Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Metabolism. Author manuscript; available in PMC Nov 15, 2010.
Published in final edited form as:
PMCID: PMC2981029
NIHMSID: NIHMS219888

A natural history of botanical therapeutics

Abstract

Plants have been used as a source of medicine throughout history and continue to serve as the basis for many pharmaceuticals used today. Although the modern pharmaceutical industry was born from botanical medicine, synthetic approaches to drug discovery have become standard. However, this modern approach has led to a decline in new drug development in recent years and a growing market for botanical therapeutics that are currently available as dietary supplements, drugs, or botanical drugs. Most botanical therapeutics are derived from medicinal plants that have been cultivated for increased yields of bioactive components. The phytochemical composition of many plants has changed over time, with domestication of agricultural crops resulting in the enhanced content of some bioactive compounds and diminished content of others. Plants continue to serve as a valuable source of therapeutic compounds because of their vast biosynthetic capacity. A primary advantage of botanicals is their complex composition consisting of collections of related compounds having multiple activities that interact for a greater total activity.

1. Natural products and drug discovery

Historically, natural products have provided an endless source of medicine. Plant-derived products have dominated the human pharmacopoeia for thousands of years almost unchallenged [1]. In 1897, Arthur Eichengrün and Felix Hoffmann, working at Friedrich Bayer, created the first synthetic drug, aspirin. Aspirin (acetylsalicylic acid) was synthesized from salicylic acid, an active ingredient of analgesic herbal remedies. This accomplishment ushered in an era dominated by the pharmaceutical industry. In 1928, penicillin was discovered by Alexander Fleming, adding microbes as important sources of novel drugs. The role of plant-derived natural products in drug discovery has recently been diminished by the advent of structure activity–guided organic synthesis, combinatorial chemistry, and computational (in silico) drug design.

Despite drug discovery technology diversification and reduced funding for natural product–based drug discovery, natural products from plants and other biological sources remain an undiminished source of new pharmaceuticals. Industrial funding for natural product–based drug discovery has been declining from 1984 to 2003, yet the percentage of natural product–derived small molecule patents has remained relatively unchanged [2]. A comprehensive review of human drugs introduced since 1981 suggests that, of 847 small molecule–based drugs, 43 were natural products, 232 were derived from natural products (usually semisynthetically), and 572 were synthetic molecules. However, 262 of the 572 synthetic molecules had a natural product–inspired pharmacophore or could be considered natural product analogs [3]. Natural products continue to make the most dramatic impact in the area of cancer. From 155 anticancer drugs developed since the 1940s, only 27% could not be traced to natural products, with 47% being either a natural product or a direct derivation thereof. Only one drug, the anticancer compound sorafenib, could be traced to completely de novo combinatorial chemistry [3]. The above analysis did not include biologics and vaccines, which are derived from nature by definition.

The decline in natural product–based drug discovery is often blamed on the advent of high throughput screening (HTS) [4]. Although well paired with combinatorial chemistry, HTS is not easily adaptable to complex mixtures produced from natural sources. This is mainly due to the high cost per sample, complexity of resupply, difficulty in isolation and characterization of actives, lack of reproducibility, and interference from compounds in complex mixtures [1,2].

Comparative analysis of structural diversity in natural-product mixtures and combinatorial libraries suggests that nature still has an edge over synthetic chemistry, despite the fact that combinatorial libraries use more nitrogen, phosphorus, sulfur, and halogens. Superior elemental diversity does not compensate for the overall molecular complexity, scaffold variety, stereochemical richness, ring system diversity, and carbohydrate constituents of natural product libraries [5-8]. It is generally believed that the complexity of plant-produced secondary metabolites and the vast number of natural products will constitute a resource beyond the capacity of current synthetic chemistry for a long time [9]. Nevertheless, the relative ease and low cost to produce combinatorial libraries, the simplicity and speed of their dereplication (favoring novel bioactive over known compounds) and deconvolution (characterization of unique active molecules), and the compatibility with HTS continue to fuel their widespread use in modern drug discovery.

2. Current categories of botanical products in the United States

The use of botanicals for improving human health has evolved independently in different regions of the world. The production, use, attitude, and regulatory aspects of botanicals continue to vary globally. In the United States, botanicals are categorized based on intended use, safety, regulatory status, and degree of characterization. The regulatory aspects of botanical products are an important issue when considering standardization and quality assessment because the regulations dictate some degree of the process. The basic regulatory categories are as follows:

  • Dietary Supplements, also commonly known as nutraceuticals, are products consisting of dietary components that are intended to supplement the diet and usually consist of vitamins, minerals, botanicals, and others. Dietary supplements are regulated by the Food and Drug Administration (FDA) under the Dietary Health and Education Act of 1994 (http://www.cfsan.fda.gov/~dms/lab-qhc.html), which makes the manufacturer responsible for ensuring the safety of the products but places the burden of proof upon the FDA for enforcement. This creates an unregulated environment where marketing powers retain control. Unless a dietary supplement contains a new ingredient, there is not even a mandate to register the product.
  • Drugs can be prescription drugs or over-the-counter drugs. These products require the most rigorous testing including 3 distinct phases of clinical testing to ensure safety and efficacy and close scrutiny by the FDA. Although most early pharmaceutical products were botanical preparations and at least 25% of the pharmaceuticals used today are based on plant-derived products [10], only pure compounds isolated from plants and subjected to the same rigors as synthetic pharmaceutical can be conventional drugs. Botanically derived pharmaceuticals that are currently being used today include taxol and morphine [4].
  • Botanical Drugs are complex extracts from a plant to be used for the treatment of disease. The guidelines for this relatively new regulatory category were released in 2004 (http://www.fda.gov/cder/Guidance/4592fnl.htm). Botanical drugs are clinically evaluated for safety and efficacy just as conventional drugs, but the process for botanical drugs can be expedited because of the history of safe human use. Botanical drugs are highly but not completely characterized and are produced under the same strictly regulated conditions as conventional pharmaceuticals. Botanical drugs, such as senna and psyllium, can be marketed and sold under the FDA’s over-the-counter drug monograph system [11].

3. Plant domestication and secondary metabolites

Recent archeological records suggest that modern agriculture started in the Near East 10 000 to 11 000 years ago with the domestication of figs, cereals, and legumes [12,13]. At that time, early Neolithic farmers maintained a subsistence strategy, collecting wild plants for food and medicine while simultaneously domesticating early crops. This point in time marked the beginning of the divergence between medicinal plants and food plants. Centuries of plant domestication improved flavor, color, yield, uniformity, disease and pest resistance, reproductive fitness, and postharvest integrity of crops but has reduced pharmacologically active compounds from major crops to levels where average daily consumption cannot produce a measurable pharmacological effect. The pharmacological side effects of food, frequently residing in poorly palatable compounds, were not likely to be preserved or even considered advantageous by our ancestors. As a result, conventional plant breeding has often reduced the content of bioactive compounds in crops (Table 1).

Table 1
Bioactive compounds that have been reduced in modern food crops

For example, a wild tomato (Lycopersicon esculentum var cerasiforme) indigenous to Peru produces fruit with very high levels of the bitter glycoalkaloid tomatine (500-5000 mg/kg dry weight) [26]. Tomatine plays a role in pest and disease resistance and also has multiple pharmacological effects in humans including cholesterol-lowering, immunomodulatory, and cardiotonic [27,28]. Its ability to inhibit acetylcholenesterase may be responsible for its potentially toxic effects [16]. Not surprisingly, tomatine is considerably lower in sweet fruited tomato cultivars (~30 mg/kg) [26], reducing the bitter flavor but also reducing potential health benefits. Wild potato species also contain considerably higher amounts of glycoalkaloids than modern cultivars [29].

Wild bean species (Phaseolus vulgaris) contain many secondary metabolites that are found in lower levels in cultivated species including trypsin inhibitors, tannins, and lectins [30]. These phytochemicals have been called anti-nutritional because they may interfere with protein digestion, although they have potential human health benefits as a therapy for cancer, heart disease, and diabetes [31].

Contrary to the trend of reducing bioactives through centuries of plant breeding, some bioactive compounds have been fortuitously enhanced in modern food crops because they impart desirable attributes like color or flavor (Table 2). Examples include pigments such as carotenoids [43,44] and flavonoids [45,46], aromatic constituents of volatile oils like menthol [47,48], and other flavor constituents including gingerols [49] and capsaicin [50,51].

Table 2
Bioactive compounds that have been increased in modern food crops

Modern agriculture has also improved various medicinal plants through years of selective breeding for bioactive compounds. For example, foxglove (Digitalis purpurea) produces digitoxin and digoxin, cardiac glycosides used to treat congestive heart failure. Modern agriculture has created uniform cultivars with high digoxin content [52]. Many common cultivated plants are also the source of compounds used as building blocks in the semisynthesis of pharmaceuticals. A number of useful phytochemicals are extracted from soybean (Glycine max) including the sterols stigmasterol, sitosterol, and campesterol [53]. Sitosterol and campesterol are esterified into plant stanol and sterol esters, both of which have been shown to lower serum cholesterol [54]. Stigmasterol and sitosterol are used in the semisynthesis of pharmaceutical steroids including progestagens, androgens, and corticosteroids [53,55]. Diosgenin, a structurally related steroid from Mexican yams (Dioscorea spp), is also used in the semisynthesis of pharmaceutical steroids [53]. The opium poppy (Papaver soniferum) produces morphinan alkaloids including morphine, codeine, thebaine, papaverine, and noscapine [56]. Opioid semisynthetic drugs include dihydrocodeine, fentanyl, and oxycodone [53]. Opioids are widely used as powerful analgesics, cough suppressants, and sedatives.

4. The power of biochemical potentiation

A recent review article defined potentiation as positive interactions that intensify the potency of a bioactive product [57]. Additive and synergistic effects are subsets of potentiation, where 2 or more compounds in a mixture interact to provide a combined effect that is equal to the sum of the effects of the individual components (additive) or where combinations of bioactive substances exert effects that are greater than the sum of individual components (synergistic). Potentiation can exist between 2 phytochemicals in a single plant extract, 2 phytochemicals from 2 different plant extracts, or between a phytochemical and synthetic drug. To validate this phenomenon, the bioactive phytochemical(s) in a mixture must first be identified and isolated. Afterward, plant extracts or mixtures of phytochemicals must be tested side by side with the single bioactive compounds to see which one has greater bioactivity. Only then can clear conclusions be made whether or not a mixture of compounds actually intensifies the potency of a single bioactive product. A good example of the multicomponent nature of botanicals is illustrated with an extract from Artemisia dracunculus L that is being researched as a botanical therapeutic for diabetes and metabolic syndrome. The extract decreases blood glucose in hyperglycemic animal models of diabetes and seems to enhance insulin sensitivity as a mode of action [58]. Based on 3 of the diabetes-related activities identified for the extract, together with activity-guided fractionation, 6 active compounds were isolated and identified (Table 3). Therefore, the activity of the total extract is the combined result of at least 6 different compounds and at least 3 different activities. The precise nature of their interaction has not yet been defined.

Table 3
Bioactive compounds isolated from an extract of A dracunculus L by activity-guided fractionation that inhibit the aldose reductase enzyme, protein tyrosine phosphatase 1B activity and expression, or phosphoenolpyruvate carboxykinase overexpression [59 ...

In the field of cancer research, phytochemicals have been shown to affect various parts of signal transduction pathways including gene expression, cell cycle progression, proliferation, cell mortality, metabolism, and apoptosis [62]. Combination chemotherapy has been the mainstay of cancer treatment for 40 years [63]. It is therefore reasonable to assume that a mixture of compounds (phytochemical or synthetic) would have greater bioactivity than a single compound because a mixture of bioactive compounds has the ability to affect multiple targets [62,64]. Studies have documented synergistic anticancer effects of phytochemicals including quercetin, catechins, reseveratrol, and curcumin with various cancer drugs and/or other phytochemicals [62]. A few other examples of synergistic anticancer activity are shown in Table 4. In addition, natural products have been shown to overcome multiple drug resistance in tumors when used in combination with other natural products or drugs [62]. Similar observations have been made in the field of antibiotic research (Table 4). A number of plant extracts and natural products have been shown to work synergistically with existing antibiotics, restoring antibiotic activity against resistant strains of Staphylococcus aureus (methicillin resistant), Escherichia coli, and Shigella [70-72].

Table 4
Examples of potentiating interactions between various natural products with other natural products or drugs in the fields of cancer and antibiotic research

5. Conclusions

Plants must maintain and protect themselves through diverse arrays of complex natural products that they make from the inorganic components of air, soil, and water because they lack the flight response. Remarkably, the oldest known living eukaryotic organism, turning 4772 years old in 2007, is a specimen of a bristlecone pine, Pinus longaeva, growing in the White Mountains of Inyo County, California [73]. Many other plants can live hundreds of years without succumbing to diseases or predation. It should come to no surprise that some of the compounds that have enabled plants to survive may also be used to maintain the health and well-being of humans.

Acknowledgment/Conflict of Interest

Research supported by NIH Grant P50 AT002776-01 from the National Center for Complementary and Alternative Medicine (NCCAM) and Office of Dietary Supplements (ODS) which funds the Botanical Research Center; also supported by Fogarty International Center of the National Institutes of Health under U01 TW006674 for the International Cooperative Biodiversity Groups; and Rutgers University. David Ribnicky, Alexander Poulev, and Ilya Raskin serve as consultants for Phytomedics.

References

[1] Raskin I, Ripoll C. Can an apple a day keep the doctor away? Curr Pharm Des. 2004;10:3419–29. [PubMed]
[2] Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005;4:206–20. [PubMed]
[3] Newman DJ, Cragg GM. Natural products from marine invertebrates and microbes as modulators of antitumor targets. Curr Drug Targets. 2006;7:279–304. [PubMed]
[4] Butler MS. The role of natural product chemistry in drug discovery. J Nat Prod. 2004;67:2141–53. [PubMed]
[5] Feher M, Schmidt JM. Property distributions: differences between drugs, natural products, and molecules from combinatorial chemistry. J Chem Inf Comput Sci. 2003;43:218–27. [PubMed]
[6] Lee ML, Schneider G. Scaffold architecture and pharmacophoric properties of natural products and trade drugs: application in the design of natural product–based combinatorial libraries. J Comb Chem. 2001;3:284–9. [PubMed]
[7] Stahura FL, Godden JW, Xue L, Bajorath J. Distinguishing between natural products and synthetic molecules by descriptor Shannon entropy analysis and binary QSAR calculations. J Chem Inf Comput Sci. 2000;40:1245–52. [PubMed]
[8] Henkel T, Brunne RM, Muller H, Reichel F. Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew Chem. 1999;38:643–7.
[9] Koch MA, et al. Charting biologically relevant chemical space: a structural classification of natural products (SCONP) Proc Natl Acad Sci U S A. 2005;102:17272–7. [PMC free article] [PubMed]
[10] Farnsworth NR, Morris RW. Higher plants—the sleeping giant of drug development. Am J Pharm Sci Support Public Health. 1976;148:46–52. [PubMed]
[11] Hassler WL. Nonpharmacologic and OTC therapies for chronic constipation. Advanced Studies in Medicine. 2006;6:S84–93.
[12] Kislev ME, Hartmann A, Bar-Yosef O. Early domesticated fig in the Jordan Valley. Science. 2006;312:1372–4. [PubMed]
[13] Abbo S, et al. The chickpea, summer cropping, and a new model for pulse domestication in the ancient near east. Q Rev Biol. 2003;78:435–48. [PubMed]
[14] Kousparou CA, Epenetos AA, Deonarain MP. Antibody-guided enzyme therapy of cancer producing cyanide results in necrosis of targeted cells. Int J Cancer. 2002;99:138–48. [PubMed]
[15] Beier RC. Natural pesticides and bioactive components in foods. Rev Environ Contam Toxicol. 1990;113:47–137. [PubMed]
[16] Tietjen KG, Hunkler D, Matern U. Differential response of cultured parsley cells to elicitors from two non-pathogenic strains of fungi. 1. Identification of induced products as coumarin derivatives. Eur J Biochem. 1983;131:401–7. [PubMed]
[17] Padilla G, et al. Variation of glucosinolates in vegetable crops of Brassica rapa. Phytochemistry. 2007;68:536–45. [PubMed]
[18] Nho CW, Jeffery E. The synergistic upregulation of phase II detoxification enzymes by glucosinolate breakdown products in cruciferous vegetables. Toxicol Appl Pharmacol. 2001;174:146–52. [PubMed]
[19] Friedman M. Potato glycoalkaloids and metabolites: roles in the plant and in the diet. J Agric Food Chem. 2006;54:8655–61. [PubMed]
[20] Genovese MI, Hassimotto NMA, Lajolo FM. Isoflavone profile and antioxidant activity of Brazilian soybean varieties. Food Sci Technol Int. 2005;11:205–11.
[21] Doerge DR, Sheehan DM. Goitrogenic and estrogenic activity of soy isoflavones. Environ Health Perspect. 2002;110(Suppl 3):349–53. [PMC free article] [PubMed]
[22] Dodou K, Anderson RJ, Small DA, Groundwater PW. Investigations on gossypol: past and present developments. Expert Opin Investig Drugs. 2005;14:1419–34. [PubMed]
[23] Goldsmith KC, Hogarty MD. Targeting programmed cell death pathways with experimental therapeutics: opportunities in high-risk neuroblastoma. Cancer Lett. 2005;228:133–41. [PubMed]
[24] Sessa RA, et al. Metabolite profiling of sesquiterpene lactones from Lactuca species. Major latex components are novel oxalate and sulfate conjugates of lactucin and its derivatives. J Biol Chem. 2000;275:26877–84. [PubMed]
[25] Bischoff TA, et al. Antimalarial activity of lactucin and lactucopicrin: sesquiterpene lactones isolated from Cichorium intybus L. J Ethnopharmacol. 2004;95:455–7. [PubMed]
[26] Rick CM, Uhlig JW, Jones AD. High alpha-tomatine content in ripe fruit of Andean Lycopersicon esculentum var. cerasiforme: developmental and genetic aspects. Proc Natl Acad Sci U S A. 1994;91:12877–81. [PMC free article] [PubMed]
[27] Morrow WJ, Yang YW, Sheikh NA. Immunobiology of the tomatine adjuvant. Vaccine. 2004;22:2380–4. [PubMed]
[28] Friedman M. Tomato glycoalkaloids: role in the plant and in the diet. J Agric Food Chem. 2002;50:5751–80. [PubMed]
[29] Gregory P, et al. Glycoalkaloids of wild, tuber-bearing solanum species. J Agric Food Chem. 1981;29:1212–5.
[30] Sotelo A, Sousa H, Sanchez M. Comparative study of the chemical composition of wild and cultivated beans (Phaseolus vulgaris) Plant Foods Hum Nutr. 1995;47:93–100. [PubMed]
[31] De Mejia EG, Del Carmen Valadez-Vega M, Reynoso-Camacho R, Loarca-Pina G. Tannins, trypsin inhibitors and lectin cytotoxicity in tepary (Phaseolus acutifolius) and common (Phaseolus vulgaris) beans. Plant Foods Hum Nutr. 2005;60:137–45. [PubMed]
[32] Zern TL, Fernandez ML. Cardioprotective effects of dietary polyphenols. J Nutr. 2005;135:2291–4. [PubMed]
[33] Canene-Adams K, et al. Combinations of tomato and broccoli enhance antitumor activity in dunning r3327-h prostate adenocarcinomas. Cancer Res. 2007;67:836–43. [PubMed]
[34] Canene-Adams K, et al. The tomato as a functional food. J Nutr. 2005;135:1226–30. [PubMed]
[35] Zhao F, et al. Inhibitors of nitric oxide production from hops (Humulus lupulus L.) Biol Pharm Bull. 2003;26:61–5. [PubMed]
[36] Murakami A, et al. Molecular phylogeny of wild hops, Humulus lupulus L. Heredity. 2006;97:66–74. [PubMed]
[37] Lampe JW. Spicing up a vegetarian diet: chemopreventive effects of phytochemicals. Am J Clin Nutr. 2003;78:579S–83S. [PubMed]
[38] Quimby EL. The use of herbal therapies in pediatric oncology patients: treating symptoms of cancer and side effects of standard therapies. J Pediatr Oncol Nurs. 2007;24:35–40. [PubMed]
[39] Wohlmuth H, Leach DN, Smith MK, Myers SP. Gingerol content of diploid and tetraploid clones of ginger (Zingiber officinale Roscoe) J Agric Food Chem. 2005;53:5772–8. [PubMed]
[40] Giaccio M. Crocetin from saffron: an active component of an ancient spice. Crit Rev Food Sci Nutr. 2004;44:155–72. [PubMed]
[41] Abdullaev FI. Cancer chemopreventive and tumoricidal properties of saffron (Crocus sativus L.) Exp Biol Med. 2002;227:20–5. [PubMed]
[42] Liu RH. Potential synergy of phytochemicals in cancer prevention: mechanism of action. J Nutr. 2004;134:3479S–85S. [PubMed]
[43] Ruiz D, Egea J, Tomas-Barberan FA, Gil MI. Carotenoids from new apricot (Prunus armeniaca L.) varieties and their relationship with flesh and skin color. J Agric Food Chem. 2005;53:6368–74. [PubMed]
[44] Dosti MP, Mills JP, Simon PW, Tanumihardjo SA. Bioavailability of beta-carotene (betaC) from purple carrots is the same as typical orange carrots while high-betaC carrots increase betaC stores in Mongolian gerbils (Meriones unguiculatus) Br J Nutr. 2006;96:258–67. [PubMed]
[45] Bavaresco L. Role of viticultural factors on stilbene concentrations of grapes and wine. Drugs Exp Clin Res. 2003;29:181–7. [PubMed]
[46] Thole JM, et al. A comparative evaluation of the anticancer properties of European and American elderberry fruits. J Med Food. 2006;9:498–504. [PubMed]
[47] Eccles R. Menthol: effects on nasal sensation of airflow and the drive to breathe. Curr Allergy Asthma Rep. 2003;3:210–4. [PubMed]
[48] Wildung MR, Croteau RB. Genetic engineering of peppermint for improved essential oil composition and yield. Transgenic Res. 2005;14:365–72. [PubMed]
[49] Shishodia S, Sethi G, Aggarwal BB. Curcumin: getting back to the roots. Ann N Y Acad Sci. 2005;1056:206–17. [PubMed]
[50] Antonious GF, Kochhar TS, Jarret RL, Snyder JC. Antioxidants in hot pepper: variation among accessions. J Environ Sci Health B. 2006;41:1237–43. [PubMed]
[51] Steenland HW, Ko SW, Wu LJ, Zhuo M. Hot receptors in the brain. Mol Pain. 2006;2:34. [PMC free article] [PubMed]
[52] Mastenbroek C. Cultivation and breeding of Digitalis lanata in the Netherlands. Br Heart J. 1985;54:262–8. [PMC free article] [PubMed]
[53] Dewick PM. Medicinal natural products: a biosynthetic approach. John Wiley & Sons Ltd; West Sussex (England): 2002.
[54] Tikkanen MJ. Plant sterols and stanols. Handb Exp Pharmacol. 2005:215–30. [PubMed]
[55] Bursi R, Groen MB. Application of (quantitative) structure-activity relationships to progestagens: from serendipity to structure-based design. Eur J Med Chem. 2000;35:787–96. [PubMed]
[56] Larkin PJ, et al. Increasing morphinan alkaloid production by over-expressing codeinone reductase in transgenic Papaver somniferum. Plant Biotechnol J. 2007;5:26–37. [PubMed]
[57] Lila MA, Raskin I. Health-related interactions of phytochemicals. J Food Sci. 2005;70:R20–7.
[58] Ribnicky DM, et al. Antihyperglycemic activity of Tarralin, an ethanolic extract of Artemisia dracunculus L. Phytomedicine. 2006;13:550–7. [PubMed]
[59] Logendra S, et al. Bioassay-guided isolation of aldose reductase inhibitors from Artemisia dracunculus. Phytochemistry. 2006;67:1539–46. [PubMed]
[60] Wang Z, et al. 66th Scientific sessions of the American Diabetes Association; Washington D.C.. June 9-13; 2006.
[61] Govorko D, et al. 66th Scientific sessions of the American Diabetes Association; Washington DC. 2006.
[62] HemaIswarya S, Doble M. Potential synergism of natural products in the treatment of cancer. Phytother Res. 2006;20:239–49. [PubMed]
[63] Waterhouse DN, et al. Development and assessment of conventional and targeted drug combinations for use in the treatment of aggressive breast cancers. Curr Cancer Drug Targets. 2006;6:455–89. [PubMed]
[64] Liu RH. Health benefits of fruit and vegetables are from additive and synergistic combinations of phytochemicals. Am J Clin Nutr. 2003;78:517S–20S. [PubMed]
[65] Eberhardt MV, Lee CY, Liu RH. Antioxidant activity of fresh apples. Nature. 2000;405:903–4. [PubMed]
[66] Mai Z, Blackburn GL, Zhou JR. Soy phytochemicals synergistically enhance the preventive effect of tamoxifen on the growth of estrogen-dependent human breast carcinoma in mice. Carcinogenesis. 2007;28:1217–23. [PMC free article] [PubMed]
[67] Boileau TW, et al. Prostate carcinogenesis in N-methyl-N-nitrosourea (NMU)-testosterone-treated rats fed tomato powder, lycopene, or energy-restricted diets. J Natl Cancer Inst. 2003;95:1578–86. [PubMed]
[68] Aqil F, Ahmad I, Owais M. Evaluation of anti–methicillin-resistant Staphylococcus aureus (MRSA) activity and synergy of some bioactive plant extracts. Biotechnol J. 2006;1:1093–102. [PubMed]
[69] Aqil F, Khan MS, Owais M, Ahmad I. Effect of certain bioactive plant extracts on clinical isolates of beta-lactamase producing methicillin resistant Staphylococcus aureus. J Basic Microbiol. 2005;45:106–14. [PubMed]
[70] Ahmad I, Aqil F. In vitro efficacy of bioactive extracts of 15 medicinal plants against ESbetaL-producing multidrug-resistant enteric bacteria. Microbiol Res. 2007;162:264–75. [PubMed]
[71] Sato M, et al. Antibacterial activity of phytochemicals isolated from Erythrina zeyheri against vancomycin-resistant enterococci and their combinations with vancomycin. Phytother Res. 2004;18:906–10. [PubMed]
[72] Sato M, et al. Synergistic effects of mupirocin and an isoflavanone isolated from Erythrina variegata on growth and recovery of methicillin-resistant Staphylococcus aureus. Int J Antimicrob Agents. 2004;24:241–6. [PubMed]
[73] Flanary BE, Kletetschka G. Analysis of telomere length and telomerase activity in tree species of various life-spans, and with age in the bristlecone pine Pinus longaeva. Biogerontology. 2005;6:101–11. [PubMed]
PubReader format: click here to try

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...