Botanical Dietary Supplements for Women's Health: 1999-2020

Results in NIHReporter  


Principal Investigator: Norman R. Farnsworth, Ph.D.
Institution: University of Illinois at Chicago, Chicago, IL

Starting with this initial project, the UIC Botanical Center focused on the establishment of rationales and methodologies for the parallel chemical and biological standardization of botanicals. This new paradigm was introduced in 1999 and its validity has been substantiated through the subsequent project cycles. The work in the first project period followed four lines of research: rigorous characterization of botanical quality; broad biological assessment of botanical extracts and their constituents; evaluation of the pharmacokinetics of botanicals; and clinical investigation of rigorously standardized botanical materials. Research projects included: Standardization of botanical dietary supplements; Estrogenic agents and bioassay development: in vitro and in vivo evaluation; In vitro studies of metabolism, absorption and toxicity, and a clinical evaluation group.

Highlighted Publications:

Chadwick L, Fröhlich R, Chen S, Bolton J, van Breemen R, Overk C, Burdette J, Nikolic D, Fong H, Farnsworth N, Pauli GF. Estrogens and congeners from hops (Humulus lupulus). J Nat Prod. 2004 Dec;67(12):2024-32. doi: 10.1021/np049783i.external link disclaimer
Established the diverse chemical space of the phytoestrogen 8-prenylnaringenin and its prenylchalcone and prenylflavanone congeners.

Dietz B, Kang YH, Liu G, Eggler A, Yao P, Chadwick L, Pauli GF, Farnsworth NR, Mesecar A, van Breemen R, Bolton J. Xanthohumol Isolated from Humulus lupulus inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol. 2005 Aug;18(8):1296-305. doi: 10.1021/tx050058x.external link disclaimer
Developed an additional set of key rationales for the biological profiling of hops with regard to their chemopreventive properties; later work linked these outcomes to potential health benefits in aging females.

Nikolic D, Li Y, Chadwick L, Pauli GF, van Breemen R. Metabolism of xanthohumol and isoxanthohumol, prenylated flavonoids from hops, in human liver microsomes. J Mass Spectrom. 2005 Mar;40(3):289-99. doi: 10.1002/jms.753external link disclaimer.
Demonstrated the impact of pharmacokinetic chemical conversion reactions on the formation of active species of the bioactive markers in hops.

Overk C, Yao P, Chadwick L, Cuendet M, Fong HHS, Pauli GF, Farnsworth NR, Bolton J. Comparison of the in vitro estrogenic activities of purified compounds from hops (Humulus lupulus) and red clover (Trifolium pratense). J Agric Food Chem. 2005 Aug 10;53(16):6246-53. doi: 10.1021/jf050448p.external link disclaimer
Provided key rationales for the subsequent biological standardization of botanicals for their phytoesterogenic properties.


Principal Investigator: Norman R. Farnsworth, Ph.D.
Institution: University of Illinois at Chicago, Chicago, IL

The Center focused on several botanical ingredients used in herbal supplements that have potential benefits for women’s health, particularly for the alleviation of symptoms of menopause. The researchers used in vitro and in vivo bioassays to investigate mechanisms of action. Active constituents were then identified and the botanical products standardized accordingly. The Center’s clinical team conducted initial Phase I trials that culminated in a Phase II clinical trial of black cohosh (Cimicifuga racemosa) and red clover (Trifolium pratense), and also conducted a Phase I study of hops (Humulus lupulus). In addition to conducting basic and clinical research, the UIC group supported research training in pharmacognosy (the study of drugs of natural origin). Research projects included: Standardization; Mechanisms of Action; and In Vitro and In Vivo Studies of Metabolism, Bioavailability, Toxicity.

Highlighted Publications:

Chen SN, Lankin D, Chadwick L, Jaki B, Pauli GF. Dynamic residual complexity of natural products by qHNMR: solution stability of desmethylxanthohumol. Planta Med. 2009 Jun;75(7):757-62. doi: 10.1055/s-0028-1112209.external link disclaimer Epub 2009 Jan 14.
Reported the previously unrecognized influence and the dynamics of the chemical mechanism of the instability of prenylchalcones and the formation of estrogenic flavanones.

Dietz B, Liu D, Hagos G, Schinkovitz A, Pro S, Deng S, Yao P, Farnsworth N, Pauli GF, van Breemen R, Bolton J. Angelica sinensis and its alkylphthalides induce the detoxification enzyme NAD(P)H:quinone oxidoreductase 1 by alkylating KEAP1. Chem Res Toxicol. 2008 Oct;21(10):1939-48. doi: 10.1021/tx8001274external link disclaimer. Epub 2008 Sep 23.
Developed new rationales for the explanation of potential health benefits from Dang Gui with regard to the detoxificaton of estrogen-related female metabolism and related it to the residually complex phthalide constituents of the plant.

Geller S, Shulman L, van Breemen R, Banuvar S, Epstein G, Hedayat S, Nikolic S, Krause E, Piersen C, Bolton J, Pauli GF, Farnsworth N. Safety and efficacy of black cohosh and red clover for the management of vasomotor symptoms. Menopause. Nov-Dec 2009;16(6):1156-66. doi: 10.1097/gme.0b013e3181ace49b.
Outcomes of a Phase II clinical trial with the following treatment arms: black cohosh and red clover extracts developed and standardized biologically and chemically in this Botanical Center; and equine steroidal estrogens as gold-standard hormone therapy.

Powell S, Goedecke T, Nikolic D, Chen S, Lankin D, Dietz B, Farnsworth N, von Breemen R, Pauli GF, Bolton J. Analysis of the in vitro serotonergic activity of black cohosh and identification of N(omega)-methylserotonin as bioactive constituent. J Agric Food Chem. 2008 Dec 24;56(24):11718-26. doi: 10.1021/jf803298zexternal link disclaimer.
First recognition of the CNS-related biological activities of black cohosh; sparked subsequent discoveries of nitrogen-containing phytoconstituents of Cimicifuga/Actaea racemosa.


Principal Investigator: Norman R. Farnsworth, Ph.D.
Institution: University of Illinois at Chicago, Chicago, IL

In this funding cycle, the UIC center focused on the safety of botanical dietary supplements that were widely available and used by women. The investigators studied the synergy of multicomponent mixtures and their mechanisms of action, metabolism and pharmacokinetics of botanical constituents, interactions with prescription drugs, and the impact of botanicals on the biological effects of endogenous estrogenic hormones. The Center continued its mission of training the next generation of pharmacognosists.  Research projects included: Metabolomic Characterization of Botanical Chemistry and Synergy; Botanical Modulation of Estrogen Carcinogenesis; and Metabolism, Safety and Efficacy.

Highlighted Publications:

Hajirahimkan A, Simmler C, Dong H, Lantvit D, Li G, Chen SN, Nikolic D, Pauli GF, van Breemen R, Bolton J. Induction of NAD(P)H:quinone oxidoreductase 1 (NQO1) by Glycyrrhiza species used for women’s health: differential effects of the Michael acceptors isoliquiritigenin and licochalcone A.Chem Res Toxicol. 2015 Nov 16;28(11):2130-41. doi: 10.1021/acs.chemrestox.5b00310.external link disclaimer Epub 2015 Nov 5.
Recognition of isoflavonones and chalcones as differential bioactive principles in various official licorice species, related to the detoxificaton of estrogen-related female metabolism. 

Nikolic D, Goedecke T, Chen SN., White J, Lankin D, Pauli GF, van Breemen R. Mass spectrometric dereplication of nitrogen-containing constituents of black cohosh (Cimicifuga racemosa L.). Fitoterapia. 2012 Apr;83(3):441-60. doi: 10.1016/j.fitote.2011.12.006external link disclaimer. Epub 2011 Dec 9. 
First structural description of the structurally diverse alkaloid metabolome of black cohosh.

Ramos Alvarenga R, Friesen JB, Nikolic D, Simmler C, Napolitano J, van Breemen R, Lankin D, McAlpine J, Pauli GF, SN Chen. K-targeted metabolomic profiling extends chemical subtraction to DESIGNER extracts: selective depletion of extracts of hops (Humulus lupulus). J Nat Prod. 2014 Dec 26;77(12):2595-604. doi: 10.1021/np500376gexternal link disclaimer. Epub 2014 Dec 1.
Introduced the concept of knock-out DESIGNER extracts as a new tool for botanical research.

van Breemen R, Yuan Y, Banuvar S, Shulman L, Qiu Z, Ramos Alvarenga R, Chen SN, Dietz B, Bolton B, Pauli GF, Krause E, Viana M, Nikolic D. Pharmacokinetics of prenylated hop phenols in women following oral administration of a standardized extract of hops. Mol Nutr Food Res. 2014 Oct;58(10):1962-9. doi: 10.1002/mnfr.201400245external link disclaimer. Epub 2014 Sep 16.
Elucidation of the pharmacokinetic impact of hops prenylchalcone and prenylflavanone profiles.


Principal Investigators: Guido F. Pauli, Ph.D. and Richard B. van Breemen, Ph.D.
Institution:  University of Illinois at Chicago, Chicago, IL
Website: link disclaimer

This Center focused on the safety and mechanisms of action of botanicals used by American women to maintain health and quality of life, especially during menopause. The team built on their prior work focusing on the safety of commonly used botanical dietary supplements such as black cohosh, hops, and licorice, and their effects on estrogenic hormone action. In this award period, the team advanced its ground-breaking work on the characterization and standardization of complex botanical products, as well as on the interactions of those products with estrogens and prescription drugs, with a continuing focus on botanical safety, as well as on training the next generation of transdisciplinary botanical experts.

Highlighted Publications:

Dietz B, Chen SN, Ramos Alvarenga R, Dong H, Nikolic D, Biendl M, van Breemen R, Bolton J, Pauli G. DESIGNER botanical extracts as tools to balance estrogenic and chemopreventive activities and optimize women’s health. J Nat Prod. 2017 Aug 25;80(8):2284-2294. doi: 10.1021/acs.jnatprod.7b00284external link disclaimer. Epub 2017 Aug 16.
Knock-out extract methodology used to show the presence of multifaceted biological interactions of active principles (“synergy”) in botanicals.

van Breemen R, Chen L, Tonsing-Carter A, Banuvar S,  Barengolts E, Viana M, Chen SN, Pauli G, Bolton J. Pharmacokinetic interactions of a hop dietary supplement with drug metabolism in perimenopausal and postmenopausal women. J Agric Food Chem. 2020 May 6;68(18):5212-5220. doi: 10.1021/acs.jafc.0c01077external link disclaimer. Epub 2020 Apr 24.
Clinical study of herb drug interactions that demonstrated safety of the investigated hops product developed in the Botanical Center.

Yu Y, Pauli G, Huang L, Gan LS, van Breemen R, Li D, McAlpine J, Lankin D, Chen SN. Classification of flavonoid metabolomes via data mining and quantification of hydroxyl NMR signals. Anal Chem. 2020 Apr 7;92(7):4954-4962. doi: 10.1021/acs.analchem.9b05084external link disclaimer. Epub 2020 Mar 26.
Demonstration of the feasibility of performing multi-targeted metabolomic standardization without the need for authentic reference materials, shown for the three official licorice species.

Prior CARBON Awards | NIH CARBON Program