Ethnopharmacology is a branch of science which integrates traditional herbal medicine and modern scientific analysis. This article shares how it has been used to give a deeper understanding of traditional Chinese medicine.
This article was first written for the Register of Chinese Herbal Medicine and has been copied with permission.
The focus of this article is to provide background information to complement the information presented on the public interpretation sign in the new ethnopharmacology display bed within the Bristol Chinese Herb Garden. In particular, it is designed to provide some scientific evidence for statements made on the sign and to present the baseline for additional articles to be posted on the RCHM outreach website. What Is Ethnopharmacology?
There are several definitions depending on your area of work (1). The one I use is: The integrated study of traditional herbal medicine with modern scientific analysis. It is a deceptively simple definition which amalgamates a range of disciplines including botany, pharmacology, anthropology, and cultural medical systems of health and disease. As a recent branch of ethnobotany, it also incorporates the botanical identity, quality and sustainability of wild herb plants through conservation and cultivation. Unlike modern drugs which are standardised to a single chemical ingredient, the quality of a herb is variable as it depends on many factors such as how it is grown and processed.
The aim that lies behind this project is not only to draw together research from traditional herbal medicine and modern science, but to give equal emphasis to both. In this way we can understand the strengths and weakness of each. There is then potential to enter a real dialogue between European and Traditional Chinese Medicine (TCM). The integration of these two systems is currently a major part of the modernisation of TCM within China.
The living pharmacy collection
The ethnopharmacology collection has been given a particular emphasis. One of the most pressing medical needs currently is to counteract antibiotic drug resistance. We have decided with this collection to gather plants which have both a long-term traditional use, and also modern history of scientific research in this area of medicine. Although many are used in Chinese herbal medicine, the list includes plants from other herbal traditions. Some of the most important and hardy herbs are grouped together in a dedicated outside display bed and others are in other areas of the botanic garden. More tender herbs will be kept in the relevant zone of the greenhouse complex.
List of plants
Anti-bacterial/parasitic/cancer herbs
- Reynoutria japonica (hu zhang)
- Phellodendron japonica (huang bai)
- Mahonia fortunei (gong lao mu)
- Berberis vulgaris (berberis)
- Rheum palmatum (da huang)
- Salvia officinalis (sage)
- Salvia rosmarinus (rosemary)
- Thymus vulgaris (thyme)
- Melaleuca alternifolia (tea tree)
- Tanacetum vulgare (feverfew)
- Glycyrrhiza glabra (gan cao)
- Artemisia annua (qing hao)
- Isatis tinctorium (da qing ye/ ban lan gen)
- Nigella sativa (nigella seed)
- Scutellaria baicalensis (huang qin)
- Dryopteris crassirhizoma (guang zhong)
- Reynoutria multiflora (he shou wu)
- Morus alba (sang ye, sang bai pi, sang zhi, sang shen)
- Zingziber officinale (sheng jiang)
- Cinnamomum vernum (cinnamon)
- Curcuma longa (jiang huang)
- Geranium strictipes
- Arctostaphylos uva ursi (bearberry)
- Andrographis paniculata
- Pelargonium sidoides
- Coptis chinensis (huang lian)
Immune tonics (adaptogens)
- Astragaulus propquuinqus (syn membranaceus ) (huang qi)
- Schisandra chinensis (wu wei zi)
- Panax quinquefolius (xi yang shen)
The display board
Interpretation of such a complex subject is a much bigger challenge than simply explaining Chinese medicine as in the case of the ‘use class’ display. It has to be easily explained by the garden tour guides and also needs to satisfy the requirements for a leading university for accurate statements based on scientific validation. I have decided that the best approach is to isolate a few fundamental principles with examples. The background can then be enlarged through articles on the website which can be kept up to date with research papers when needed.
Principle 1: New drugs from old herbs
Around 40% of approved drugs during the last 30 years are derived from plants (4). Some studies have also indicated that of 122 plant derived drugs, 80% of their use in modern medicine was related to the same medical application used in the original traditional medicine (5). Herb plants from China and the far east are one of the richest regions for drug prospectors today (2,7). China has over 30,000 species of plant, of which 3000 have been claimed to have specific traditional medicinal use. The process of finding and testing the chemicals is a long and expensive process and funding has reduced considerably in developing new drugs from natural materials (1). However, there are several which show potential to assist with drug resistance (1,3).
In 1967 the Vietnamese army asked China to assist with persistent malaria in the troops. Herbs were sourced from traditional herbal medical texts. These texts are known as the ‘Ben Cao’ and are a major resource as documented records of herbal use for over 2000 years (6,8). They represent a long-term human clinical trial but without the control required by scientific RCT (random controlled trials). Traditional herbs which have been used for malaria symptoms were screened. The most effective was the herb Artemisia annua (qing hao) which first appeared in the Shen Nong Ben Cao written around 150AD. This led to the discovery of the drug artemisinin, as the main active anti-malarial component.
The sesquiterpene lactone (9,10,12) drug artemisinin has a unique and highly unstable structure due to the double bond trioxane group shown at the bottom of the molecule.
The effect of the trioxane bond is to oxidise iron to form toxic free radicals. The malaria parasite Plasmodium vivax survives by digesting the host’s haemoglobin. It is more sensitive to the free radicals than the human host cells and hence the parasite is killed, and the malaria halted. The drug also attacks in a second way at the same time to disrupt the DNA of the parasite. Artemisinin has also been found to kill the liver fluke parasite responsible for schistosomiasis which is second only to malaria as a parasitic killer in the tropics (16,17).
The effect on cancer cells is also interesting. Some cancer cells are also high in iron and are also damaged by the iron oxidising effects of artemisinin. Because artemisinin is so unstable, it proved very difficult and expensive to synthesise as a drug. New strains of Artemisia annua were cultivated with 20 times the content of artemisinin. Genetically modified yeast has also been developed, which manufacture the drug, making it less dependent on the plant source (13). It is often forgotten that chemical synthesis of drugs is an important factor in the conservation of the original wild herb plants which would otherwise be over-exploited.
As this was a new method of attack compared to the quinine drug, artemisinin was able to provide an effective treatment for the problem of drug resistance which had developed with quinine drugs and had fewer side effects compared to piperaquine alone. Initially the mortality rate was 30% lower compared to treatment with quinine (14,15).
Artemisinin is a very fast acting drug with a half-life of 1 hour, hence it is best used with a slow release drug to combat the parasite and prevent resistance. WHO guidelines now state that it should not be used on its own for this reason (18). Despite its initial dramatic Artemisia annua effect, drug resistance to artemisinin is becoming apparent (20). Adaptation is occurring.
There is no doubt that concentrated artemisinin as a drug is a more powerful antimicrobial than the herb. Artemisinin as a drug however, is not exactly the same as Artemisia annua the herb.
Artemisia annua also contains many other chemicals including the anti-inflammatory scopoletin, which could explain its ability to reduce fever. One of these other chemicals is a methylated flavonoid which increases the action of the artemisinin, although it does not actually kill the parasite itself. Could these play a part in its action in preventing drug resistance to artemisinin?
Principle 2: Chemical cocktails
A single herb plant has manufactured many chemicals which have evolved to enable growth and reproduction and to protect themselves from environmental stress. Plants have an immune system which can react within seconds to a predator to protect them from being eaten or resist disease pathogens such as virus or bacteria. As these pathogens have evolved new methods of attack, so the plant has manufactured new chemicals. But they also retain the old chemical defences creating a historical armoury and ability to act in several ways at the same time.
Bacteria and other pathogens that attack humans are not that different in structure than those that attack plants. They have similar cell walls and use similar methods to attack. Hence it is not surprising that they can also work for human pathogens.
One drug that has attracted research is the alkaloid berberine. This is a chemical found in many herbs used in most traditional medicine systems for treating infection and also the underlying inflammation. Examples include Phellodendron amurense, Coptis chinensis, Mahonia species, and Berberis species.
Isolated berberine alkaloids in pure form do have antimicrobial activity. When there are only a few bacteria they secrete a chemical that attracts other bacteria. However, when the bacterial colony reaches a certain size, they produce a different chemical which causes them to secrete a slimy biofilm over the entire bacterial colony. This alteration in response to bacterial population numbers is known as quorum sensing. Berberine is thought to destroy the biofilm protection defences by the bacteria. Berberine can also weaken the bacterial cell wall and enter the bacteria causing more damage. The bacteria have evolved a mechanism known as an ‘efflux pump’ which literally pumps the berberine back out. As a counter strategy the plant produces another chemical (5 methoxyhydnocarpin) which inhibits the action of the efflux pump.
One of the reasons that penicillin was so effective for so long was that it contains two lines of attack on the pathogen. When we subject a pathogen to a single attack, it is relatively easy for it to evolve a response. A simple attack promotes a simple evolutionary defence and drug resistance can develop more quickly. This may explain why plants have often developed diverse chemical strategies. These may include chemicals which can attack in more than one way, or a group of chemicals which can launch a complex attack or increase the action of each other.
Principle 3: Synergy – more than the sum of the parts
The ability for a mixture of chemicals to have a greater effect than ether on its own is termed synergy. We can see this in all the examples given but I would suggest that synergy is central to the action of all herbs and it is what distinguishes the action of a drug from that of a herb.
Synergy has been observed where a herb or extracted chemical from a herb is given at the same time as an antibiotic drug which has ceased to become effective as in drug resistance. The combination can be more powerful than either the herb alone or the antibiotic (38-47).
The root of Scutellaria baicalensis (huang qin) is a traditional Chinese herb that has been used for at least 200 years as a herb in the damp heat class (6,7,8). From a western perspective it has been employed for reducing fever, treating hepatitis and for infection in the lungs, bowel and bladder. The main active component has been isolated as the polyphenolic flavonoid drug baicalein. Phenolic compounds are often used as antimicrobial compounds (3).
Recently attention has been turned on the ability of baicalein to kill cancer cells. Drugs used in the treatment of cancer are also becoming less effective due to drug resistance by cancer cells (4-52). Baicalein as a drug has shown potent activity against pancreatic cancer cells, which are by nature fiercely resistant to cell death (21-24). It also has few side effects which is a bonus when treating this disease. The mechanism of action on cancer cells is multi layered. In this case 3 mechanisms have been found. It appears to decrease the ability of the cancer cells to produce a protein which enables the cancer cell to evade cell death. All cells, including cancer cells, have a programme which causes the cell to die. This is called apoptosis. Baicalein is causing this apoptosis programme to be triggered in the cancer cell. Finally, baicalein inhibits the fat metabolism pathway that enables proliferation of the cancer cells. In other words, this appears to be a highly sophisticated multi action weapon developed by the plant. Plants also suffer from cancer diseases.
Baicalein is also only 1 of 50 flavonoids in the plant which act more effectively if used together as opposed to a single drug extract (25-27). A whole extract of Scutellaria baicalensis has been demonstrated to resensitise drug resistant MRSA bacteria to become susceptible again to conventional antibiotic (26-31). The use of complex whole herb extracts at the same time as a lower dose of strong antibiotic drugs is a novel approach to antibiotic resistance. Synergy research has become a new development in the pharmaceutical industry so we may see a new approach developing in the future (38,39,40).
Principle 4: Regulate the immune system
All the above examples are focused on killing parasites. This is a natural way of approaching the problem. The battle between pathogens and host is as old as cellular life evolved and drug resistance is not a new event. The creation of concentrated antibiotics drugs has been a true life saver and the search for new antibiotic drugs with new strategies of attack will continue as it has done in plants.
However, if a person is weak then it is just as important to regulate the host immune system.
Herbal medicine does not have the same power to deal with acute infection, but it does have a potential role in long-term balancing of the immune system. Within the Chinese materia medica there are herbs which are traditionally used to strengthen the immune system.
One key herb is Astragalus propinquus (huang qi). Over 100 chemicals have been isolated from this herb including polysaccharides, flavonoids and saponins (7). Most attention with respect to immunity has centered on the effects of the saponins which are steroidal in form.
Unbalanced immunity can be deficient leading to a lack of response. However, it can also be excessive causing allergies, autoimmune diseases or chronic inflammation. The pharmacology of Astragalus has yet to be studied in any real detail but there is some evidence that in vitro, these saponins promote B cell proliferation and antibody production. Whilst it may appear that Astragalus does have some components in the form of steroidal saponins, which have effects similar to or are synergistic with the drug interferon (7) which triggers immune responses, as a whole herb it has demonstrated an ability to control chronic bowel inflammation from an overactive immune response (54,55).
Astragalus membranaceus belongs to a class of herbs which are considered to be adaptogenic. This means they have the ability to help the body adapt to stress, which includes attack by a pathogen. The action of adaptogens is complex but thought to work in general through the hormone mechanism by regulation of cortisone and adrenal function (53).
Plants also have a well developed hormonal system, and the structure of hormones across plants, insects and man is similar. It is interesting to note that the chemistry of these steroidal compounds in Astragalus, which is in the plant family of Fabaceae, are similar to other key adaptogenic herbs in an unrelated family. Panax ginseng (ren shen) and Eleutherococcus gracilistylus (wu jia pi) in Araliaceae also contain steroidal based glycosides.
Panax ginseng (ren shen) has been studied in more depth and it appears that there are 2 main groups of steroidal glycosides at work. The first are the triol gingenosides (Rg1) which stimulate the body and the other are the diol gingenosides (Rb1) which are sedating and calming. The action of these on the body is considered to be via the hypothalamus and adrenal glands (56). Contradictory actions within a single herb are not uncommon and this may be how they can regulate. This is also seen in sugar regulation where the whole extract of Panax will reduce blood sugar levels in hyperglycaemia but raise it in hypoglycaemia. They are more homeostatic in action than simply synergistic.
What can we gain from this type of analysis? With the combined knowledge of traditional herbal experience and modern scientific precision we can learn from plants which have been working on the problem of drug resistance for millions of years longer than humans.
References
More insight on TCM and the gardens in Bristol are shared on the RCHM youtube channel.
General references
- Heinrich M, Jäger A. Ethnopharmacology.; 2015.
- Wiart C. Medicinal Plants Of The Asia-Pacific.; 2006.
- Cowan M. Plant Products as Antimicrobial Agents. Clin Microbiol Rev. 1999;12(4):564-582. doi:10.1128/cmr.12.4.564
- Veeresham C. Natural products derived from plants as a source of drugs. Journal of Advanced Pharmaceutical Technology & Research. 2012;3(4):200. doi:10.4103/2231-4040.104709
- Fabricant D, Farnsworth N. The Value of Plants Used in Traditional Medicine for Drug Discovery. Environ Health Perspect. 2001;109:69. doi:10.2307/3434847
- Chen J, Chen T. Chinese Medical Herbology And Pharmacology. Art of Medicine Press; 2000.
- Zhu Y. Chinese Materia Medica. Amsterdam, The Netherlands: Harwood Academic; 1998.
- Bensky D, Gamble A, Clavey S, Stöger E, Bensky L. Chinese Herbal Medicine. Eastland Press; 2004.
- Pengelly A. Constituents of medicinal plants Routledge; 2004.
- Bone K, Mills S. Principles And Practice Of Phytotherapy. Churchill Livingstone; 2007.
- Zuo G, Zhang X, Yang C, Han J, Wang G, Bian Z. Evaluation of Traditional Chinese Medicinal Plants for Anti-MRSA Activity with Reference to the Treatment Record of Infectious Diseases. Molecules. 2012;17(3):2955-2967. doi:10.3390/molecules17032955
Artemisia Annua - Rodriguez E, Towers G, Mitchell J. Biological activities of sesquiterpene lactones. Phytochemistry. 1976;15(11):1573-1580. doi:10.1016/s0031-9422(00)97430-2
- Ro D, Paradise E, Ouellet M et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature. 2006;440(7086):940-943. doi:10.1038/nature04640
- Stockman J. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Yearbook of Pediatrics. 2012;2012:252-254. doi:10.1016/j.yped.2011.04.056
- Gogtay N, Kannan S, Thatte U, Olliaro P, Sinclair D. Artemisinin-based combination therapy for treating uncomplicated Plasmodium vivax malaria. Cochrane Database of Systematic Reviews. 2013. doi:10.1002/14651858.cd008492.pub3
- Utzinger J, N’Goran E, N’Dri A, Lengeler C, Shuhua X, Tanner M. Oral artemether for prevention of Schistosoma mansoni infection: randomised controlled trial. The Lancet. 2000;355(9212):1320-1325. doi:10.1016/s0140-6736(00)02114-0
- Li Y, Chen H, He H, Hou X, Ellis M, McManus D. A double-blind field trial on the effects of artemether on Schistosoma japonicum infection in a highly endemic focus in southern China. Acta Trop. 2005;96(2-3):184-190. doi:10.1016/j.actatropica.2005.07.013
- WHO | WHO calls for an immediate halt to provision of single-drug artemisinin malaria pills. Apps.who.int. https://apps.who.int/mediacentre/news/releases/2006/pr02/en/index.html. Published 2006. Accessed August 31, 2022.
- Wright C, Linley P, Brun R, Wittlin S, Hsu E. Ancient Chinese Methods Are Remarkably Effective for the Preparation of Artemisinin-Rich Extracts of Qing Hao with Potent Antimalarial Activity. Molecules. 2010;15(2):804-812. doi:10.3390/molecules15020804
- Ashley E. Spread of Artemisinin Resistance in Plasmodium falciparum Malaria. New England Journal of Medicine. 2014;371(8):786-786. doi:10.1056/nejmx140047
Scutellaria baicalensis - Bonham M, Posakony J, Coleman I, Montgomery B, Simon J, Nelson P. Characterization of Chemical Constituents in Scutellaria baicalensis with Antiandrogenic and Growth-Inhibitory Activities toward Prostate Carcinoma. Clinical Cancer Research. 2005;11(10):3905-3914. doi:10.1158/1078-0432.ccr-04-1974
- Ma Z, Otsuyama K et al, “Baicalein leads to suppression of proliferation and induction of apoptosis in human myeloma cells”, Blood. 2005; 105 (527)
- Donald G, Hertzer K, Eibl G. Baicalein – An Intriguing Therapeutic Phytochemical in Pancreatic Cancer. Curr Drug Targets. 2012;13(14):1772-1776. doi:10.2174/138945012804545470
- Chiu YW, Lin TH et al; “Baicalein mediates inhibition of migration and invasiveness of skin carcinomas in A431 cells” Article has since been retracted. Toxicology Applied Pharmacology, 11 (527)
- Hui K, Wang X, Xue H. Interaction of Flavones from the Roots of Scutellaria baicalensis with the Benzodiazepine Site. Planta Med. 2009;66(01):91-93. doi:10.1055/s-0029-1243121
- Chen L, Dou J, Su Z. Synergistic activity of baicalein with ribavirin against influenza A (H1N1) virus infections in cell culture and in mice. https://pubmed.ncbi.nlm.nih.gov/21782851/. Published 2011. Accessed September 31, 2011.
- Chan B, Ip M, Lau C et al. Synergistic effects of baicalein with ciprofloxacin against NorA over-expressed methicillin-resistant Staphylococcus aureus (MRSA) and inhibition of MRSA pyruvate kinase. J Ethnopharmacol. 2011;137(1):767-773. doi:10.1016/j.jep.2011.06.039
- Fu Z, Lu H, et al, “ Combination of baicalein with beta lactam antibiotics against methycillin resistant Staphylococcus aureus”, Biol Pharma Bull. 2011; 34 (2), 214-8
- PC C, HY L, HJ T, JW L, JJ W, YC C. In vitro synergy of baicalein and gentamicin against vancomycin-resistant Enterococcus. PubMed. https://pubmed.ncbi.nlm.nih.gov/17332908/. Published 2022. Accessed August 31, 2022.
- Sato Y, Suzaki S, Nishikawa T, Kihara M, Shibata H, Higuti T. Phytochemical flavones isolated from Scutellaria barbata and antibacterial activity against methicillin-resistant Staphylococcus aureus. J Ethnopharmacol. 2000;72(3):483-488. doi:10.1016/s0378-8741(00)00265-8
- Fujita M, Shiota S, Kuroda T et al. Remarkable Synergies between Baicalein and Tetracycline, and Baicalein and β-Lactams against Methicillin-ResistantStaphylococcus aureus. Microbiol Immunol. 2005;49(4):391-396. doi:10.1111/j.1348-0421.2005.tb03732.x
- LUO J, YAN D, YANG M. Study of the anti-MRSA activity of Rhizoma coptidis by chemical fingerprinting and broth microdilution methods. Chin J Nat Med. 2014;12(5):393-400. doi:10.1016/s1875-5364(14)60049-2
Berberine - Zuo G, Li Y, Han J, Wang G, Zhang Y, Bian Z. Antibacterial and Synergy of Berberines with Antibacterial Agents against Clinical Multi-Drug Resistant Isolates of Methicillin-Resistant Staphylococcus aureus (MRSA). Molecules. 2012;17(9):10322-10330. doi:10.3390/molecules170910322
- Zhang S, Zhang B, Xing K, Zhang X, Tian X, Dai W. Inhibitory effects of golden thread (Coptis chinensis) and berberine on Microcystis aeruginosa. Water Science and Technology. 2010;61(3):763-769. doi:10.2166/wst.2010.857
- Stermitz F, Lorenz P, Tawara J, Zenewicz L, Lewis K. Synergy in a medicinal plant: Antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proceedings of the National Academy of Sciences. 2000;97(4):1433-1437. doi:10.1073/pnas.030540597
- Stermitz F, Beeson T, Mueller P, Hsiang J, Lewis K. Staphylococcus aureus MDR efflux pump inhibitors from a Berberis and a Mahonia (sensu strictu) species. Biochem Syst Ecol. 2001;29(8):793-798. doi:10.1016/s0305-1978(01)00025-4
- Wojtyczka R, Dziedzic A, Kapa M. et al; Berberine Enhances the Antibacterial Activity of Selected Antibiotics against Coagulase-Negative Staphylococcus Strains in Vitro. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272005/. Published 2014. Accessed September 1, 2022.
Synergy - Wagner H. Synergy research: Approaching a new generation of phytopharmaceuticals. Fitoterapia. 2011;82(1):34-37. doi:10.1016/j.fitote.2010.11.016
- Hemaiswarya S, Kruthiventi A, Doble M. Synergism between natural products and antibiotics against infectious diseases. Phytomedicine. 2008;15(8):639-652. doi:10.1016/j.phymed.2008.06.008
- Gertsch J. Botanical Drugs, Synergy, and Network Pharmacology: Forth and Back to Intelligent Mixtures. Planta Med. 2011;77(11):1086-1098. doi:10.1055/s-0030-1270904
- Yang Z, Wang B, Yang X, Wang Q, Ran L. The synergistic activity of antibiotics combined with eight traditional Chinese medicines against two different strains of Staphylococcus aureus. Colloids and Surfaces B: Biointerfaces. 2005;41(2-3):79-81. doi:10.1016/j.colsurfb.2004.10.033
- Yang Y, Zhang Z, Li S, Ye X, Li X, He K. Synergy effects of herb extracts: Pharmacokinetics and pharmacodynamic basis. Fitoterapia. 2014;92:133-147. doi:10.1016/j.fitote.2013.10.010
- Liu Q, Niu H, Zhang W, Mu H, Sun C, Duan J. Synergy among thymol, eugenol, berberine, cinnamaldehyde and streptomycin against planktonic and biofilm-associated food-borne pathogens. Lett Appl Microbiol. 2015;60(5):421-430. doi:10.1111/lam.12401
- Lee Y, Kang O, Choi J et al. Synergistic effect of emodin in combination with ampicillin or oxacillin against methicillin-resistantStaphylococcus aureus. Pharm Biol. 2010;48(11):1285-1290. doi:10.3109/13880201003770150
- JOUNG D, JOUNG H, YANG D et al. Synergistic effect of rhein in combination with ampicillin or oxacillin against methicillin-resistant Staphylococcus aureus. Exp Ther Med. 2012;3(4):608-612. doi:10.3892/etm.2012.459
- Jung H, Lee D. Synergistic antibacterial effect between silybin and N,N’-dicyclohexylcarbodiimide in clinical Pseudomonas aeruginosa isolates. https://pubmed.ncbi.nlm.nih.gov/18758739/. Published 2008. Accessed September 1, 2022.
- Hemaiswarya S, Doble M. Synergistic interaction of eugenol with antibiotics against Gram negative bacteria. Phytomedicine. 2009;16(11):997-1005. doi:10.1016/j.phymed.2009.04.006
Cancer - Nobili S, Landini I, Giglioni B, Mini E. Pharmacological Strategies for Overcoming Multidrug Resistance. Curr Drug Targets. 2006;7(7):861-879. doi:10.2174/138945006777709593
- Molnar J, Gyemant N, Tanaka M et al. Inhibition of Multidrug Resistance of Cancer Cells by Natural Diterpenes, Triterpenes and Carotenoids. Curr Pharm Des. 2006;12(3):287-311. doi:10.2174/138161206775201893
- Gottesman M. Mechanism of cancer drug resistance. Annu Rev Med. 2002. https://pubmed.ncbi.nlm.nih.gov/11818492/. Accessed September 1, 2022.
- Bansal T, Jaggi M, Khar R, Talegaonkar S. Emerging Significance of Flavonoids as P-Glycoprotein Inhibitors in Cancer Chemotherapy. Journal of Pharmacy & Pharmaceutical Sciences. 2009;12(1):46. doi:10.18433/j3rc77
- Nobili S, Landini I, Mazzei T, Mini E. Overcoming tumor multidrug resistance using drugs able to evade P-glycoprotein or to exploit its expression. Med Res Rev. 2011;32(6):1220-1262. doi:10.1002/med.20239
Immune regulation (adaptogenic) - Panossian A, Wikman G, Wagner H. Plant adaptogens III. Earlier and more recent aspects and concepts on their mode of action. Phytomedicine. 1999;6(4):287-300. doi:10.1016/s0944-7113(99)80023-3
- Auyeung K, Han Q, Ko J. Astragalus membranaceus: A Review of its Protection Against Inflammation and Gastrointestinal Cancers. Am J Chin Med. 2016;44(01):1-22. doi:10.1142/s0192415x16500014
- Qi Y, Gao F, Hou L, Wan C. Anti-Inflammatory and Immunostimulatory Activities of Astragalosides. Am J Chin Med. 2017;45(06):1157-1167. doi:10.1142/s0192415x1750063x
- Pharmacology and applications of chinese materia medica. Eur J Med Chem. 1987;22(6):589. doi:10.1016/0223-5234(87)90305-9
