Research Advances - American Chemical Society

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Research Advances Getting Plants To Rid Themselves of Pesticide Residues; “Dung of the Devil” Plant Roots Point to New Swine Flu Drugs; Kudzu Shows Promise as a Dietary Supplement; Freshly Crushed Garlic Better for the Heart Than Processed; Curcumin Stabilizes Membranes by Angela G. King Wake Forest University, Winston-Salem, North Carolina 27109 [email protected]

Earth is known as the “green planet” for a reason: it is laden with abundant and diverse plant life that uses photosynthesis to produce the oxygen we breathe. In addition, plants present a cornucopia of chemistry from which scientists can get new leads for medicine and learn how to better feed our hungry and growing population. Getting Plants To Rid Themselves of Pesticide Residues Scientists in China are reporting the discovery that a natural plant hormone, when applied to crops, can help plants eliminate residues of certain pesticides (1). Jing Quan Yu and colleagues note that pesticides are essential for sustaining food production for the world's growing population. Farmers worldwide use about 2.5 million tons of pesticides each year. Scientists have been seeking new ways of minimizing pesticide residues that remain in food crops after harvest, but with little success (2). Previous research suggested that plant hormones called brassinosteroids (BRs) might be an answer to the problem. Plants transform pesticides through a phased detoxification system involving many enzymes. Phase I is metabolic activation, phase II involves conjugation to glutathione and glucose, and phase III is the sequestration and storage of soluble metabolites. The scientists treated the plants with various pesticides, including chloropyrifos (CPF, 1), a broad-spectrum commercial insecticide, after treating a study group of cucumber plants with 24-epibrassinolide (EBR, 2) (Figures 1 and 2). Levels of CPF on the study and control plants were determined by gas chromatography with a flame photometric detector. The researchers say that EBR significantly accelerated metabolism of CPF and reduced CPF toxicity and residues in the plants (3). EBR's effects on the expression and activity of enzymes involved in pesticide metabolism were analyzed to determine its mechanism of action. The results showed that EBR had a positive effect on the activation of glutathione-S-transferase, peroxidase, and glutathione reductase after treatment with CPF. Further work attributed this effect to enhanced expression of detoxification genes. BRs may be “promising, environmentally friendly, natural substances suitable for wide application to reduce the risks of human and environmental exposure to pesticides”, the scientists note. They add that the substances do not appear to be harmful to people or other animals (4).

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Figure 1. In comparison to control plants, levels of chloropyrifos (1) residue on plants treated with 24-epibrassinolide (2) are decreased due to an increase in metabolism rate. Image credits: Structures provided by A. King.

Figure 2. Scientists have discovered that a naturally occurring plant hormone helps plants rid themselves of certain pesticide residues. Image credits: USDA Agricultural Research Service.

“Dung of the Devil” Plant Roots Point to New Swine Flu Drugs Recent laboratory experiments by scientists in Taiwan (5) have revealed that the roots of a plant used a century ago during the

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r 2010 American Chemical Society and Division of Chemical Education, Inc. pubs.acs.org/jchemeduc Vol. 87 No. 2 February 2010 10.1021/ed800061e Published on Web 01/12/2010

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great Spanish influenza pandemic contain substances with powerful effects in killing the H1N1 swine flu virus. The plant has a pleasant, onion-like taste when cooked, but when raw, its sap is so foul smelling that some call it the “Dung of the Devil” plant (6). In the study, Fang-Rong Chang, Yang-Chang Wu, and colleagues note that the plant Ferula assa-foetida grows mainly in Iran, Afghanistan, and mainland China. People used it as a remedy during the 1918 Spanish influenza pandemic that killed between 20 and 100 million people. Until now, however, no one had determined whether the plant produces natural antiviral compounds. Before the current work, 239 natural products had been identified from the plant genus (7-9). The recent breakthrough came when scientists noted that a chloroform extract of the plant was bioactive. Chang and Wu used a bioassay-directed (anti-H1N1 activity) chromatographic separation to separate and identify compounds in the plant, including both known and new molecules. A group of chemical compounds in methanol extracts of the plant showed greater potency against influenza A (H1N1) than a prescription antiviral drug available for the flu. After separation, the scientists used a combination of IR and UV spectroscopy, mass spectrometry, and NMR techniques to

Figure 3. Structures of compounds identified from devil's dung extracts. Image credits: Structures provided by A. King.

identify the compounds. Compound 3, which had been previously identified in the plant's extract, showed not just excellent anti-H1N1 properties but also the greatest potency against several cancer cell lines. Compounds 4, 5, and 6 had not been previously identified (Figure 3). “Overall, the present study has determined that sesquiterpene coumarins from F. assa-foetida may serve as promising lead components for new drug development against influenza A (H1N1) viral infection”, the authors wrote (5). Nuisance or Nutrient? Kudzu Shows Promise as a Dietary Supplement Kudzu, which was originally grown in the United States to decrease erosion, has become a nuisance vine that has overgrown almost 10 million acres in the southeastern United States, but it may sprout into an important dietary supplement. Scientists in Alabama and Iowa are reporting the first evidence that root extracts from kudzu show promise as a dietary supplement for a high-risk condition, metabolic syndrome, that affects almost 50 million people in the United States alone (10, 11). J. Michael Wyss and colleagues (12) note in the new study that people with metabolic syndrome have obesity, high blood pressure, high blood cholesterol, and problems with their body's ability to use insulin. These disorders put people at a high risk for heart attacks, strokes, and other diseases. Scientists have been seeking natural substances that can treat metabolic syndrome, and there has been growing interest in the impact of dietary phenols (13). Previous work demonstrated that dietary grape seed and soy isoflavone lower salt-sensitive hypertension in rats on a diet free of polyphenols. The new study evaluated kudzu root (Radix pueraria from Pueraria lobota) extracts, which contain a unique isoflavone, puerarin (Figure 4). People in China and Japan long have used kudzu supplements as a health food, and it is now commercially available as a dietary supplement marketed toward women's health in the United States. The study found that a kudzu root extract had beneficial effects in lab rats used as a model for research on metabolic syndrome. After 2 months of taking the extract, the rats had lower levels of cholesterol, blood pressure, blood sugar, and insulin than a control group not given the extract. This work indicates that kudzu root “may provide a dietary supplement that

Figure 4. HPLC chromatogram of the aqueous acetonitrile extract of kudzu root dietary preparation identifying the peaks for the major isoflavones in the supplement and retention times. Image credits: Reprinted with permission from J. Agric. Food Chem. 2009, 57, 7268-7273. Copyright 2009 American Chemical Society.

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Figure 5. Chemical reactions of formation of allicin and H2S from raw garlic. Image credits: Reprinted with permission from J. Agric. Food Chem. 2009, 57, 7137-7144. Copyright 2009 American Chemical Society.

Figure 6. Effect of fresh and processed garlic on myocardial infarct size (A), and cardiomyocytes apoptosis (B). Results are shown as mean SEM (*p < 0.05 vs I/R, n = 3 in each group; I/R is ischemia/reperfusion). Image credits: Reprinted with permission from J. Agric. Food Chem. 2009, 57, 7137-7144. Copyright 2009 American Chemical Society.

significantly decreases the risk and severity of stroke and cardiovascular disease”. The exact mechanisms of the kudzu root's action remain to be determined. Freshly Crushed Garlic Better for the Heart Than Processed A new study (14) reports what scientists term the first scientific evidence that freshly crushed garlic has more potent heart-healthy effects than dried garlic. It also challenges the widespread belief that most of garlic's benefits are due to its rich array of antioxidants. Instead, garlic's additional heart-healthy effects seem to result from hydrogen sulfide (H2S), a chemical signaling substance that forms after garlic is cut or crushed and relaxes blood vessels when garlic is eaten (15).


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In the study, Dipak K. Das and colleagues point out that raw, crushed garlic generates hydrogen sulfide through a series of chemical reactions (Figure 5). Alk(en)ylcysteines and γ-glutamyl alk(en)ylcysteines are converted to S-allylcysteine (deoxyallin) when the enzyme allinase is activated upon crushing. S-allylcysteine then produces allicin, which breaks down into several volatile components, including H2S. Although best known as the stuff that gives rotten eggs their distinctive odor, H2S also acts as a chemical messenger in the body, relaxing blood vessels and allowing more blood to pass through. Processed garlic allows H2S to form and then escape into the air before entering the body. The scientists gave freshly crushed garlic and processed garlic to two groups of lab rats and then studied how well the animals' hearts recovered from simulated heart attacks (Figure 6).


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Figure 7. Keto-enol form of curcumin, the dominant tautomer of curcumin. The keto-enol form is stabilized by an intramolecular hydrogen bond. Image from the January 2010 JCE Featured Molecules (DOI: 10.1021800038w).

lipid bilayers because it influences the function of numerous unrelated membrane proteins (17-19). Using solid-state NMR spectroscopy and differential scanning calorimetry, the scientists studied the interaction of curcumin with membranes and discovered that molecules of curcumin act like a biochemical disciplinarian. Curcumin molecules insert themselves into cell membranes and make the membranes more stable and orderly in a way that increases cells' resistance to infection by disease-causing microbes. The molecule inserts itself deep in the membrane in a trans-bilayer manner, using hydrogen bonding to anchor itself to a lipid phosphate group. NMR results demonstrate that curcumin forms concentration-dependent higher-order oligomeric structures in the membrane; these structures most likely span the membrane and thin the bilayer (Figure 8) (20). The results are exciting to medical researchers exploring how other membrane-altering drugs, such as capsaicin, achieve their effects. Literature Cited

Figure 8. Cartoon schematic of the physical changes induced by curcumin in the membrane. Curcumin at low molar concentrations is monomeric and oriented with its long axis along the membrane normal. Curcumin is effective at these concentrations in ordering the membrane except for the terminal carbons below the curcumin molecule. At higher concentrations, curcumin oligomerizes in the membrane, reducing its thickness and molecular order relative to the samples with lower concentrations of curcumin. Image credits: Reprinted with permission from J. Am. Chem. Soc. 2009, 131, 4490-4498. Copyright 2009 American Chemical Society.

“Both crushed and processed garlic reduced damage from lack of oxygen, but the fresh garlic group had a significantly greater effect on restoring good blood flow in the aorta and increased pressure in the left ventricle of the heart”, Das said. The freshly crushed garlic group displayed significantly greater degrees of survival by boosting antiapoptotic enzymes and suppressing the death signal by decreasing the phosphorylation of proapoptotic proteins. This work, which clearly indicates that cardiovascular patients are better served by fresh garlic than by processed garlic products, should be of great interest to the one-third of American adults using some type of alternative medicine. Curcumin Stabilizes Membranes Scientists in Michigan are reporting discovery of the secret behind the fabled healing power of curcumin, a component of the spice turmeric, which is revered in India as “holey powder” (Figure 7). In the study (16), Ayyalusamy Ramamoorthy and colleagues point out that turmeric has been used for centuries in folk medicine to treat wounds, infections, and other health problems. Although modern scientific research on the spice has burgeoned in recent years and the compound has demonstrated antioxidant, anticarcinogenic, antimutagenic, and anti-inflammatory action, until now scientists did not know exactly how curcumin works inside the body. Previous data suggested that curcumin affects 126


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1. Xia, X. J.; Zhang, Y.; Wu, J. X.; Wang, J. T.; Zhou, Y. H.; Shi, K.; Yu, Y. L.; Yu, J. Q. Brassinosteroids Promote Metabolism of Pesticides in Cucumber. J. Agric. Food Chem. 2009, 57, 8406– 8413. 2. Research Advances has previously reported on research addressing pesticide buildup. See J. Chem. Educ. 2006, 83, 346-348. 3. These Web sites lead to profiles of the insecticide CPF: http:// extoxnet.orst.edu/pips/chlorpyr.htm and http://www.atsdr.cdc. gov/tfacts84.html (accessed Dec 2009). 4. J. Chem. Educ. 2006, 83, 270-272 describes a green synthesis of a natural insecticide for an undergraduate experiment and lemon balm ; J. Chem. Educ. 1984, 61, 742 and 1976, 53, 173 report on the synthesis of carbaryl and analysis of sprayed plants, respectively. 5. Lee, C.-L.; Chiang, L.-C.; Cheng, L.-H.; Liaw, C.-C.; Abd El-Razek, M. H.; Chang, F.-R.; Wu, Y.-C. Influenza A (H1N1) Antiviral and Cytotoxic Agents from Ferula assa-foetida. J. Nat. Prod. 2009, 72, 1568–1572. 6. These Web sites offer cultural information on the use of this plant as a spice: http://www.saudiaramcoworld.com/issue/200904/ devil.s.dung-the.world.s.smelliest.spice.htm and http://blogs.ngm. com/blog_central/2009/08/hold-the-onions-cooking-with-devilsdung.html (accessed Dec 2009). 7. J. Chem. Educ. 2007, 84, 1982-1984 and 2007, 84, 1502-1504 describe the quantitative analysis of the natural products in traditional Chinese medicines and lemon balm, respectively. 8. Research Advances has previously reported on natural products obtained from dragon's blood. See J. Chem. Educ. 2008, 85, 764-767. 9. This Journal profiled the career of a natural product chemist in 2007, 84, 1582. 10. Peng, N.; Prasain, J. K.; Dai, Y.; Moore, R.; Arabshahi, A.; Barnes, S.; Carlson, S.; Wyss, J. M. Chronic Dietary Kudzu Isoflavones Improve Components of Metabolic Syndrome in Stroke-Prone Spontaneously Hypertensive Rats. J. Agric. Food Chem. 2009, 57, 7268–7273. 11. The American Heart Association offers more information on metabolic syndrome at http://www.americanheart.org/presenter. jhtml?identifier=4756 (accessed Dec 2009). 12. More details on research in the Wyss lab are available online: http://main.uab.edu/show.asp?durki=8048 (accessed Dec 2009).


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Chemical Education Today 13. J. Chem. Educ. 1999, 76, 1710-1711 describes an undergraduate experiment measuring red wine polyphenols. 14. Mukherjee, S.; Lekli, I.; Goswami, S.; Das, D. K. Freshly Crushed Garlic Is a Superior Cardioprotective Agent Than Processed Garlic. J. Agric. Food Chem. 2009, 57, 7137–7144. 15. Information on the chemistry associated with garlic is provided in an interview with Erik Block of the University of New York at Albany, available online at http://www.healthy.net/scr/Interview. asp?Id=173. Block is the author of Garlic and Other Alliums: The Lore and the Science (accessed Dec 2009). 16. Barry, J.; Fritz, M.; Brender, J. R.; Smith, P. E. S.; Lee, D.-K.; Ramamoorthy, A. Determining the Effects of Lipophilic Drugs on Membrane Structure by Solid-State NMR Spectroscopy: The Case


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of the Antioxidant Curcumin. J. Am. Chem. Soc. 2009, 131, 4490– 4498. More information on the research in Ramamoorthy's laboratory is available online: https://www.chem.lsa.umich.edu/chem/faculty/ facultyDetail.php?Uniqname=ramamoor (accessed Dec 2009). J. Chem. Educ. 2000, 77, 359-360 describes the isolation of curcumin from turmeric in an undergraduate experiment. Research Advances has previously reported on the health benefits of curcumin. See J. Chem. Educ. 2006, 83, 346-348 and 2004, 81, 1386-1389. This Journal has previously published an experiment using Raman spectroscopy to investigate cell membranes. See 2003, 80, 1282-1288.


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