Dillapiol is a naturally occurring methylenedioxyphenyl compound with insecticide-synergizing activity comparable to piperonyl butoxide (PBO). This study identified structurally related molecules with practical potential for managing insecticide-resistant insects. Six new dillapiol analogs, containing ester- or ether-linked side chains, were synthesized and evaluated as pyrethrum synergists against the Colorado potato beetle (CPB) Leptinotarsa decemlineata (Say) (Coleoptera: Chrysomelidae). Their activity was assessed through bioassays and by quantifying inhibition of Phase I and II detoxification enzymes in vitro and in vivo. All six compounds displayed higher synergistic activity by ingestion than by topical exposure, and each structural class included at least one compound with a synergism ratio greater than 20. In the resistant CPB strain (RS-CPB), two ester compounds inhibited P450 monooxygenase activity in vitro as effectively as PBO, while dillapiol and one ether analog reduced P450 activity in vivo. Notably, all six analogs reduced glutathione S-transferase (GST) activity; the most active was an ether analog with an in vitro IC50 of 0.23 (±0.04) mM. Dillapiol also significantly reduced GST activity in vivo. These analogs demonstrated PBO-equivalent P450 inhibition combined with unique GST inhibition and show promise as alternative synergists for managing insecticide-resistant insects.

Epigenetic mechanisms such as microRNA (miRNA) deregulation seem to exert a central role in breast cancer initiation and progression. Therefore, targeting epigenetics deregulation may be an effective strategy for preventing and halting carcinogenesis. Studies have revealed the significant role of naturally occurring polyphenolic compounds derived from fermented blueberry fruits in cancer chemoprevention by modulation of cancer stem cell development through the epigenetic mechanism and regulation of cellular signaling pathways. In this study, we first investigated the phytochemical changes during the blueberry fermentation process. Fermentation favored the release of oligomers and bioactive compounds such as protocatechuic acid (PCA), gallic acid, and catechol. Next, we investigated the chemopreventive potentials of a polyphenolic mixture containing PCA, gallic acid, and catechin found in fermented blueberry juice in a breast cancer model by measuring miRNA expression and the signaling pathways involved in breast cancer stemness and invasion. To this end, 4T1 and MDA-MB-231 cell lines were treated with different doses of the polyphenolic mixture for 24 h. Additionally, female Balb/c mice were fed with this mixture for five weeks; two weeks before and three weeks after receiving 4T1 cells. Mammosphere formation was assayed in both cell lines and the single-cell suspension obtained from the tumor. Lung metastases were counted by isolating 6-thioguanine-resistant cells present in the lungs. In addition, we conducted RT-qPCR and Western blot analysis to validate the expression of targeted miRNAs and proteins, respectively. We found a significant reduction in mammosphere formation in both cell lines treated with the mixture and in tumoral primary cells isolated from mice treated with the polyphenolic compound. The number of colony-forming units of 4T1 cells in the lungs was significantly lower in the treatment group compared to the control group. miR-145 expression significantly increased in the tumor samples of mice treated with the polyphenolic mixture compared to the control group. Furthermore, a significant increase in FOXO1 levels was noted in both cell lines treated with the mixture. Overall, our results show that phenolic compounds found in fermented blueberry delay the formation of tumor-initiating cells in vitro and in vivo and reduce the spread of metastatic cells. The protective mechanisms seem to be related, at least partly, to the epigenetic modulation of mir-145 and its signaling pathways.

Traditionally the role of phytochemistry in the ethnopharmacology of North and Central America has been to characterize plant materials so that they can be produced reproducibly for commercial use or to identify active principles in unstudied traditional medicines for drug discovery. With new decolonial objectives coming from Indigenous communities, emphasis has shifted to evaluating the safety and efficacy of traditional medicines and preparations for community use. With new techniques and technologies available, scientific focus has shifted from individual bioactives to more rapid and comprehensive chemical characterizations and polypharmacy of traditional medicines. Untargeted metabolomics and associated statistical treatments have greatly expanded identification of components, improved species and cultivar identification and provided means for identifying multiple activity biomarkers, via chemometric and biochemometric analysis. New integrated techniques are available for identifying multiple active principles and synergists. The recent explosion of information is not without problems that need to be addressed including many unconfirmed tentative identifications of phytochemicals, lack of quantitative testing, superficial chemical activity testing and continuing need for dereplication.

Brian Foster, PhD, who made many contributions to Natural Health Product Research in the area of herb-drug interactions, passed away at his home in Nordegg, AB, on Friday, October 15, 2021, at the age of 69 years. Brian is survived by his wife Deborah Lynn Foster (Cheple) and daughter Meredith.

An ethnopharmacological metanalysis was conducted with a large database available on antidiabetic activities of plant foods and medicines from the northern boreal forest, which are traditionally used by the indigenous Cree of James Bay, Quebec, Canada. The objective was to determine which bioassays are closely associated with the traditional knowledge of the Cree and which pharmacological metrics and phytochemical signals best define these plants and their groups. Data from 17 plant species, ethnobotanically ranked by syndromic importance value for treatment of 15 diabetic symptoms, was used along with 49 bioassay endpoints reported across numerous pharmacological studies and a metabolomics dataset. Standardized activities were separated into primary, secondary and safety categories and summed to produce a Pharmacological Importance Value (PIV) in each of the three categories for each species. To address the question of which pharmacological metrics and phytochemical signals best define the CEI anti-diabetes plants, multivariate analyses were undertaken to determine groupings of plant families and plant parts. The analysis identified Larix larcina as the highest PIV species in primary assays, Salix planifolia in secondary assays, and Kalmia angustifolia in safety assays, as well as a ranking of other less active species by PIV. Multivariate analysis showed that activity in safety PIV monitored mainly with cytochrome P450 inhibition patterns best reflected patterns of traditional medicine importance in Cree traditional knowledge, whereas potent primary bioactivities were seen in individual plants determined to be most important to the Cree for anti-diabetes purposes. In the secondary anti-diabetes assays, pharmacological variability was better described by plant biology, mostly in terms of the plant part used. Key signal in the metabolomics loadings plots for activity were phenolics especially quercetin derivatives. Traditional Indigenous knowledge in this analysis was shown to be able to guide the identification of plant pharmacological qualities in scientific terms.

This review describes an Indigenous-led project run by Q’eqchi’ Maya Healers of Belize meant to strengthen and improve traditional botanical healing. The goals of this project were to conserve medicinal plant knowledge by way of ethnobotanical studies, and to conserve the plants themselves by creating a community ethnobotanical garden. A total of 169 medicinal species were collected in the ethnobotanical survey, which provided unique knowledge on many rainforest species of the wet lowland forest of southern Belize, not found in neighbouring Indigenous cultures. Consensus on plant uses by the Healers was high, indicating a well-conserved, codified oral history. After horticultural experimentation by the Healers, the Indigenous botanical garden provided a habitat for and conservation of 102 medicinal species including many epiphytes that were rescued from forested areas. Ethnopharmacological studies by the university partners showed a pharmacological basis for, and active principles of, plants used for epilepsy and anxiety, for inflammatory conditions such as arthritis, for dermatological mycoses, and for type 2 diabetes complications. Overall, the project has provided a model for Indigenous empowerment and First Nation’s science, as well as establishing traditional medicine as an important, unified healing practice that can safely and effectively provide primary health care in its cultural context.

The 17th Annual Natural Health Products Research Conference hosted by the NHP Research Society of Canada (NHPRS) will be held from June 7-9 & 14-16, 2021, virtually hosted by the University of Ottawa, in Ottawa, Ontario. Founded in 2003 by a collaboration of academic, industry, and government researchers from across Canada, the NHPRS is a Canadian federally incorporated non-profit organization. The goals of the NHPRS are; (a) to promote scientifically rigorous research and education on natural health products (NHPs), (b) to develop a national research community that encompasses academic, health professional, government and a broad-base of industry stakeholders, (c) to support national research priorities that best enable the informed and appropriate use of NHPs that are safe and efficacious, (d) to increase the capacity for NHP research and education, (e) to facilitate effective NHP knowledge transfer and translation, (f) to support the use of science-based product quality standards and the use of well-characterized materials and protocols in research and (g) to foster value-chain development through interdisciplinary NHP research collaborations and networking. To forward these objectives, the NHPRS has held annual research conferences since inception with themes that highlight the important trends in the ever growing and changing field of NHP Research. The theme of the 17th Annual Conference is “Canada and the Changing Global NHP Landscape” , featuring six "live" sessions (Global Stewardship and Sustainability, NHPs in the Time of the Pandemic, Indigenous Traditional Medicine, Global Advances in NHP Research, NHPs in Clinical Practice and Research, and Regulation, Policy, Commerce) and contributed sessions on topics such as cancer, cannabis, functional foods. natural product chemistry, and more. The abstracts are ordered alphabetically by presenting author last name, divided by topic sessions. For more information, please visit: http://www.nhprs.ca/.

Historical ethnobotanies of indigenous peoples of the North American prairies reveal treatment of many painful conditions by Echinacea spp. Recent evidence suggests a pharmacological basis for such use as the bioactivity of E. angustifolia and E. purpurea is mediated, in part, through activation of the endocannabinoid system (ECS). Whereas the cannabimimetic effects of individual echinacea products and alkylamides have been described, the activity of crude extracts has not been compared between cannabinoid (CB) receptors or across species or genotypes. Moreover, few studies have explored echinacea's engagement of the ECS for historic treatments or new therapeutic applications in peripheral inflammatory pain. We hypothesized that 1) the in vitro effects of root extracts on CB receptor internalization would vary with species and phytochemistry, and that echinacea root extracts would reduce inflammatory pain in vivo through activation of the ECS. Root extracts of different E. angustifolia and E. purpurea accessions were prepared, analyzed by HPLC-DAD to quantify caffeic acid derivatives and alkylamides (AKA), and tested for agonist and antagonist activities using receptor redistribution assays. Linear regression of activity relative to phytochemistry identified predictive compounds that were assessed individually in redistribution assays. Extracts were evaluated in the Hargreaves model of chronic inflammatory pain in rats with co-administration of selective CB1/2 antagonists to gauge involvement of the ECS. CB receptor agonist activity varied among accessions of both species with linear regression revealing a significant relationship between CB1 activity and AKA2 for E angustifolia, and AKA 9 + 10 for E purpurea. CB2 activity was positively related with AKA 9 + 10 and total AKAs in E. angustifolia. Four isolated AKA demonstrated agonist activity in the CB2, but not CB1, assay. In the inflammatory pain model, oral administration of either E angustifolia or E. purpurea root extract produced dose-dependent analgesic effects that were partially reversed by co-administration of CB receptor antagonists. This study demonstrates that in vitro effects of crude echinacea root extracts on CB receptors is predicted by phytochemistry. In vivo, echinacea has potential applications for peripheral inflammatory pain such as arthritis and burns, reflecting the traditional uses of Indigenous North Americans.

A novel botanical dietary supplement, formulated as a chewable tablet containing a defined mixture of Souroubea spp. vine and Platanus spp. Bark, was tested as a canine anxiolytic for thunderstorm noise-induced stress (noise aversion). The tablet contained five highly stable triterpenes and delivered 10 mg of the active ingredient betulinic acid (BA) for an intended 1 mg/kg dose in a 10 kg dog. BA in tablets was stable for 30 months in storage at 23 °C. Efficacy of the tablets in reducing anxiety in dogs was assessed in a blinded, placebo-controlled study by recording changes in blood cortisol levels and measures of behavioral activity in response to recorded intermittent thunder. Sixty beagles were assigned into groups receiving: placebo, 0.5×, 1×, 2×, and 4× dose, or the positive control (diazepam), for five days. Reduction in anxiety measures was partially dose-dependent and the 1× dose was effective in reducing inactivity time (p = 0.0111) or increased activity time (p = 0.0299) compared with placebo, indicating a decrease in anxiety response. Cortisol measures also showed a dose-dependent reduction in cortisol in dogs treated with the test tablet.

Antipredation strategies contribute to the lifetime reproductive success of organisms, particularly in more vulnerable life stages that look to survive until reproduction. In insects, eggs and larval stages are often immobile or unable to rapidly flee and hide from predators. Understanding what alternative antipredation strategies they use, but also how these change over development time, is required to fully appreciate how species adapt to biotic threats. Murgantia histrionica is a stink bug, conspicuously colored from egg to adult, known to sequester defensive glucosinolates from its cruciferous hosts as adults. We sought to assess whether this chemical defense is also present in its eggs and early nymphal instars and quantified how it fluctuates among life stages. In parallel, we looked at an alternative antipredation strategy, described for the first time in this species: tonic immobility (i.e., death feigning). We also qualitatively investigated ultraviolet reflectance in eggs and adults as a proxy of conspicuousness against UV-absorbing leaves. Our results show that the eggs are significantly more chemically defended than the first two but not third mobile life stages, yet compound concentrations do not statistically differ across nymphal instars. Tonic immobility is favored by hatchlings, but less so by subsequent instars. Eggs also had obvious ultraviolet reflectance, suggesting that they would contrast against a leaf substrate and, considering their chemical load, that they may be aposematic. We argue that there are two possible interpretations of our results. One is that, throughout ontogeny, tonic immobility is a useful defensive strategy until adequate chemical protection is achieved over an extended feeding period. The other is that both aposematism and tonic immobility are used by this species, but variation in strategy use throughout ontogeny is decoupled.

The Maya employed the k’an |K’AN| glyph in Late Classic (~750 CE) hieroglyphs on murals and polychrome pottery as an adjective meaning precious, yellow. On cacao drinking vessels, the k’an glyph was suggested as a descriptor for a flavoring ingredient, allspice, Pimenta dioica (L.) Merr. (Myrtaceae). However, our previous consensus ethnobotanical fieldwork with Q’eqchi’ Maya healers of Belize revealed another candidate among antidiabetic plants, Tynanthus guatemalensis Donn. Sm. (Bignoniaceae), which was the healers’ top selection for treatment of diabetes and an exceptionally active extract in an antidiabetic assay for inhibition of protein glycation. Traits of T. guatemalensis observed after cross sectioning the liana were: (1) a cross-shaped xylem organization similar to the k’an glyph; (2) an allspice-like aroma; and (3) yellow color. Based on taxonomy and ethnobotany, confirmation of the allspice-like aromatic compound eugenol, and antidiabetic activity, we determined the plant described by the k’an glyph to be T. guatemalensis (chib’ayal in Q’eqchi’), not P. dioica (allspice). In contemporary Q’eqchi’ tradition, the section of the chib’ayal vine with its cross is associated with the eighth day of their Tzolk’in calendar, which is called the “nawal” (energy) of “q’anil” (ripe, full yellow). This day is represented with a different glyph from the k’an glyph, but notably has a cross representing the four cardinal points. The identification of a potent medicinal plant used in the late classic as well as contemporary times may suggest the long-term preservation of traditional medicinal knowledge in Maya culture for pharmacologically significant plants.

INTRODUCTION: A protocol for the in vitro culture of the anxiolytic medicinal plant Souroubea sympetala (Marcgraviaceae) was developed, representing one of the first in vitro cultures for the family. This species was previously very difficult to cultivate from seed or cuttings. METHODS: Methods included (1) the improvement of seed germination by axenic culture (2) development of regenerative cultures in vitro, then cultivation under greenhouse and finally field conditions and (3) creation of cell suspensions. Phytochemical analysis was undertaken by liquid chromatography coupled to mass spectrometry (HPLC-MS). RESULTS: The percentage of seed germination was improved from 2% to 59% in axenic culture and the full development of the seedling with its apical shoot and root took twenty-four days. The best seedling development was obtained in Gamborg B5 culture medium. Most friable callus formation, (66.7%) was obtained in the Murashige and Skoog medium supplemented with naphthalene acetic acid (1 mg · L–1) and kinetin (0.5 mg · L–1) from which viable cell cultures were developed. Analysis identified 4 main triterpenes with both in vitro plants and greenhouse grown plants derived from them. The triterpenes were betulinic acid, ursolic acid, alpha-amyrin and beta-amyrin. The betulinic acid found in greenhouse plants was comparable to wild plants. The cell suspension cultures had much lower levels of betulinic acid than plants and are not at present a viable source of this anxiolytic triterpene. DISCUSSION: The improvement in seed germination of this recalcitrant tropical species was highly successful. The subsequent in vitro propagation and progression of plants through greenhouse and field conditions to provide mature plants with active principle concentrations comparable to wild plants was promising. Friable callus was achieved but phytochemical analysis showed that the level of betulinic acid in callus was much lower than that found in mature plant tissue. CONCLUSION: The method provides healthy plants for cultivation of this new medicinal plant and consequently harvesting of wild plants is not required.

Recent research demonstrates that Echinacea possesses cannabimimetic activity with potential applications beyond common contemporary uses for relief of cold and flu symptoms. In this study, we investigated the in vitro inhibitory effect of root extracts of Echinacea purpurea and Echinacea angustifolia on fatty acid amide hydrolase, the main enzyme that degrades the endocannabinoid anandamide. The objective was to relate variation in bioactivity between commercial Echinacea genotypes to their phytochemical profiles and to identify determinants of activity using biochemometric analysis. Forty root extracts of each of species were tested for inhibition of fatty acid amide hydrolase and analyzed by HPLC-DAD/MS to identify and quantitate alkylamides and caffeic acid derivatives. Fatty acid amide hydrolase inhibition ranged from 34-80% among E. angustifolia genotypes and from 33-87% among E. purpurea genotypes. Simple linear regression revealed the caffeic acid derivatives caftaric acid and cichoric acid, and the alkylamide dodeca-2 E ,4 Z -diene-8,10-diynioc acid 2-methylbutylamide, as the strongest determinants of inhibition in E. purpurea (r*=0.53, 0.45, and 0.20, respectively) while in E. angustifolia , only CADs were significantly associated with activity, most notably echinacoside (r*=0.26). Regression analysis using compound groups generated by hierarchical clustering similarly indicated that caffeic acid derivatives contributed more than alkylamides to in vitro activity. Testing pure compounds identified as determinants of activity revealed cichoric acid (IC (50) =45 +/- 4 mu M) and dodeca-2 E ,4 E ,8 Z ,10 E -tetraenoic acid isobutylamide (IC (50) =54 +/- 2 mu M) as the most active. The results suggest that several phytochemicals may contribute to Echinaceas cannabimimetic activity and that ample variation in genotypes exists for selection of high-activity germplasm in breeding programs.

Modern Natural Health Products (NHPs) are medicinal dosage forms also known and regulated variously as Dietary Supplements, Phytomedicines and Complementary and Alternative Medicines in different countries. Related regulated food products include Medicinal Foods, Supplemented Foods, Functional Foods, and Nutraceuticals, while cannabis products are regulated separately. All of the above are derived from or inspired by natural products that have existed for millennia. Most have been developed through ancient medical systems (e.g. Traditional Chinese Medicine and Ayurveda) and distinct indigenous cultures, which combine worldview, beliefs, practices, into “ways of knowing”. Others were identified or advanced through scientific discovery and biotechnology. Together, they have contributed—and will continue to contribute—to human health and economy at a global scale.

Extraction of plants for drug discovery, ethnopharmacology or application as nutraceuticals and natural health products (NHPs; also known as dietary supplements, phytomedicines and complementary and alternative medicines) is described for scientists new to the field. Primary identification and handling of plant material for extraction is a key first step. Simple solvent extractions are described with routine procedures in the lab to produce crude extracts for bioassay screening or industrial use. Specialized methods targeting specific groups of compounds but rarely producing pure compounds can also be used. These methods include soxhlet, accelerated solvent, subcritical water, supercritical CO2, ultrasound, microwave, countercurrent, steam distillation and other technologies. Ultimately, researchers must identify the active principles and/or unique marker compounds in their extracts and this is accomplished by bioassay guided isolation or newer metabolomics methods. Once bioactive compounds are identified, standardized products can be produced that are reproducible and can be compared to clinically tested materials.

ADVERTISEMENT RETURN TO ISSUEEditorialNEXTSpecial Issue in Honor of Professor Rachel MataJohn T. ArnasonJohn T. ArnasonDepartment of Biology, University of Ottawa, Ottawa, CanadaMore by John T. Arnasonhttp://orcid.org/0000-0001-5354-5715, Mario FigueroaMario FigueroaFacultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, MéxicoMore by Mario Figueroahttp://orcid.org/0000-0001-7004-0591, Rogelio Pereda-MirandaRogelio Pereda-MirandaFacultad de Química, Universidad Nacional Autónoma de México, Ciudad de México, MéxicoMore by Rogelio Pereda-Mirandahttp://orcid.org/0000-0002-0542-0085, and Nicholas H. OberliesNicholas H. OberliesUniversity of North Carolina at Greensboro, Greensboro, North Carolina, United StatesMore by Nicholas H. Oberlieshttp://orcid.org/0000-0002-0354-8464Cite this: J. Nat. Prod. 2019, 82, 3, 423–424Publication Date (Web):March 22, 2019Publication History Published online22 March 2019Published inissue 22 March 2019https://pubs.acs.org/doi/10.1021/acs.jnatprod.9b00067https://doi.org/10.1021/acs.jnatprod.9b00067editorialACS PublicationsCopyright © 2019 American Chemical Society and American Society of Pharmacognosy. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views1234Altmetric-Citations-LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail PDF (1 MB) Get e-AlertscloseSUBJECTS:Fungi,Inhibitors,Pharmaceuticals Get e-Alerts

A new anti-anxiety dietary supplement was developed for the animal health market, by combining 2 triterpene containing botanicals, Souroubea sympetala (Marcgraviaceae) with Platanus occidentalis (Platanaceae) A validated method for a quality control of the botanical blend was achieved using HPLC-APCI-MS. The method resulted in the detection and quantitative determination of betulinic acid (1), and ursolic acid (2) in P. occidentalis and 1, 2, lupeol (3), β-amyrin (4) and α-amyrin (5) in S. sympetala and the finished product Zentrol TM . Detections were at low ng on column for 1 and 2 and in low μg range for 3, 4 and 5 using calibration curves within 10-100 ng (R 2 > 0.993). Recovery of spiked samples for all the recoveries observed were > 94%. Inter-day and intra-day variations were 0.8-3.5% and 5-10.4%, respectively. These results indicate the suitability of the developed analytical method to detect and quantify triterpenes of raw materials used in the manufacture of natural health products.