that both artificially and NHG can be reared in free-range production systems without any loss in performance and in deference to animal welfare.

International Energy Annual, 1992

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

Not Available

1994-01-14

This report is prepared annually and presents the latest information and trends on world energy production and consumption for petroleum, natural gas, coal, and electricity. Trade and reserves are shown for petroleum, natural gas, and coal. Prices are included for selected petroleum products. Production and consumption data are reported in standard units as well as British thermal units (Btu) and joules.

Tissue culture of woody plants and its relevance to molecular biology

Treesearch

R. Minocha; S.M. Jain

2000-01-01

The ever increasing demand for forest products and the progressive deterioration of natural forests means that the forest industry cannot continue to rely on the exploitation of natural forests ( Jain, 1997; Tzfira et al., 1998). To meet the increasing demand for forest products while more forest land is needed for non-timber uses, the replacement of natural...

Productivity as related to diversity and age in planted versus natural forests

Treesearch

Qinfeng Guo; Hai Ren

2014-01-01

Little is known about the performance of plantations relative to natural forests of the same climate zone and age. China has more plantations than any other country as a consequence of massive afforestation efforts.We use data from China to comparatively examine tree biomass and productivity of planted and natural stands in relation to climate zone, latitude, elevation...

Trends in the discovery of new marine natural products from invertebrates over the last two decades--where and what are we bioprospecting?

PubMed

Leal, Miguel Costa; Puga, João; Serôdio, João; Gomes, Newton C M; Calado, Ricardo

2012-01-01

It is acknowledged that marine invertebrates produce bioactive natural products that may be useful for developing new drugs. By exploring untapped geographical sources and/or novel groups of organisms one can maximize the search for new marine drugs to treat human diseases. The goal of this paper is to analyse the trends associated with the discovery of new marine natural products from invertebrates (NMNPI) over the last two decades. The analysis considers different taxonomical levels and geographical approaches of bioprospected species. Additionally, this research is also directed to provide new insights into less bioprospected taxa and world regions. In order to gather the information available on NMNPI, the yearly-published reviews of Marine Natural Products covering 1990-2009 were surveyed. Information on source organisms, specifically taxonomical information and collection sites, was assembled together with additional geographical information collected from the articles originally describing the new natural product. Almost 10000 NMNPI were discovered since 1990, with a pronounced increase between decades. Porifera and Cnidaria were the two dominant sources of NMNPI worldwide. The exception was polar regions where Echinodermata dominated. The majority of species that yielded the new natural products belong to only one class of each Porifera and Cnidaria phyla (Demospongiae and Anthozoa, respectively). Increased bioprospecting efforts were observed in the Pacific Ocean, particularly in Asian countries that are associated with the Japan Biodiversity Hotspot and the Kuroshio Current. Although results show comparably less NMNPI from polar regions, the number of new natural products per species is similar to that recorded for other regions. The present study provides information to future bioprospecting efforts addressing previously unexplored taxonomic groups and/or regions. We also highlight how marine invertebrates, which in some cases have no commercial value, may become highly valuable in the ongoing search for new drugs from the sea.

Trends in the Discovery of New Marine Natural Products from Invertebrates over the Last Two Decades – Where and What Are We Bioprospecting?

PubMed Central

Leal, Miguel Costa; Puga, João; Serôdio, João; Gomes, Newton C. M.; Calado, Ricardo

2012-01-01

It is acknowledged that marine invertebrates produce bioactive natural products that may be useful for developing new drugs. By exploring untapped geographical sources and/or novel groups of organisms one can maximize the search for new marine drugs to treat human diseases. The goal of this paper is to analyse the trends associated with the discovery of new marine natural products from invertebrates (NMNPI) over the last two decades. The analysis considers different taxonomical levels and geographical approaches of bioprospected species. Additionally, this research is also directed to provide new insights into less bioprospected taxa and world regions. In order to gather the information available on NMNPI, the yearly-published reviews of Marine Natural Products covering 1990–2009 were surveyed. Information on source organisms, specifically taxonomical information and collection sites, was assembled together with additional geographical information collected from the articles originally describing the new natural product. Almost 10000 NMNPI were discovered since 1990, with a pronounced increase between decades. Porifera and Cnidaria were the two dominant sources of NMNPI worldwide. The exception was polar regions where Echinodermata dominated. The majority of species that yielded the new natural products belong to only one class of each Porifera and Cnidaria phyla (Demospongiae and Anthozoa, respectively). Increased bioprospecting efforts were observed in the Pacific Ocean, particularly in Asian countries that are associated with the Japan Biodiversity Hotspot and the Kuroshio Current. Although results show comparably less NMNPI from polar regions, the number of new natural products per species is similar to that recorded for other regions. The present study provides information to future bioprospecting efforts addressing previously unexplored taxonomic groups and/or regions. We also highlight how marine invertebrates, which in some cases have no commercial value, may become highly valuable in the ongoing search for new drugs from the sea. PMID:22276216

Aircraft-Based Estimate of Total Methane Emissions from the Barnett Shale Region.

PubMed

Karion, Anna; Sweeney, Colm; Kort, Eric A; Shepson, Paul B; Brewer, Alan; Cambaliza, Maria; Conley, Stephen A; Davis, Ken; Deng, Aijun; Hardesty, Mike; Herndon, Scott C; Lauvaux, Thomas; Lavoie, Tegan; Lyon, David; Newberger, Tim; Pétron, Gabrielle; Rella, Chris; Smith, Mackenzie; Wolter, Sonja; Yacovitch, Tara I; Tans, Pieter

2015-07-07

We present estimates of regional methane (CH4) emissions from oil and natural gas operations in the Barnett Shale, Texas, using airborne atmospheric measurements. Using a mass balance approach on eight different flight days in March and October 2013, the total CH4 emissions for the region are estimated to be 76 ± 13 × 10(3) kg hr(-1) (equivalent to 0.66 ± 0.11 Tg CH4 yr(-1); 95% confidence interval (CI)). We estimate that 60 ± 11 × 10(3) kg CH4 hr(-1) (95% CI) are emitted by natural gas and oil operations, including production, processing, and distribution in the urban areas of Dallas and Fort Worth. This estimate agrees with the U.S. Environmental Protection Agency (EPA) estimate for nationwide CH4 emissions from the natural gas sector when scaled by natural gas production, but it is higher than emissions reported by the EDGAR inventory or by industry to EPA's Greenhouse Gas Reporting Program. This study is the first to show consistency between mass balance results on so many different days and in two different seasons, enabling better quantification of the related uncertainty. The Barnett is one of the largest production basins in the United States, with 8% of total U.S. natural gas production, and thus, our results represent a crucial step toward determining the greenhouse gas footprint of U.S. onshore natural gas production.

Natural pet food: a review of natural diets and their impact on canine and feline physiology.

PubMed

Buff, P R; Carter, R A; Bauer, J E; Kersey, J H

2014-09-01

The purpose of this review is to clarify the definition of "natural" as it pertains to commercial pet food and to summarize the scientific findings related to natural ingredients in pet foods and natural diets on the impact of pet health and physiology. The term "natural," when used to market commercial pet foods or pet food ingredients in the United States, has been defined by the Association of American Feed Control Officials and requires, at minimum, that the pet food be preserved with natural preservatives. However, pet owners may consider natural as something different than the regulatory definition. The natural pet food trend has focused on the inclusion of whole ingredients, including meats, fruits, and vegetables; avoiding ingredients perceived as heavily processed, including refined grains, fiber sources, and byproducts; and feeding according to ancestral or instinctual nutritional philosophies. Current scientific evidence supporting nutritional benefits of natural pet food products is limited to evaluations of dietary macronutrient profiles, fractionation of ingredients, and the processing of ingredients and final product. Domestic cats select a macronutrient profile (52% of ME from protein) similar to the diet of wild cats. Dogs have evolved much differently in their ability to metabolize carbohydrates and select a diet lower in protein (30% of ME from protein) than the diet of wild wolves. The inclusion of whole food ingredients in natural pet foods as opposed to fractionated ingredients may result in higher nutrient concentrations, including phytonutrients. Additionally, the processing of commercial pet food can impact digestibility, nutrient bioavailability, and safety, which are particularly important considerations with new product formats in the natural pet food category. Future opportunities exist to better understand the effect of natural diets on health and nutrition outcomes and to better integrate sustainable practices in the production of natural pet foods.

American Indian Systems for Natural Resource Management.

ERIC Educational Resources Information Center

Quintana, Jorge O.

1992-01-01

Outlines the philosophy and general principles of "primitive" indigenous production technologies and natural resource management systems in North and South America. Discusses indigenous practices that promote sustainable production in gathering, hunting and fishing, minerals extraction, and agriculture. (SV)

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

PubMed Central

Tran, Anh T.; Watson, Emma E.; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J.; Giltrap, Andrew M.; Pang, Angel; Wong, Weng Ruh; Linington, Roger G.; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A.; West, Nicholas P.; Bugg, Timothy D. H.; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Crick, Dean C.; Britton, Warwick J.; Payne, Richard J.

2017-01-01

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis. PMID:28248311

Enzymatic Reductive Dehalogenation Controls the Biosynthesis of Marine Bacterial Pyrroles.

PubMed

El Gamal, Abrahim; Agarwal, Vinayak; Rahman, Imran; Moore, Bradley S

2016-10-12

Enzymes capable of performing dehalogenating reactions have attracted tremendous contemporary attention due to their potential application in the bioremediation of anthropogenic polyhalogenated persistent organic pollutants. Nature, in particular the marine environment, is also a prolific source of polyhalogenated organic natural products. The study of the biosynthesis of these natural products has furnished a diverse array of halogenation biocatalysts, but thus far no examples of dehalogenating enzymes have been reported from a secondary metabolic pathway. Here we show that the penultimate step in the biosynthesis of the highly brominated marine bacterial product pentabromopseudilin is catalyzed by an unusual debrominase Bmp8 that utilizes a redox thiol mechanism to remove the C-2 bromine atom of 2,3,4,5-tetrabromopyrrole to facilitate oxidative coupling to 2,4-dibromophenol. To the best of our knowledge, Bmp8 is first example of a dehalogenating enzyme from the established genetic and biochemical context of a natural product biosynthetic pathway.

Sansanmycin natural product analogues as potent and selective anti-mycobacterials that inhibit lipid I biosynthesis

NASA Astrophysics Data System (ADS)

Tran, Anh T.; Watson, Emma E.; Pujari, Venugopal; Conroy, Trent; Dowman, Luke J.; Giltrap, Andrew M.; Pang, Angel; Wong, Weng Ruh; Linington, Roger G.; Mahapatra, Sebabrata; Saunders, Jessica; Charman, Susan A.; West, Nicholas P.; Bugg, Timothy D. H.; Tod, Julie; Dowson, Christopher G.; Roper, David I.; Crick, Dean C.; Britton, Warwick J.; Payne, Richard J.

2017-03-01

Tuberculosis (TB) is responsible for enormous global morbidity and mortality, and current treatment regimens rely on the use of drugs that have been in use for more than 40 years. Owing to widespread resistance to these therapies, new drugs are desperately needed to control the TB disease burden. Herein, we describe the rapid synthesis of analogues of the sansanmycin uridylpeptide natural products that represent promising new TB drug leads. The compounds exhibit potent and selective inhibition of Mycobacterium tuberculosis, the etiological agent of TB, both in vitro and intracellularly. The natural product analogues are nanomolar inhibitors of Mtb phospho-MurNAc-pentapeptide translocase, the enzyme responsible for the synthesis of lipid I in mycobacteria. This work lays the foundation for the development of uridylpeptide natural product analogues as new TB drug candidates that operate through the inhibition of peptidoglycan biosynthesis.