Medicinal plants candidates for thyroid hormone analogs according to ethnobotanical research in Salvador-Bahia, Brazil (Cunha Lima, 2008).
Nuclear receptors (NRs) are transcription factors that regulate gene expression in response to small signaling molecules. The NR family includes receptors for thyroid hormone (TH) (Yen, 2001), retinoids, vitamin D, steroid hormones, fatty acids, bile acids and cholesterol derivatives, a variety of xenobiotics and other ligands. Additionally, other members are called orphans and could either bind to ligands that have not yet been identified or modulate gene expression in a ligand independent fashion (Webb et al., 2002).
Since NR play important roles in development and disease, they are important candidates for pharmaceuticals. This family of proteins can be modulated by natural and synthetic ligands and are therefore promising targets for drug discovery. The natural ligands may include different kinds of plant molecules or even a combination of compounds present in raw extracts of medicinal plants.
1.1. Compounds that bind NR
Ligands that target NRs include TH, glucocorticoids, estrogens for hormone replacement therapy (HRT), the diabetes drug thiazolidinedione, synthetic retinoids, and many others. Though the list of possible targets is extensive, it is restricted by the fact that NR ligands have both beneficial and deleterious effects. For instance, TH improves overall lipid balance and promotes weight loss by increasing metabolism, but causes tachycardia that can be severe enough to lead to heart failure, muscle wasting and osteoporosis (Felig & Baxter, 1995; Braverman et al. 2000). Likewise, estrogen use in HRT alleviates symptoms of hot flashes and reverses bone loss, but increases the risk of breast and uterine cancers, and stroke (Gustafsson, 1998; McKenna & O´Mally, 2000; McDonnel & Norris, 2002).
1.2. Thyroid hormone receptor (TR) isoforms
Studies of TR isoform-specific knockout mice and patients with resistance to thyroid hormone syndrome suggest that TR α mediates the effects of thyroid hormone on heart rate, whereas analogs that exclusively stimulate TR beta might have desirable effects without causing cardiac distress. Indeed, animal studies using thyroid receptor agonists with modest TR beta selectivity have validated this hypothesis (Taylor et al. 1997; Baxter et al., 2001; Grover et al., 2003). However, structure-based approaches to develop ligands with further improvements in isoform specificity are limited by the fact that the LBDs of TR alfa and TR beta are ~75% identical in amino acid sequence, and that the internal hydrophobic cavities that hold the hormone, called the pocket of the receptor, differ by just one amino acid (Ser-277 in TR alfa versus Asn-331 in TR beta). Therefore, it would be interesting to develop selective TR agonists that increase metabolism and improve lipid balance, but do not cause side effects on the heart. The first compound to show this property was GC-1 (Figure 2), an analog of T3 (Chiellini et al., 2002).
2. TR antagonists
2.1. First generation of synthetic ligands
TR antagonists would be useful for short-term relief from the symptoms of hyperthyroidism, and might even be used on a long term basis. The first generation of T3 antagonists, which include DIBRT, HY-4, and GC-14, used the “extension hypothesis” as a general guideline in hormone antagonist design (Baxter et al., 2002; Yashihara et al., 2001; Chiellini et al., 2002). This extension in the ligand structure blocks normal receptor function by occupying the pocket region where the hormone normally binds.
2.2. Novel series of antagonist compounds
Although the “extension hypothesis” is applicable to the design of nuclear receptor antagonists, the nature of chemical groups that convert agonist ligands to antagonists will likely depend on specific interactions between residues of the receptor and the ligand extension, to help stabilize the antagonist conformation. Following the first designed TR antagonists it was reported the design and synthesis of a novel series of compounds sharing the GC-1 halogen-free thyronine scaffold (second generation). One of them (NH-3) is a T3 antagonist with improved TR binding affinity and potency that allow for further characterization of its observed activity. One mechanism for antagonism appears to be the ability of NH-3 to block TR-coactivator interactions (Ngoc-Ha et al., 2002). NH-3 (Figure 4.) is the first T3 antagonist to exhibit potent antagonism in vivo and therefore may prove to be a generally useful tool for studying the effects of TR inactivation in a variety of animal models. Until now, such studies have been done primarily using TR-knockout mice because a pharmacological tool for inducing TR inactivation has not been available. TR inactivation was limited under previous ligands because they have only a modest affinity and potency for the thyroid hormone receptor (TR), which limits studies of their actions. T3 antagonists such as NH-3 may be useful therapeutic agents in the treatment of hyperthyroidism and other metabolic disorders.
3. Plant ligands of nuclear receptors
3.1. Estrogen analogs
Although modern research on drug discovery involves the design of hormone analogs based on the structure of the receptor, natural ligands can also be found in nature. Estrogen analogs are most common and have been discovered in a variety of plants. Ginsenosides (Figure 5.) for instance, found in
3.2. Androgen analogs
As compared to estrogen analogs, androgen-like compounds in the flora are less frequently referred in scientific literature. But a few chemicals have shown androgen-like activity. Andrographolide (Figure 7.), an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth (Chun et al., 2010). According to the author, this phytochemical could be developed as a therapeutic agent to treat both androgen-stimulated and castration-resistant prostate cancer. Another compound, Isoangustone A, present in hexane/ethanol extract of
3.2.1. Androgen ligands in the diet
Some studies have specifically demonstrated that consuming one or more portions of broccoli per week can reduce the incidence of prostate cancer, and also induce the progression from localized to aggressive forms of prostate cancer (Trakka, et al. 2008). The reduction in risk may be modulated by glutathione S-transferase mu 1 (GSTM1) genotype, with individuals who possess at least one GSTM1 allele (i.e. approximately 50% of the population) gaining more benefit than those who have a homozygous deletion of GSTM1, according to the author.
From these studies, we can conclude that diet has a significant influence on the activity of the androgen receptors and possibly other types of nuclear receptor. If so, a wide range of diseases may be avoided by increasing intake of food that contains hormone analogs or other nuclear receptor modulators.
3.3. Plant thyroid hormone analogs
Concerning the thyroid hormone receptor, we find even fewer studies about thyroid hormone (T3 and T4) analogs in plants. In a work about patients where thyroid have been removed partially or totally due to thyroid cancer, the plant
Genistein (Figure 7.) and daidzein, the major components of soy, influence thyroid hormone synthesis by inhibition of the iodide oxidizing enzyme thyroperoxidase. This interferes with thyroid hormone transport proteins and 5′-deiodinase type I activities in peripheral tissues, leading to altered thyroid hormone action at the cellular level. Synthetic flavonoids, such as F21388, which is structurally similar to thyroxine, cross the placenta and also reach the fetal brain of animal models (Hamann et al. 2008).
The cruciferous family was also referred when we consider thyroid modulators in plant. In a study that examined the effects of both soy-foods and specific phytoestrogenic molecules on the development of thyroid cancer in humans it was demonstrated that intake of plants from that family decreases the risk of this kind of cancer (Horn-Ross et al., 2002). The compounds that may be associated with this effect are, according to the author, isoflavones, lignans and 2-hydroxyestrogens. Although anti-carcinogenic response was linked to those molecules, it was not explained how they may affect metabolism in humans or their physiological mechanism of action. Another compound, indole-3-carbinol, the most studied component of cruciferous vegetables, has been demonstrated to have chemopreventive activity in several different animal models of carcinogenesis, including mammary gland, but in another hand, the same compound has also been reported to exhibit adverse promoting effects, including liver and thyroid gland tumorigenesis (Murilo & Mehta, 2001).
It seems to have a cross talk between the thyroid hormone receptor and the estrogen receptor. Our recent results (Cunha Lima et al, not published) have shown that ligands originally referred for thyroid diseases have activated estrogen receptor in transient transfection assays. This could explain why phytoestrogens have caused responses in thyroid cancer and thyroid hormone analogs have also effect in breast cancer, for example.
3.4. Toxicity of thyroid hormone analogs
Considering medications used for thyroid hormone replacement, as sodic levothyroxine, aT4 analog, the side effects referred (Cunha Lima, 2008) may include headache, chest pain, rapid or irregular heartbeat, shortness of breath, trembling, sweating, diarrhea and weight loss. The most severe responses are those related to the heart, which can lead to serious cardiopathies and are due to the α isoform of the receptor, as cited previously. A single base difference in the pocket of the protein can lead to these harmful responses. This means that we have a two step work on the search for new agonists and antagonists: they should mimesis the response caused by the thyroid hormone (or antagonize it, depending on the disease) and second, they should have a β specificity to avoid tachycardia and more serious heart problems.
In the other hand, some compounds that modulate TR may not be specific for this receptor, as it is very common with estrogen ligands. Since women hormone analogs may interfere with the function of the thyroid, as referred before with some flavonoids, they may have beneficial effects in cases of thyroid cancer. Nevertheless those compounds may influence thyroid actions at the cellular level and could cause side effects harmful for healthy individuals.
3.5. Ethnobotanical search for TR plant ligands
Since thyroid hormone analogs have much fewer discovered natural ligands, and most of those nuclear receptor ligands are found from plant sources, ethnobotanical surveys can be a good strategy to discover hormone analogs in nature. This approach has an increased probability of success in locations with higher biodiversity; because they contain a privileged number of candidate species. Along with botanical diversity, ethnobotanical surveys are likely to succeed where the population has an in depth knowledge of medicinal plants and systematically uses those plants to treat a range of metabolic disorders.
In a recent work (Cunha Lima et al., 2008) we investigated the medicinal flora used for the treatment of metabolic disorders in Salvador, Bahia, in Northeastern Brazil. The city has hot, tropical weather, with average daily highs reaching 170C in the winter and 380C in the summer. Northeastern Brazil is the economically poorest region of the country, 60% of the active population has an income under $100 per month, (Brazilian Institute of Statistics and Geography, 2003) and many residents depend on medicinal plants to treat multiple ailments and diseases.
The referred study analyzed the knowledge of the urban population of Bahia city on the use of potentially therapeutic plants for the treatment of Diabetes mellitus type 2 (DM2), thyroid diseases, obesity and cardiopathies. Questionnaires were applied to traditional healers as well as to patients of the thyroid disease and diabetes ambulatory in the Hospital from Federal University of Bahia (UFBA). Thirty-one cited species were collected, taxonomically classified, and stored in Alexandre Leal Costa Herbarium (ALCB) from UFBA. Leaves were most commonly used in preparations (87%), followed by the whole plant (10%), and fruits and seeds (3%). The majority of the preparation (88%) required decoction (boiling the plant tea for at least 5 minutes); the rest includes infusion (liquid preparation without boiling) and ingestion of the fresh plant. Among the plant parts used the leaves were more frequent (87%), followed by the whole plant (10%), seeds and fruits (3%). The families Asteraceae (17%), Lamiaceae (15%) and Myrtaceae (12%) were the most cited among plants referred.
This survey identified botanical families frequently cited in other surveys of medicinal plant use in Brazil. In two studies conducted in the state of Rio de Janeiro, one in Rio city (Azevedo & Silva) and one in the reservation of Mangaratiba (Medeiros et al., 2005), the Asteraceae and Lamiaceae family of plants were the most frequently cited, the same happening in Conceição Açú-MT (Pasa et al., 2005). Species from the Asteraceae family were also the most frequently noted for medicinal use in a survey done in Ingaí-MG (Botrel et al., 2006) and by a “quilombola”(community of people descended from former Brazilian slaves), among the plants with possible action in the central nervous system (Rodrigues & Carlini, 2004). These data suggest that the Asteraceae and Lamiaceae family have excellent pharmacological potential on different kinds of diseases and they are currently being investigate in many clinical studies.
In the survey performed by our group in Salvador (Cunha Lima, 2008), the plant most used for the treatment of DM2 belongs to the genus Bauhinia (pata-de-vaca). The most commonly cited species in this work,
Among the plants used for obesity control, with probable effect on the metabolism,
The problems related to the thyroid attended at the Hospital of Federal University of Bahia include throat itch, tachycardia, arm pain, chokings, dizziness and fainting. The most extreme side effects symptoms are associated with the T4 hormone replacement for patients whose thyroid was partially or completely removed. The doses used vary from 50 to 200mcg/day of sodic levotiroxine. In addition to the plants cited for treatment of thyroid problems, watercress (
Ethnobotanical surveys are good source of information for drug candidates and offer a less expensive way of finding hormone analogs than the design of synthetic compounds. The cited information represents an important source of regional knowledge on plants with pharmacological potential and presents 31 candidates (Table 1) that might contain triiodothyronine (T3) and thyroxin (T4) analogs, including agonists, antagonists and other compounds able to modulate thyroid receptor that may act against metabolic disorders.
Brazil has more than 55.000 species of cataloged plants (Simões & Schenkel, 2002), a significant portion of which has some phytotherapic activity known by the local population. However, the number of patents on plant-based pharmaceuticals is very small. In particular, the capital of Bahia has numerous plants used by inhabitants to treat diseases and this use is part of the local culture, based in the Candomblé (religion of African origin which uses many plants in rituals and treatments). Traditionally, information about medicinal plants is shared orally. Therefore, it is necessary to scientifically systematize and analyze this phytotherapic knowledge so that those species can be identified and their pharmacological properties tested.
Table 2 lists the species referred in this survey that had their active principles identified and/or properties confirmed, and the bibliographic references where the data was obtained. These works include results from clinical and experimental studies aiming the confirmation of therapeutic properties.
|aroeira||76103||Anacardiaceae||Schinus terebinthifolius Raddi|
|graviola||76101||Annonaceae||Annona muricata L.|
|jaca-de-pobre||76154||Annonaceae||Annona montana Macfad|
|carrapixo-de-agulha||76135||Asteraceae||Bidens bipinnata L.|
|carrapixo-preto||76111||Asteraceae||Bidens pilosa L.|
|chapéu-de-couro||76138||Asteraceae||Zinnia elegans Jacq.|
|urucum||76100||Bixaceae||Bixa orellana L.|
|cactus||78152||Cactaceae||Cereus sp. L.|
|pata-de-vaca||76159||Caesalpiniaceae||Bauhinia forficata Link|
|amendoeira||76096||Combretaceae||Terminalia catappa L.|
|cana-de-macaco||76122||Costaceae||Costus spiralis (Jacq,) Roscoe|
|mamona||76141||Euphorbiaceae||Ricinus communis (L.) Müll. Arg.|
|urtiga||76108||Euphorbiaceae||Tragia volubilis (L.) Müll. Arg.|
|alecrim ou alecrim-do-reino||76128||Lamiaceae||Rosmarinus officinalis L.|
|hortelã-grosso||76110||Lamiaceae||Plectranthus amboinicus (Lour.) Spreng|
|quiôiô||76112||Lamiaceae||Ocimum gratissimum L.|
|canela||76099||Lauraceae||Cinnamomum zeylanicum Breyn|
|erva-de-passarinho||76107||Loranthaceae||Struthanthus flexicaulis Mart.|
|Murici||78150||Malpighiaceae||Byrsonima sericea DC.|
|barbatimão||76158||Leguminosae||Abarema cochliocarpum (Gomez) Barnbey|
|jamelão||76156||Myrtaceae||Syzygium cumini (L.) Skeels|
|pitangueira||76163||Myrtaceae||Eugenia uniflora L.|
|capim- cidreira ou capim-santo||75150||Poaceae||Cymbopogon citratus Stapf.|
|roma||76162||Punicaceae||Punica granatum L.|
|carqueija ou vassourinha-de-botão||76132||Rubiaceae||Borreria verticillata (l.) G.Mey|
|laranjeira||76097||Rutaceae||Citrus aurantium L.|
|vassourinha||76114||Scrophulariacea||Scoparia dulcis L.|
|cacau||78148||Sterculiaceae||Theobroma cacao L.|
|erva cidreira||76105||Verbenaceae||Lippia alba N.E.Brown|
|melissa||76120||Verbenaceae||Lippia alba L..|
|levante||76123||Zingiberaceae||Alpinia nutans Roscoe|
|Species||Properties associated to the referred use||Reference|
|Bauhinia forficata||The flavonoids Kaempferitrin and Kaempferol-3-O-α-Diraminoside and the steroid Sitosterol found in the extract own hypoglycemic properties.||da Silva & Cechinel Filho (2002)|
|Terminalia catappa||Leaf extract prepared in different ways produced antidiabetic response with 1/5 of the lethal dose revealed by the lipid, creatine and urea profile as also serum alkaline phosphatase. The same dose caused anti-diabetic effects with fruit extracts.||Ahmed et al (2005)
Nagappa et al (2003)
|Rosmarinus officinalis||The anti-oxidants impair the mechanism of oxidation that occurs in cancer, heart disease , atherosclerosis and aging.||Ibanez et al (2000)|
|Cymbopogon citratus||Intense anti-oxidant activity due to the phenolic composition. The essential oil extracted from the leaf causes depression of the CNS in rats.||Prakash et al (2007);
|Bidens pilosa||Deposits of opaline silica in the leaves and extracts of the whole plant obtained with n- hexane demonstrated significant anti-cancer activity.||Parry (1986); Sundararajan et al (2006)|
|Lippia alba||Flavonoids found in this plant are active against different kinds of cancer including thyroid cancers.||Ren et al (2003)|
|Annona muricata||Graviola, a Brazilian fruit from the plant Annona muricata demonstrated anti-diabetic effect greater than the medication Clorpropamide, oral hypoglycemic from the sulphonilurea class.||Carvalho (2005)|
|Annona montana||The plant has kinase protein inhibitors that act creating obesity resistance and increasing insulin production.||Bialy et al (2005)|
|Syzygium cumini||The species presents anti-diabetic action in clinical and animal studies. Stem extracts stimulate the development of cells positive for insulin in the pancreatic epithelial duct.||Mentreddy (2007); Teixeira et al (2004); Schossler et al (2004)|
|Citrus aurantium||The combination of C. aurantium extract, caffeine and Saint John´s Herb (Hypericum perforatum) is safe and effective for weight lost and improvement of lipid levels in obese adults.||Colker et al (1999)|
|Alpinia nutans||The hidroalcoolic extract induces a dose-dependent decrease in artery pressure in rats and dogs.||Mendonça et al (1991)|
|Lippia alba||The aqueous extract of leaves from this plant, associated to the ones from Melissa officinalis and Cymbopogon citratus caused significant reduction in cardiac rhythm in rats, without changing the contractile strength.||Gazola et al (2004)|
|Bauhinia forficata||The rats treated with decoction of the plant leaves demonstrated significant reduction in serum and urine glucose. The results obtained with the purified extracts confirmed the therapeutic use for treatment of diabetes in clinical studies.||Pepato et al (2002); da Silva & Cechinel Filho (2002)|
|Eugenia uniflora||The empiric use of this plant is due to the hypotensive effect, mediated by vessel dilatation and weak diuretic effect that may be related to increased renal blood flow.||Consolini et al (1999)|
|Punica granatum||Flavonoid rich fractions obtained from fruit extracts demonstrated antiperoxidative effect. Malondialdehyde, hydroperoxide, and conjugated dienes were significantly decreased in the liver, while enzymatic activity of catalase, superoxide dismutase and glutathione reductase have shown significant increase.||Sudheesh (2005)|
|Scoparia dulcis||Plant extracts were effective on decreasing hyperglycemia and the susceptibility to free oxygen radicals in rats.||Latha & Pari (2004)|
Studying medicinal plants can be a less expensive way of finding treatments for hundreds of diseases. This can be an important factor in areas where a great part of the population lacks financial conditions of buying allopathic medication and, in the other hand, have a big incidence of metabolic disorders.
The search for hormone analogs in medicinal plants is extremely promising. Over 100 existing nuclear receptors have been identified, not counting the orphan NRs that lack known ligands. Since those transcription factors modulate almost all genetic activity and human physiology, they are important targets for drug discovery. Besides the ligands, usually hormones, other molecules can also modulate nuclear receptors, including cofactors (co-activators and co-repressors), responsive elements, and other ligands (not exclusively the hormone that naturally binds this receptor). According to that, the molecules found in plants do not have to be only analogs of hormones, but also compounds similar to all other complementary modulators of NRs.
Countries with higher biodiversity are good targets for discovery of plant molecules that can control the activity of thyroid receptor. Unfortunately there is not enough scientific knowledge about their medicinal plants or about patent procedures that would guarantee intellectual property of discoveries made by local scientists. In addition to that, the forests are being devastated very fast before important plant compounds can be found. Therefore, additional research needs to be done to identify new ligands and other molecules in the flora that can modulate TR and may be used in the treatment of diseases related to thyroid malfunction.
Ahmed S. M. Vrushabendra B. M. Dhanapal P. G. Chandrashekara V. M. 2005 Anti-Diabetic activity of Terminalia catappa Linn. Leaf extracts in alloxan-induced diabetic rats. , 4 1 36 39. 1735-2657
Azevedo S. K. S. Silva I. M. 2006 Plantas medicinais e de uso religioso comercializadas em mercados e feiras livres no Rio de Janeiro, RJ, Brasil. , 20 1 185 194. 0102-3306
Baxter J. D. Dillmann W. H. West B. L. Huber R. Furlow J. D. Fletterick R. J. Webb P. Apriletti J. W. Scanlan T. S. 2001 Selective modulation of thyroid hormone receptor action. 76 1-5, 31 42. 0960-0760
Baxter J. D. Goede P. Apriletti J. W. West B. L. Feng W. 2002 Structure-Based Design and Synthesis of a Thyroid Hormone Receptor (TR) Antagonist., 143 2 517 524. 1945-7170
Botrel R. T. Rodrigues L. A. Gomes L. J. Carvalho D. A. Fontes M. A. L. 2006Uso da vegetação nativa pela população local no município de Ingaí, MG, Brasil. , 20 1 143 156. 0102-3306
Bialy L. Waldmann H. Chemie A. 2005Review. Inhibitors of protein tyrosine phosphatases: Next-generation drugs? , 44 25 3814 3839. 1521-3773
Braverman E. Utiger R. D. 2000Ingbar, S.H. & Werner, S.C. The Thyroid: A Fundamental and Clinical Text (9th Edition), Lippincott Williams & Wilkins, Philadelphia. 100781750474
Carvalho A. C. B. Diniz M. F. F. M. Mukherjee R. 2005Hypoglycemic activity studies of some plants used in diabetes treatment in Brazilian traditional medicine. 86 1 11 16. 2176-0667
Chan R. Y. Chen W. F. Dong A. Guo D. Wong M. S. 2002 Estrogen-like activity of ginsenoside Rg1 derived from Panax notoginseng. The , 87 8 3691 3695. 1945-7197
Chiellini G. Nguyen N. H. Apriletti J. W. Baxter J. D. Scanlan T. S. 2002 Synthesis and biological activity of novel thyroid hormone analogues: 5’-aryl substituted GC-1 derivatives.Letters, 10 2 333 346. 0096-0894X.
Chiellini G. Nguyen N. Apriletti J. W. Baxter J. D. Scanlan T. S. Laudet V. Gronemeyer H. 2002, 1st ed., Academic Press, London. 100124377356
Chun J. Y. Tummala R. Nadiminty N. Lou W. Liu C. Yang J. Evans C. P. Zhou Q. Gao A. C. 2010 Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth. . 1 8 868 876. 1947-6019
Colker C. M. Kalman D. S. Torina G. C. Perlis T. Street C. 1999 Effects of Citrus aurantium extract, caffeine, and St. John’s Wort on body fat loss, lipid levels, and mood states in overweight healthy adults. , 60 3 145 153. 0001-1393X.
Consolini A. E. Baldini O. A. Amat A. G. 1999 Pharmacological basis for the empirical use of Eugenia uniflora L. (Myrtaceae) as antihypertensive., 66 1 33 39. 0378-8741
Cunha Lima. S. T. Rodrigues E. D. Melo T. Nascimento A. F. Guedes M. L. S. Cruz T. Alves C. Meyer R. Toralles M. B. 2008 Levantamento da flora medicinal usada no tratamento de doenças metabólicas em Salvador, BA- Brasil., 10 4 83 89. 1516-0572
Da Silva K. L. Cechinel Filho V. 2002Plants of the genus Bauhinia: chemical composition and pharmacological potential. Química Nova, 25 3 449 454.
Felig P. F. Baxter J. D. 1995The thyroid: physiology, thyrotoxicosis, hypothyroidism, and the painful thyroid. Frohman (Eds.), Endocrinology and Metabolism, McGraw-Hill, New York. 0070204489 / 0-07-020448-9.
Gauthier K. Chassande O. Plateroti M. Roux J. P. Legrand C. Pain B. Rousset B. Weiss R. Trouillas J. Samarut J. 1999Different functions for the thyroid hormone receptors TRα and TRβ in the control of thyroid hormone production and post-natal development. EMBO Journal, 18 3623- 631. 0261-4189
Gazola R. Machado D. Ruggiero C. Singi G. Macedo Alexandre. M. 2004 Lippia alba, Melissa officinalis and Cymbopogon citratus: effects of the aqueous extracts on the isolated hearts of rats. , 50 5 477 480. 1096-1186
Grover G. J. Mellström K. Ye L. Malm J. Li Y. L. Bladh L. G. Sleph P. G. Smith M. A. George R. Vennström B. Mookhtiar K. Horvath R. Speelman J. Egan D. Baxter J. D. 2003Selective thyroid hormone receptor-β activation: A strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. , 100 17 10067 10072. 0027-8424
Gustafsson J. A. 1998Therapeutic potential of selective estrogen receptor modulators. , 2 4 508 511. 1367-5931
Hamann I. Seidlova-Wuttke D. Wuttke W. Köhrle J. 2008Environment and endocrinology: The case of thyroidology. , 69 2 116 122. 0003-4266
Hegazy M. E. Mohamed A. E. El -Halawany A. M. Djemgou P. C. Shahat A. A. Paré P. W. 2011Estrogenic Activity of Chemical Constituents from . Journal of Natural Products, 74 5 937 942. 0163-3864
Horn-Ross P. L. Hoggatt K. J. Lee M. M. 2002Phytoestrogens and Thyroid Cancer Risk: The San Francisco Bay Area Thyroid Cancer Study. 11 42 49. 1055-9965
Ibañez E. Cifuentes A. Crego A. L. Señoráns F. J. Cavero S. Reglero G. 2000Combined use of supercritical fluid extraction, micellar electrokinetic chromatography, and reverse phase high performance liquid chromatography for the analysis of antioxidants from rosemary ( L.). Journal of Agricultural and Food Chemistry, 48 9 4060 4065. 0021-8561
Latha M. PARI L. 2004Effect of an aqueous extract of Scoparia dulcis on blood glucose, plasma insulin and some polyol pathway enzymes in experimental rat diabetes. Brazilian Journal of Medical and Biological Research, 37 4 577 586. 1678-4510
Lim W. Nguyen N. Ha Y. Y. Scanlan T. S. Furlow J. D. 2002A Thyroid Hormone Antagonist That Inhibits Thyroid Hormone Action 277 38 35664 35670. 0108-3351X.
Mc Donnell D. P. Norris J. D. 2002Connections and regulation of the human estrogen receptor, , 296 5573 1642 1644. 1095-9203
Mc Kenna N. J. O’Malley B. W. 2000An issue of tissues: divining the split personalities of selective estrogen receptor modulators. 6 960 962. 0154-6170X.
Medeiros M. F. T. Fonseca V. S. Andreata R. H. P. 2004Plantas medicinais e seus usos pelos sitiantes da reserva do Rio das Pedras, Mangaratiba, RJ, Brasil. , 18 2 391 399. 0102-3306
Mendonça V. L. M. Oliveira C. L. A. Craveiro A. A. Rao V. S. Fonteles M. C. 1991Pharmacological and toxicological evaluation of . Memórias do Instituto Oswaldo Cruz, 86 2 93 97. 0074-0276
Mentreddy S. R. 2007Medicinal plant species with potential antidiabetic properties. , 87 5 743 750. 1097-0010
Murillo G. Mehta R. G. 2001Cruciferous Vegetable and Cancer Prevention. 411-2), 17 28. 0163-5581
Nagappa A. N. Thakurdesai P. A. Rao N. V. Singh J. 2003Antidiabetic activity of Linn fruits. Journal of Ethnopharmacology, 88 1 45 50. 0378-8741
Negrelle R. R. B. Gomes E. C. 2007(DC.) Stapf.: chemical composition and biological activities. Revista Brasileira de Plantas Medicinais, 9 1 80 92. 1516-0572
Ngoc-Ha N. Apriletti J. W. Cunha Lima. S. T. Webb P. Baxter J. D. Scanlan T. S. 2002Rational Design and Synthesis of a Novel Thyroid Hormone Antagonist That Blocks Coactivator Recruitment. 45 15 3310 3320. 0022-2623
Parry D. W. O’neill C. H. Hodson M. J. 1986Opaline silica deposits in the leaves of L. and their possible significance in cancer. Annals of Botany, 58 5 641 647. 1095-8290
Pasa M. C. Soares J. J. Germano G. N. 2005Estudo etnobotânico na comunidade de Conceição-Açú. , 19 2 195 207. 0102-3306
Pepato M. T. Keller E. H. Baviera A. M. Kettelhut I. C. Vendramini R. C. Brunetti I. L. 2002Anti-diabetic activity of decoction in streptozotocin-diabetic rats. Journal of Ethnopharmacology, 81 2 191 197. 0378-8741
Pianjing P. Thiantanawat A. Rangkadilok N. Watcharasit P. Mahidol C. Satayavivad J. 2011Estrogenic activities of sesame lignans and their metabolites on human breast cancer cells. , 12 1 212 221. 0021-8561
Prakash D. Suri S. Upadhyay G. Singh B. N. 2007Total phenol, antioxidant and free radical scavenging activities of some medicinal plants. , 58 1 18 28. 0963-7486
Ren W. Qiao Z. Wang H. Zhu L. Zhang L. 2003Flavonoids: Promising anticancer agents. 23 4 519 534. 0198-6325
Rodrigues E. Carlini E. A. 2004Plants used by a Quilombola group in Brazil with potential central nervous system effects. , 18 9 748 753. 0095-1418X.
Schossler D. R. C. Mazzanti C. M. da Luz. S. C. A. Filappi A. Prestes D. da Silveira. A. F. Cecim M. 2004Syzygium cumini and the regeneration of insulin positive cells from the pancreatic duct. , 41 4 236 239. 1413-9596
Seon M. R. Lim S. S. Choi H. J. Park S. Y. Cho H. J. Kim J. K. Kim J. Kwon D. Y. Park J. H. 2010Isoangustone A present in hexane/ethanol extract of induces apoptosis in DU145 human prostate cancer cells via the activation of DR4 and intrinsic apoptosis pathway. Molecular Nutrition & Food Research, 54 9 1329 1339. 1613-4133
Simões C. M. O. Schenkel E. P. 2002A pesquisa e a produção brasileira de medicamentos a partir de plantas medicinais: a necessária interação da indústria com a academia. 2 1 35 40. 0010-2695X.
Sudheesh S. Vijayalakshmi N. R. 2005Flavonoids from - potential antiperoxidative agents. Fitoterapia, 76 2 181 186. 0036-7326X.
Sundararajan P. Dey A. Smith A. Doss A. G. Rajappan M. Natarajan S. 2006Studies of anticancer and antipyretic activity of whole plant (2006). African Health Sciences, 6 1 27 30. 1680-6905
Taylor A. H. Stephan Z. F. Steele R. E. Wong N. C. 1997Beneficial Effects of a Novel Thyromimetic on Lipoprotein Metabolism. 52 3 542 547. 0002-6895X.
Teixeira C. C. Weinert L. S. Barbosa D. C. Ricken C. Esteves J. F. Fuchs F. D. 2004(L.) Skeels in the treatment of type 2 diabetes: results of a randomized, double-blind, double-dummy, controlled trial. Diabetes Care, 27 12 3019 3020. 0149-5992
Traka M. Gasper A. V. Melchini A. Bacon J. R. Needs P. W. Frost V. Chantry A. Jones A. M. E. Ortori C. A. Barrett D. A. Ball R. Y. Mills R. D. Mithen R. F. 2008Broccoli Consumption Interacts with GSTM1 to Perturb Oncogenic Signalling Pathways in the Prostate. , 3 7 1 14. 1932-6203
Vieira I. J. C. Mathias L. Braz-Filho R. Schripsema J. (1999)..Iridoids from Borreria verticillata.Organic Letters, 1 1 8 1169 1171. 1523-7052
Webb P. Nguyen N. H. Chiellini G. Yoshihara H. A. Cunha Lima. S. T. Apriletti J. W. Ribeiro R. C. Marimuthu A. West B. L. Goede P. Mellstrom K. Nilsson S. Kushner P. J. Fletterick R. J. Scanlan T. S. Baxter J. D. 2002Design of thyroid hormone receptor antagonists from first principles. 83 1-5, 59 73. 0960-0760
Yen P. M. 2001Physiological and molecular basis of thyroid hormone action. , 81 3 1097 1142. 0031-9333
Yoshihara H. A. Apriletti J. W. Baxter J. D. Scanlan T. S. 2001A designed antagonist of the thyroid hormone receptor. 11 21 2821 2825. 0096-0894X.
Zubeldia J. M. Nabi H. A. Jiménez D. R. M. Genovese J. 2010Exploring new applications for : can we improve the quality of life of patients with short-term hypothyroidism induced by hormone withdrawal? Journal of Medicinal Food, 13 6 1287 1292. 0109-6620X.