Methee-Fenugreek (Trigonella foenum-graecum L)
Methee-Fenugreek (Trigonella foenum-graecum L)
Methee or Fenugreek an annual, leafy, small herb is native to India. It is commonly found growing in the Mediterranean region. Though it is now cultivated worldwide, India remains the largest producer of Methee or Fenugreek. (1), (2)
Methee has been around for thousands of years being used as a medicine, spice and food for both humans and animals. It is one of the oldest medicinal plants in medical history. Its description is found in Ayurvedic scriptures, (Bhaawaprakaash, Ayurvedic Pharmacopoeia etc.) the oldest repository of medicinal plants. The description of this plant is also found in the Ebers Papyrus (the oldest Egyptian compilation of medical texts), 1500 BC.
Zohary D and Hopf M, authors of the book “Domestication of Plants in the Old World… 2000” note that it is not yet certain which wild strain of the genus Trigonella gave rise to the domesticated Methee-Fenugreek. They believe it was brought in to cultivation in the Near East.
Zohary D and Hopf M, authors of the book “Domestication of Plants in the Old World… 2000” note that it is not yet certain which wild strain of the genus Trigonella gave rise to the domesticated Methee-Fenugreek. They believe it was brought in to cultivation in the Near East.
Zohary D and Hopf M, authors of the book “Domestication of Plants in the Old World… 2000” note that it is not yet certain which wild strain of the genus Trigonella gave rise to the domesticated Methee-Fenugreek. They believe it was brought in to cultivation in the Near East.
Charred Methee-Fenugreek seeds have been recovered from Tell Halal, Iraq, (radiocarbon dating to 4000 BC); and Bronze Age level of Tel Lachish, a National park in Israel. Desiccated seeds of Fenugreek were recovered from the tomb of Tutankhamen. Fenugreek has been listed as a crop grown to feed cattle. (3)
According to Claire Kowalchik, one of the editors of Rodale’s Illustrated Encyclopedia of Herbs (1998), Methee possibly got this name based upon its use as a fodder crop prior to the discovery of its medicinal values in ancient Egypt. (4)
According to some researchers, the word Fenugreek comes from the Latin term Foenum-graecum meaning Greek Hay. The plant has a musty, disagreeable smell.
In German it is called Bockshornklee, in Danish Bukkehornsklover, in Swedish Bockhornsklover and in Norwegian Bukkehornkloverwhich all mean buck- horn’s clover. These names are derived from long and pointed pods of the plant resembling the horns of a Billy goat.
[Note: Buck-Horn: A plant with leaves branched, e.g. Plantago coronopus, also Lobelia coronopifolia (We bster’s Revised Unabridged Dictionary, published 1913 by C. & G. Merriam Co.)
Clover: Herbs having leaves with usually three but occasionally four leaflets.] [7], [8]
In India Methee-Fenugreek seeds are largely employed as spice, as medicine for diabetes, fever, anorexia, cough, inflammatory swellings, abscesses, ulcers, menstrual disorders, menopausal symptoms, stimulation of milk production in breast feeding women. The fresh plant is used as a vegetable. (9)
Traditionally Fenugreek has been used to improve libido and correct impotence (erectile dysfunction). A recent study by the Centre for Integrative Clinical and Molecular Medicine in Australia shows that Fenugreek can ‘spice up’ sex life. Since then Fenugreek is called as‘Natural Viagra’ (10), (11), (12)
In a double blind, randomized, placebo controlled study conducted at the University of Queensland with colleagues at Applied Science and Nutrition (ASN) the scientists found that daily supplements containing an extract from fenugreek appeared to enhance male libido and normalize testorone levels. The research team used a supplement Gencor’s Testofen containing a standardized extract of fenugreek. The researchers stated that saponins found in fenugreek may be the key to the herb’s sexual health benefits. The results were published in the journal of Phytotherapy Research. (13), (14)
The Traditional Chinese herbalists used it for kidney problems and for disorders of male reproductive system. The North African women use the paste of seeds with sugar to gain weight. (15)
The Egyptian women, ancient and modern alike; use Methi-Fenugreek to increase milk flow, to relieve menstrual disorders and abdominal pain. For this they make hilba tea of the herb. The Chinese call it hu lu ba and use it for similar problems. They also use Fenugreek for PMS, menopausal problems, to lessen hot flashes, to increase libido and male potency and to treat arthritis, digestive disorders, GERD and many skin problems.
In folk medicine, Fenugreek has been used to treat boils, cellulitis and tuberculosis. It was a key ingredient in a 19th century patent medicine, Lydia Pinkham’s Vegetable Compound, for dysmenorrhea and postmenopausal symptoms. It also has been recommended to promote lactation. (16), (17), (18), (19)
Botanical: Trigonella foenum-graecum L
English: Greek hay
Sanskrit: Methikaa, Methee
Hindi: Methee
Marathi: Methee
Gujarati: Methee
Kannada: Menthya
Tamil: Vendayam or Venthiyam
Telgu: Mentulu or Menthulu
Bengali: Methe
Russian: Pazhitniik
Japanese: Koroha
Chinese: Ku- Tou
French: Fenugrec
Arabic: Hulba
German: Bockshornklee
AKA Alhova, Bird’s Foot, Greek Clover, Bockshornsamen, Chilbe, Fenegrec, Foenugraeci Semen, Foenugreek, Graine de fenugrec, Greek Hay Seed, Griechische Heusamen, Hu Lu Ba, Trigonella Semen (20), (21), (22)
Kingdom: Plantae
(Unranked): Angiosperm
(Unranked): Eudicots
(Unranked): Rosids
Division: Magnoliphyta (flowering plant)
Class: Magnolipsida
Order: Fabales
Family: Fabaceae, Leguminoseae, Papilionaceae (23), (24), (25)
Indian Agriculture Research Institute has developed two varieties which give high yield and are resistant to diseases. They are:
A. Pusa Early Bunching. It is a quick growing variety. It produces upright shoots. It is a high yielder and gives 2-3 cuttings. This is released by IARI, New Delhi.
B. Kasuri/ Kasun /Champa Methee having heart shaped leaves. It is a late flowering variety. It gives 5-6 cuttings and thus is a heavy yielder. Leaves have special fragrance. This is also released by IARI, Pusa, New Delhi.
Geographical Distribution
Methee-Fenugreek is essentially a cold season crop but off-season cultivation is also practiced. The crop is of 2.5 to 3 month duration. It is also cultivated as a mixed crop along with oats for fodder. It tolerates low temperatures and even frost. It is best suited to tracts of moderate to low rainfall. It is sown in all types of soil. It prefers clayey loam with soil pH of 5.3 to 8.2 and proper drainage of water. It can also grow on black cotton soils. It thrives in full sun.
Though a native of Mediterranean area and India, it is now grown in Pakistan, Argentina, France, North Africa and the United States as a food, condiment, spice, medicinal, dye and forage plant. (27), (28)
Plant MorphologyIt is an erect, strongly scented, leguminous annual about 30-60 cm (1-2 feet) in height (29). It is a hardy and fast growing plant which can grow on field edges, uncultivated land, hillsides and dry grasslands; but requires good sunlight. It needs little if any nitrogen fertilizer and it can enrich soils with nitrogen. 
Methee Plant Methee Flower
 
Methee Plant with Flower Methee Seeds
 
Root: Long, tap root
The herb possesses bacterial nodules on its roots that fix nitrogen which is essential for the plant growth. (30), (31)
Stem: Round with few branches
Leaves: Leaves are light green in color, compound, trifoliate, on hairy petioles, ¾ inch long, lanceolate or obovate, toothed. They are deciduous during the dry season in the tropics or during the winter in temperate regions. (32)
Flowers: White or yellow, pea- like, appear in early summer, axillary, one to two in number, sessile. The flower has 5 petals which make up what is referred to as banner, wing and keel. The banner is the largest upper petal and has two lobes. Two smaller petals form the wings. The last two usually fused together make up the keel below the wings. (33)
Fruit: It is15-20 cm (5-6 inches) long, thin, slender, pointed, beaked, yellow brown malodorous pod or legume containing 10 to 20 seeds.
Seeds: Small, hard, yellowish brown, smooth, about 5 mm long, some are oblong, some rhombic other virtually cubic. A deep furrow splits them giving them a hooked appearance. The groove divides the seed into two parts; a larger and a smaller. Seeds are bitter in taste.(34), (35), (36), (37)
Microscopic Structure
Seed
 
A, vertical section, showing the radicle, one of the cotyledons, and hilum, n.
B, transversesection, showing the radicle, r; both cotyledons, c; and endosperm, e. Magnified (Moeller). (38), (39)
The seed shows a layer of thick-walled, columnar palisade, covered externally with thick cuticle; cells flat at base, mostly pointed but a few flattened at apex, supported internally by a tangentially wide bearer cells having radial rib-like thickenings; followed by 4-5 layers of tangentially elongated, thin-walled parenchymatous cells; endosperm consists of a layer of thick-walled cells containing aleurone grains, several layers of thin-walled, mucilaginous cells, varying in size,long axix radially elongated in outer region and tangentially elongated in inner region; cotyledons consist of 3-4 layers of palisade cells varying in size with long axix and a few layers of rudimentary spongy tissue; 114 rudimentary vascular tissue situated in spongy mesophill; cells of cotyledon contain aleurone grains and oil globules.
Powder- Yellow; shows groups of palisade parenchymatous cells, aleurine grains, oil globules, endosperm and epidermal cells of testa. (37a)
Parts Used
Seeds, leaves and whole plant
Phytochemistry
Fenugreek seeds/ leaves contain:
Carbohydrates: Sucrose, Glucose, Fructose, Myoinositol, Galactose, Raffinose, Verbascose, Digalactosylmyoinositol, Galactomannan, Xylose, Aarabinose.
Protein: 30-36%, with high quality protein; (higher in lysine, and isoleucine than soy bean)
Fats: Bitter fixed oils (Linoleic, Linolenic and Oleic acids) 5%, Volatile oils (very low, less than 0.02%)
Volatile Oils: n- alkanes, and sesquiterpenes
Alkaloids: Trimethylamine, Neurin, Trigonelline, Choline, Gentianine, Carpaine and Betain
Glycosides: Foenugracin, Trigonoesides, Fenugrin
Saponins: Graecunins (they are glycosides of diosgenin, yamogenin, tigonenin, neotigogenin), Fenugrin B, Fenugreekine, Trigofoenosides A-G, Hederagin, Cholesterol and Sitosterol.
Steroidal sapinogens: Yamogenin, Diosgenin, Smilagenin, Sarsasapogenin, Tigogenin, Neotigogenin, Gitogenin, Neogitogenin, Yuccagenin
Phytosterols: Phytoestrogen, Sitosterol
Flavonoids: Orientin, Iso-orientin, Quercetin, Vitexin, Iso-vitexin, Luteolin, Saponaretin, Vicenin-1, Kaempferol, Lilyn, Tricin 7-O-D-glucopyranoside, Naringenin and Apigenin
Coumarins: Trimethyl coumarin, Methyl coumarin, Trigocoumarin
Hormones: Growth hormone, Estrogen (For details see below)
Amino acids: Isoleucine, Leucine, Lysine, 4-Hydroxyisoleucine, Histidine,
L-Tryptophan, Arginine, Cystine, Tyrosine
Vitamins: A (Carotene), B1, B2, B3 (Niacin), B6 (Pyridoxin), B15 (Pangamic acid), B17 (Amygdalin), C, D, E, Folic acid, Inositol, PABA
Minerals: Ash, Sodium, potassium, Magnesium, Calcium, Phosphorus, Iron, Chromium, Iodine, Manganese, Molybdenum, Silicon, Selenium, Sulphur, Zinc
Fiber: Crude fiber, soluble fiber 30%, Insoluble fiber 20%
Mucilage: 28%,
Gum: 23.06%
Neutral detergent
Salicylates
SOD
Co-enzyme Q-10
Calorific value: 370 cal/100 gm. (40), (41), (42), (43)
The C-glycoside flacons Vitexin, Vitexin glycoside and the arabinoside isoorientin have been isolated from the plant.
Fenugreek gel consists chiefly of galactomannans characterized by their high water-holding capacity. These galactomannans have a unique structure and may be responsible for some of the characteristic therapeutic properties attributed to fenugreek. (44), (45), (46)
Researchers have isolated an anti-hyperglycemic compound (GII) from the water extract of the seeds of fenugreek. This compound was different from trigonelline and nicotinic acid isolated earlier. GII at 50mg/kg body weight reduced blood glucose in rabbits as was proved by GTT. Treatment of diabetic rabbits for seven days with GII improved GTT without reducing fasting blood glucose below normal level. After treatment with GII (100mg/kg for three weeks) glycosylated hemoglobin came down and insulin increased to normalvalues in diabetic rabbits. Treatment with GII also brought back the altered TC (total cholesterol), HDL, TAG, PLs and FFAs to normal levels. The treatment with GII is said to be better and safer than the treatment with tolbutamide.
The hypoglycemic effect of GII is said to be mediated through stimulating insulin synthesis and/or increased secretion of insulin by the beta cells. Prolonged administration of GII lowered fasting blood glucose significantly but could elevate the fasting insulin level to a much lower extent suggesting an extra-pancreatic mode of action of GII. The hypoglycemic effect was slow but sustained without any risk of developing severe hypoglycemia. (47), (48), (49), (50)
With the help of modern technology scientists from Beijing Institute of Radiation Medicine, PR China, have identified and isolated rapidly new furostanol saponins from fenugreek seeds. Based on the online screening performance, totally forty six furostanol saponins were detected. Among them twenty were predicted to be new. Finally six were named as (1) trigoneosides XIV, (2) XV, (3) XVI, (4) XVIIa, (5) XVIIb and (6) XIV. (52)
Uptil now, according to the research paper published in February 2013, Kang LP et al of Beijing Institute of Radiation Medicine, No. 27 Taiping Road, Beijing 100850, PR China; have identified ninety five steroidal saponins from the seeds of fenugreek, which included twenty-two pairs of isomers. Thirty of these saponins were identified for the first time. (53)
Researchers working in the Department of Biotechnology, Beijing Institute of Radiation Medicine, PRChina; obtained from the seeds of fenugreek, nine spirostanol saponins and seven mixtures of 25R and 25S spirostanol saponin isomers. Their structures were determined by NMR and MS spectroscopy. In addition, the inhibitory effects of saponins were also evaluated. (54)
Recently researchers isolated a galactagogue principle from fenugreek. The author regrets to elucidate the chemical nature and pharmacology of the principle as he does not find further information about it. (55)
Identity, Purity and Strength
Foreign matter Not more than 2 percent
Total ash Not more than 4 percent
Acid-insoluble ash Not more than 0.5 percent
Alcohol-soluble extractive Not less than 5 percent (55 a)
The Ayurvedic Pharmacopoeia of India
Rasa (Taste): Katu (Acrid, Pungent), Tikta (Bitter), Kashaaya (Astringent), Madhur (Sweet)
Weerya/Virya (Energy State): Ushna (Hot)
Wipaaka/ Vipak (End result, Post digestive effect): Katu (Pungent)
Prabhaawa/ Prabhav (Special Effect, Prominent Effect):
[Note: Here I wish to clarify the meaning of these technical words:
Virya (Weerya): Potency, power, vigor
Vipak (Wipaak): After digestion change of taste. The food we take is acted upon by jatharagni (digestive activity) and the taste of the food changes. The original rasa (taste) changes to vipak (new or same taste.)
[Prabhav (Prabhaawa): Effect, prominent, peculiar or special action of an herb; innate and specific property.]
Gunas (Qualities): Laghu (Light)
Effects on Doshas: Waata, Pitta, Kapha
Actions on Dhaatus (Tissues): Rasa (Lymphatic), Rakta (Blood), Meda (Fat) Asthi (Bones), Shukra
Ayurvedic ActionsDeepan: AppetizerPaachana: DigestiveAnuloman: ProkineticVirechan: LaxativeWaata-Kaphaghna: Alleviates nerve problems and suppresses phlegmPramehaghna: Alleviates diabetes (56)In the Ayurvedic pharmacopoeia (1999) the following properties are mentioned:Rasa (Taste): Tikta (Bitter)Weerya/Virya (Energy State): Ushna (Hot)Wipaaka/ Vipak (End result, Post digestive effect): Katu (Pungent)Guna (Quality): Snigdha (Unctuous), Laghu (Light)Karma (Actions): Ayurvedic Actions:Deepana: DigestiveRuchya: Improves tasteWaatahara: ProkineticKaphahara: Allays phlegm
Actions on Srotas (Systems): Rasawaha (Lymphatic), Rakta (Blood), Annawaha (GI System), Majjaa (Bone marrow), Mootrawaha (Excretory), Respiratory, Sweat, Lactation, Shukra-aartawa (Reproductive) (57)
The following information is available about Methee (Fenugreek) in the Ayurvedic pharmacopeia (1999).
Rasa (Taste): Tikta (Bitter)
Veerya (Virya): Ushna (Heating)
Vipaaka (Vipaka- Post digestion/post digestive effect): Katu (Pungent)
Guna (Quality): Snigdha (Unctous)
Karma (Actions): Deepana (Appetizer), Ruchya (Improves taste), Waatahara (Carminative), Kaphahara (Removes phlegm)
Bhaavaprakaash (2005) is in agreement with the information given above.
Drawyaguna, the textbook of Ayurvedic Pharmacopeia describes the following properties and actions of Methee (Nichteswar, 2007):
Rasa (Taste): Katu (Pungent)
Veerya (Virya): Ushna (Heating)
Vipaaka (Vipaka- Post digestion/post digestive effect): Katu (Pungent)
Guna (Quality): Laghu (Light), Snigdha (Unctous)
Karma (Actions): Deepana (Appetizer), Waatahara (Carminative), Raktapittahara (Anti Gout) when entered into the prakopa awasthaa (i. e. when the disease is well established by well developed pathology)
According to Lad (1988), Methee acts on the following Dhatus (Body tissues):
Annawaha (Digestive System), Rasa (Lymph), Rakta (Blood), Majjaa (Bone marrow and nerves), Shukra and Aartawa (Reproductive system).
Note the difference of opinion of experts. (58)
Methee- Fenugreek has antipyretic, astringent, aphrodisiac, carminative, demulcent, diuretic, emmenagogue, emollient, expectorant, galactogogue, restorative, spermicidal, stomachic, tonic, vermifugal and anabolic properties. (59), (60).
According to modern view, Methee-Fenugreek has antiinflammatory, antioxidant, antipyretic, diaphoretic, antimicrobial, antiviral, antiseptic, disinfectant, vulnerary, neuromuscular stimulant, expectorant, antihypertensive, cardiotonic, digestive, nutritive, antispasmodic, carminative, stomachic, antacid, astringent, emollient, demulcent, laxative, tonic, antifatigue, anabolic, adaptogenic, antidiabetic, hypolipidemic, lactogenic, aphrodisiac, utero tonic, emmenagogue, antitumor properties. (61)
Pharmacology of FenugreekCarbohydrates Fructose Molecular formula: C6H12O6 Structural formula: 
Fructose or fruit sugar, a simple monosaccharide, is an isomer of glucose. It is found in fruits, vegetables, sugar cane, sugar beets, flowers, berries, most root vegetables and honey. It exists in foods as a free monosaccharide or bound to glucose as sucrose. Fructose, glucose and sucrose may all be present in food simultaneously at varying proportion of each of these three sugars.
Fructose was discovered by a French chemist Augustine-Pierre Dubrunfaut in 1847. Fructose is a white, odorless, crystalline solid and is the most water-soluble of all the sugars. It is the sweetest of all the sugars.
While sperm cells and some intestinal cells do use fructose directly, it is primarily metabolized in the liver.
Compared with consumption of high glucose beverages; drinking high fructose beverages with meals results in lower circulating levels of insulin and leptin and higher levels of ghrelin after meal. Insulin and leptin decrease appetite and ghrelin increases it. Researchers therefore believe that eating large amounts of fructose can cause weight gain. Excessive consumption of fructose may contribute to the development of NASH.
A person’s blood glucose level rises following consumption of food, relative to consumption of pure glucose. Glycemic index of glucose is 100. The Glycemic Index (GI) is a numerical scale used to indicate how fast and how high a particular food can raise our blood glucose level. Fructose has the lowest glycemic index (GI=19) of all the natural sugars. (62).
Fructose is metabolized by insulin-independent pathways in the liver, intestinal wall, kidney and adipose tissue. This is good news for diabetics. Hence recently fructose has been widely used in diabetic patients for intravenous feeding in medicine and surgery. However, the rapid infusion of large amounts of fructose may cause accumulation of lactic acid in the extracellular fluid culminating into lactate acidosis with concomitant impairment of acid-base balance. This is a relative contraindication to the use of intravenous fructose in the treatment of diabetes ketoacidosis. It has been reported that the administration of fructose in large amounts induces hyperlipidemia, but its atherogenic properties have recently been challenged.
Fructose accelerates ethanol metabolism in the liver. But no well-documented reports on the use of fructose in the treatment of alcohol intoxication have been published. Recently it has been suggested that fructose might be of value in the treatment of delirium tremens.(63), (64)
A new study has revealed that fructose rapidly causes liver damage in an animal model. (65)
It is widely known that various cancers use glucose to fuel their growth. But Dr. Anthony Heaney an associate professor of medicine and neurosurgery and researcher at Jonsson Cancer Center has for the first time shown a link between fructose and cancer proliferation, especially the pancreatic cancers. (66)
Fructose may not influence metabolic activity or blood flow in brain regions regulating satiety, and hence may promote overeating.
A study in 2008 found a link between consumption of fructose and development and precipitation of gout. (67)
Myo-inositol Molecular formula: C6H12O6 Structural formula:  Inositol or cyclohexane-hexol or myoinositol (former name meso-inositol) is a carbohydrate though not a classical sugar. It has half the sweetness of sucrose. It exists in nine possible stereoisomers.
Myo- Inositol was once considered as a member of the vitamin B complex, however because it is produced by the human body from glucose, it is now omitted from that group.
Myo-inositol is produced in many human tissues. Myo-inositol or its phosphates are found in many foods, in particular fruits such as oranges. The best sources of Myo-Inositol are fruits, beans, grains and nuts. There is very little Myo-Inositol in milk, curd and yogurt.
Inositol and some of its mono and polyphosphates function as the basis for a number of signaling and secondary messenger molecules. They are involved in: insulin signal transduction, cytoskeleton assembly, nerve guidance, intracellular calcium concentration control, maintenance of cell membrane potential, breakdown of fats and reducing blood cholesterol, gene expression and polycystic ovarian syndrome. (68)
Inositol is used for diabetic neuropathy, panic disorder, insomnia, liver diseases, lowering high cholesterol, lowering high levels of triglycerides, lowering high blood pressure, depression, schizophrenia, Alzheimer’s disease, attension deficit-hyperactivity disorder (ADHD), autism, respiratory distress syndrome, promoting hair growth, psoriasis, PCOD, lowering high levels of testosterone and some cancers. (69)
Side effects:
Allergic reactions (skin rashes, itching of the skin etc.), breathing problems, chest pain, flatulent dyspepsia, nausea, vomiting and diarrhea may be noticed.
Information from modern research:
In one study it was found that the administration of myo-inositol was associated with a decrease of serum testosterone and a great improvement of the ovulatory function. Myo-inositol improves the number and the quality of oocytes collected after ovarian stimulation in patients undergoing IVF. (70)
Treatment of PCOS patients with Myo-inositol decreased serum insulin and total testosterone levels as well as improved other metabolic factors. (71)
The patients of PCOS develop hirsutism, acne, a characteristic pattern of baldness (alopecia), ovulation disorders and insulin resisrance resulting in impaired glucose tolerance. Researchers from IRCCS San Raffaele Hospital, Vita-Salute University, Milan, Italy; found that after 3 months of administration of Myo-inositol plasma LH, total and free testosterone, insulin significantly reduced. No significant change was observed in plasma FSH and androstenedione levels. Further, after 6 months of therapy hirsutism and acne decreased significantly. (72)
Galactose
Molecular formula: C6H12O6Structural formula: 
Galactose or “milk sugar” is a simple sugar (monosaccharide). It is less sweet than glucose. It is found in dairy products, beets, gums and mucilages. It is also synthesized by the body where it forms part of glycolipids and glycoproteins in several tissues. When combined with glucose, through a dehydration reaction, the result is the disaccharide lactose. The hydrolysis of lactose is catalysed by the enzyme lactase. In the human body glucose is changed into galactose to enable the mammary glands to secrete lactose.
Galactose is a component of antigens present on red blood cells that determine ABO blood group system. In O and A antigens, there are two monomers of galactose on the antigens, where as in the B antigen there are three monomers of glucose.
High doses of galactose have a laxative effect.
Alpha galactose can cause delayed allergy in some hypersensitive subjects.
Inborn errors of galactose metabolism are known. Those individuals suffering from galactosemia cannot properly breakdown galactose as the result of a genetically inherited mutation in one enzyme. To them even small amount of galactose is harmful.
Galactokinase deficiency can result in the formation of nuclear cataracts without provoking symptoms of intolerance.
Some ongoing studies suggest galactose may have a role in the treatment of focal segmental glomerularsclerosis (a kidney disease resulting in kidney failure and proteinuria). This effect is likely to be a result of binding of galactose to focal segmental glomerularsclerosis (FSGS) factor. (73)
Raffinose
Molecular formula: C18H32O16 5 H2OStructural formula:  Verbascose Molecular formula: C30H52O26 Structural formula:  (75)
Digalactosylmyoinositol /Galactomannan
Vide infraXylose Molecular formula: C5H10O5 Structural formula: 
Protein
Methee-Fenugreek contains 30-36% high quality protein; (higher in lysine, and isoleucine than soybean)
Fats
Bitter fixed oils (Linoleic, Linolenic and Oleic acids) 5%, Volatile oils (very low, less than 0.02%)
Linoleic acidMolecular formula: C18H32O2 Structural formula:  (78)
LA is an essential fatty acid. The human body cannot synthesize it from other food components. The two families of essential fatty acids (EFAs) that humans require are omega-3 or n-3which comes mainly from fish oils and omega-6 or n-6 which comes from vegetable oils. LA belongs to the second family. (79)
It is abundant in poppy seeds, safflower, sunflower and corn.
LA is a polyunsaturated fatty acid (PUFA) used in the biosynthesis of arachidonic acid (AA) and thus some prostaglandins. It is found in the lipids of cell membranes. Excessive levels of certain omega-6 fatty acids relative to omega-3 fatty acids have negative health effects; but increased intake of certain omega-3 fatty acids with a decrease in omega-6 fatty acids has been shown to attenuate inflammation.
The survivors of a first myocardial infarction, assigned to a Mediterranean alpha-linoleic acid rich diet, had a markedly reduced rate of recurrence, other cardiac mortality and overall mortality.
LA can be useful in prevention of cancers, cystic fibrosis and dementias.
It may be interesting to know that along with oleic acid, linoleic acid is released by cockroaches upon death that prevents other roaches from entering the area.
Over eating of LA may lead to obesity by damaging the arcuate nucleus in the hypothalamus. (80)
If a person does not eat sufficient amounts of essential oils, he may develop dry hair, hair loss and poor wound healing. (81)
Linolenic acid
Molecular formula: C18H30O2 (82)Structural formula:  (83)
Linolenic acid, an unsaturated fatty acid is an essential oil. Linolenic acid should not be confused with linoleic acid or lipoic acid. Linolenic acid is an Omega-3 fatty acid and linoleic acid is an Omega-6 fatty acid. The technical term for linolenic acid is Alpha linolenic acid (ALA).
ALA was first isolated by Rollette in 1942 and was first artificially synthesized in 1995.
Apart from methee-fenugreek, it occurs in soya bean oil, flax seed oil (linseed oil), rapeseed oil (canola oil) and walnuts.
ALA maintains the blood pressure to normal levels and lowers the risk of cardiovascular disease. It also has neuroprotective effect.
A study was conducted on 50,000 women at Havard University. For ten years the womwn had higher intake of ALA combined with lower intake of LA. The study showed that they had significant reduction of mental depression.
In a study in 2005 it was found that daily administration of ALA significantly reduced anxiety, stress levels and cortisol levels in college students.
High doses of ALA have been linked to possible increase in risk for prostate cancer or macular degeneration, so it is essential to consume this essential nutrient in moderate amounts. (84), (85)
Oleic acid
Molecular formula: C18H34O2Structural formula:  Oelic acid is a monounsaturated fatty acid (MUFA) that occurs naturally in many plant sources and various animal products. It is an odorless, colorless liquid. It is omega-9 fatty acid and is considered one of the healthier sources of fat in the diet. The term “Oleic” means related to or derived from oil or olive.
It is abundantly present in pecan oil, canola oil, peanut oil, sunflower oil, grape-seed oil, sesame oil, poppy-seed oil. While many nuts contain oleic acid as the primary fat, most meats (chicken, turkey, lard) contain a combination of both saturated and monounsaturated elements.
Oleic acid is the most abundant fatty acid in human adipose tissue.
In triglyceride form oleic acid is included in normal human diet as part of animal fats and vegetable oil.
Oleic acid decreases elevated low-density lipoprotein (LDL) cholesterol and increases high-density lipoprotein (HDL) cholesterol. However its ability to raise HDL is debated. It may be responsible for hypotensive effect.
Oleic acid may arrest the progression of adrenoleukodystrophy (ALD), a fatal disease that affects the brain and adrenal glands.
[Note: ALD is a disorder in which very-long chain fatty acids accumulate in the tissues throughout the body. The exact mechanism of the pathogenesis of the various forms of ALD is not known. The most severely affected tissues are the myelin in the CNS, the adrenal cortex and the Leyding cells in the testis.
The white matter, with reduced volume and increased signal intensity, the anterior white matter is spared. The features are consistent with x-linked adrenoleukodystrophy
Clinically ALD has a bizarre patern. As an x-linked disorder ALD presents most commonly in males. Approximately 50% of heterozygote females show symptoms of ALD in later life. Approximately one third of ALD patients will present in the childhood with signs of cerebral involvement. It is characterized by normal development in early childhood, followed by rapid degeneration to a vegetative state. The other forms of ALD may present with adrenal insufficiency or progressive paraparesis in early adulthood. This form is typically known as adrenomyeloneuropathy.]
Increased levels of oleic acid and MUFA in the membranes of RBCs have been associated with increased risk of breast cancer. (86), (87), (88)
Volatile Oils:
Sesquiterpenes
Sesquiterpenes are a class of terpenes that consist of three isoprene units and have the molecular formula C15H24.
Sesquiterpenes are found naturally in plants and insects as defensive agents or pheromones. They are found in some essential oils. (89)
Sesquiterpenes have anti-inflammatory, anti-allergy and anti-septic properties. They can produce profound effects on emotions and maintain hormonal balance via pineal and pituitary gland. They cross the Blood-Brain Barrier increasing the oxygen supply to the brain. They are hepatoprotective. (90)
Alkaloids:
Trimethylamine
Molecular formula: C3H9NSrtyctural formula: 
Trimethylamine is a colorless, hygroscopic, flammable tertiary amine having a strong “fishy” odor in low concentrations and an ammonia-like odor in higher concentrations. It is a product of decomposition of plants and animals.
It is the substance mainly responsible for the odor associated with rotting fish, some infections, foul breath and obnoxious vaginal odor due to bacterial vaginosis seen in women having new or multiple sex partners. It is also associated with taking large doses of choline and carnitin.
Trimethylaminuria is a rare genetic disorder in which the body is unable to metabolize trimethylamine from food sources. It is an autosomal recessive disorder involving trimethylamine oxidase deficiency. Patients develop a characteristic strong fishy odor of their sweat, urine and breath after consumption of soya beans, egg yolk, butter, peanuts, potatoes, cauliflower, lentils, oats, sesame seeds, flax seeds, grass-fed beef i. e. foods rich in choline. (91)
Neurine (also written as Neurin)
Molecular formula: C5H13NO,
Structural formula:
 (92), (93)
Neurine is a quaternary ammonium salt with three methyl groups and one vinyl group attached to the nitrogen atom. Synthetically it can be prepared by the reaction of acetylene with trimethylamine. It is unstable and decomposes readily to form trimethylamine.
Neurine is an alkaloid found in fenugreek, egg yolk, brain, bile and cadavers. It is formed during putrefaction of biological tissues, flesh by the dehydration of choline. It is a poisonous, syrupy liquid with a strong fishy odor. (94)
It was for a long time considered identical with choline. Chemically, however, they are different from each other. (95)
Neurine/Neurin was formerly thought to constitute the nerve tissue hence the name. This toxic amine is produced by bacterial decomposition of choline in the intestines. (96), (97)
Neurine is an acetylcholine autolysis product. It elevates secreted amyloid-beta protein precursor and amyloid-beta peptide levels, and lowers neuronal cell viability in culture. Hence currently its role in Alzheimer’s disease (AD) is being investigated. (98)
Trigonelline
Other names: Nicotinic acid N-methylbetaine, Coffearine, Caffearine, Gynesine, Trigenolline
Molecular formula: C7H7NO2
Structural formula:
Trigonelline is an alkaloid isolated first from fenugreek seeds (Trigonella foenum-graecum, hence the name). It also occurs in garden peas, hemp seed, oats, potatoes and many plants. Holtz, Kutscher and Theilmann have recorded its presence in many animals. It is a product of niacin (vitamin B3) metabolism that is excreted in urine.
Trigonelline is also found in coffee where it may help to prevent dental decay by preventing the bacteria Streptococcus mutans from adhering to teeth. Higher levels of trigonelline are found in robusta coffee.
Trigonelline has antimicrobial, antiviral, neuroprotective, sedative, antimigraine, memoryenhancing, memoryimproving, hypoglycemic, hypoliledemic, gastric stimulant, estrogenic, galactogogue and antitumor activity. It improves diabetic auditory neuropathy. It prevents platelet aggregation. While it acts as secretogogue, it regenerates the beta cells of the pancreas. It is free radical scavenger and reduces oxidative stress. For more details refer: Some Testimonials from Modern Research. (99), (100)
Molecular formula: C5H14NO
Structural formula:
(Note: SAMe or SAM is required for cellular growth and repair. It is also involved in the biosynthesis of Choline a quaternary ammonium salt is a water soluble essential nutrient in the B vitamin family. But by strict definition choline is not a vitamin. It is the precursor molecule for the neurotransmitter acetylcholine. It can be synthesized in the liver and protects the liver from accumulating fat in it. Its dietary source is liver, meat, fish, egg yolk, milk, butter, nuts, peanuts, sesame seeds, oats, lentils, flax seeds, beans, peas, wheat germ, potatoes, cauliflower, sunflower oil and spinach.
Choline and its metabolites are needed for:
1. The integrity and signaling roles for cell membranes
2. The synthesis of neurotransmitter hormone acetylcholine and cholinergic neurotransmission
3. Methyl groups which participate in the S-adenosylmethionine (SAMe) synthesis pathways.
hormones and neurotransmitters. )
Choline is used in the synthesis of the constructional components in the body’s cell membranes. It supports the developing nervous system of the fetus. It is particularly important for brain health and its potential use in brain disorders is great. It has been used experimentally to help improve neuromuscular function in Alzheimer’s disease. It is important for the transmission messages from cells to cells. It is also important for the function of genes. People whose diets are rich in choline have lower levels of inflammatory markers (at least 20%).
Athletes, alcoholics, pregnant women, older children, men and women having faulty dietary habits are at a risk for choline deficiency.
Most common effects of choline deficiency are: fatty liver and hemorrhagic kidney disease. Unexplained fatigue, insomnia and neuromuscular problems are also associated with choline deficiency. (101), (102)
Administration of 14 mg/kg of choline to mice, attenuated the cardiac hypertrophic responses, as indicated by the reduced heart weight, LV weight, LV thickness, and reduced expression of biomarker genes of cardiac hypertrophy. This anti-hypertrophic efficacy was reproduced in a cellular model of cardiomyocyte hypertrophy induced by isoproterenol (ISO) in cultured neonatal cardiomyocytes.
This research showed the cardio-protective effect of choline against cardiac hypertrophy, with correction of expression of miR-133a and calcineurin as possible mechanism. This study suggests that choline supplementation may be considered for prevention and treatment of cardiac hypertrophy. (103)
Gentianine
Molecular formula: C10H9NO2
Structural formula:
It is a bitter crystallizable substance. (104), (105)
Gentianine suppresses increased levels of TNF alpha and IL-6 (anti-inflammatory activity) (106)
Gentianine exhibits anti-diabetic activity. (107)
Gentianine exhibits hypotensive activity. (108)
Gentianine exhibits antipsychotic activity. (109)
Carpaine
Molecular formula: C28H50N2O4
Structural formula:
Carpaine is a crystalline, intensely bitter alkaloid which has the formula C14H25NO2. (110)
When used in increasing doses (from 0.5 mg/kg to 2.0 mg/kg) in male Wistar rats, carpaine progressively decreases the systolic, diastolic and mean arterial pressure. At the dose 2mg/kg, it reduces the stroke volume and cardiac output but the peripheral resistance remains unchanged. Selective autonomic nervous blockade with atropine sulfate (1 mg/kg) or propranolol hydrochloride (8 mg/kg) did not alter the circulatory response to carpaine. From these results it was concluded that carpaine affects the myocardium directly. (111)
Betain (pronunciation: BEET-uh-een)
Molecular formula of Trimethylglycine: C5H11NO2
Structural formula of Trimethylglycine:
Other Names: Betaine Hydrochloride, Trimethyl Glycine, TMG
Trimethylglycine (TMG) is an organic compound that occurs in plants. It was the first betaine discovered by science. Originally it was simply called betaine because it was discovered in sugar beets. Subsequently many other betaines have been discovered.
It is a white crystalline powder freely soluble in water.
TMG is an important cofactor in methylation processes required for the biosynthesis of neurotransmitters, melatonin, and coenzyme Q 10. The major step in the methylation cycle is the remethylation of homocysteine. Betaine is thus involved in the synthesis of many biologically important molecules.
Intracellular accumulation of betaine permits water retention in cells thus protecting them from the perils of dehydration. Although supplementation of TMG or betaine decreases the amount of adepose tissue in pigs, research on human subjects has not shown satisfactory results. It may lower high blood levels of homocysteine and also is useful in the treatment of homocystinuria. Betaine hydrochloride was sold as a “stomach acidifier and digestive aid” but it does not increase gastric acid secretion. Two clinical trials have indicated that TMG may be useful for the treatment of NASH. TMG is sometimes used to treat depression.
Betaine hydrochloride is also used to treat hypokalemia, hay fever, anemia, bronchial asthma, atherosclerosis, gallstones, otitis interna, RA, thyroid disorders and liver disorders.
How it works is not known.
TMG is not free from side effects. TMG supplementation may cause stomach upset, nausea and diarrhea. Total cholesterol levels may be increased in obese persons and in those suffering from kidney disease. (112), (113), (114), (115)
Glycosides/Saponins:
Graecunins (grecunins) are glycosides of diosgenin.
There are two types of testosterone in the body, free and bound. It is the free testosterone which is active. Graecunin is a clinically proven extract of fenugreek that increases free testosterone in the body. Thus grecunin will help the body increase lean muscle mass, loose body fat and increase body strength and libido. (116)
Trigonoesides, Fenugrin, Fenugrin B, Fenugreekine Trigofoenosides A-G. Hederagin are glycosides having a “group or class” action.
Steroidal Sapinogens:
Yamogenin
Molecular formula: C27H42O3
Srtuctural formula:
Yamogenin is a chemical compound of the class called sapogenins found in fenugreek and other plants.
Sapogenins are of two types steroidal and triterpenoidal. Steroidal sapogenins are used in commercial production of sex hormones and triterpenoidal sapogenins in bath and body formulations. (117), (118)
Protodioscin
Molecular formula: C51H84O22
Structural formula:
Though the mechanism for these effects is unclear, protodioscin has been demonstrated to trigger release of NO (nitric oxide) in corpus cavernosum and produce increases in the levels of the hormones testosterone, dihydrotesterone and dihydroepiandrosterone in animal studies; but studies in humans have failed to show efficacy. Therefore its use remains controversial. (119)
Methyl protodioscin (MPD) is an active ingredient of yamogenin. MPD protects the cardiomyocytes (CMC) against anoxia/ reoxygenation (reperfusion) injury. (120)
Methyl protodioscin (MPD) showed distinct antitumor activity. (121)
Methyl protodioscin (MPD) shows the anti-proliferative effect on Hep G2 cells. It arrests the growth and induces apoptosis in Hep G2 cells. These effects were attributed to down-regulation of Cyclin B1 and signaling pathways leading to up-regulation of Bax and down-regulation of BCL2, suggesting that MPD may be a novel anti-mitotic agent.( 122)
Diosgenin
Molecular formula: C27H47O3
Structural formula:
Diosgenin a steroidal sapogenin is the product of hydrolysis by acids, strong bases or enzymes of saponins. It is present in Costus speciosus, Smilax menispermoidea, Aletris, Trigonell and Trillium.
Diosgenin is the precursor for the semi synthesis of progesterone which in turn was used in early combined oral contraceptive pills. The unmodified steroid has estrogenic activity. It can reduce the serum cholesterol levels.
Diosgenin is used for the commercial synthesis of cortisone, pregnenolone, progesterone and many other steroid products. (123)
In obesity, adipocyte hypertrophy and chronic inflammation in adipose tissue cause insulin resistance and type-2 diabetes. Diosgenin in fenugreek decreases the size of adipocytes and reduces inflammation of the adipose tissue by inhibiting macrophage infiltration of the adipocytes. Thus diosgenin ameliorates diabetes. (124)
The steroidal saponin diosgenin found in Fenugreek induces apoptosis in HT-29 human colon cancer cells (at least in part) by inhibition of bcl-2 and by induction of capsase-3 protein expression. It also inhibits azomethane-induced aberrant crypt foci (ACF) formation in F344 rats or preneoplastic colonic lesions. Further detailed studies show that, in rats, diosgenin a major steroidal constituent of Fenugreek prevents azoxymethane-induced colon carcinogenesis during initiation and promotion stages. Thus diosgenin seems to have potential as a novel colon cancer preventive agent. (125)
Smilagenin
Molecular formula: C27H44O3
Structural formula:
 (126)
It is a steroid sapogenin obtained from a Sarsaparilla (Smilax ornata) and is stereoisomeric with sarsapogenin (sarsasapogenin).
Sarsaparilla is used as the basis for a soft drink called Sarsaparilla. Sarsaparilla has also been used as a medicine.
Smilax regelii extracts have in vitro, antioxidant properties.
Smilax regelii, a variety of sarsaparilla, was used by Europeans to treat syphilis. From 1820 to 1910, it was registered in the U.S. Pharmacopoeia as a treatment for syphilis.
Today Sarsaparilla is an important remedy for cystitis, renal colic and kidney stones. It has also been used for eczema, psoriasis, herpes, arthritis, leprosy and impotence (ED). (127), (128), (129)
Sarsasapogenin
Molecular formula: C27H44O3
Structural formula:
Sarsasapogenin
Sarsasapogenin found as a glycoside in the roots of many plants is a steroidal sapogenin. It was first isolated in 1914 from Sarsaparilla root and hence was named after it.
C- 25 epimer smilagenin
Sarsasapogenin and its C-25 epimer smilagenin lowered blood sugar in experiments with mice. They also halted the decline in muscarinic acetylcholine receptors in animal models of Alzheimer’s disease.
(Note: In stereochemistry the term ‘epimer’ refers to one of a pair of sterioisomers. The two isomers differ in configuration at only one steriogenic centre. All other steriocentres in the molecules, if any are the same in each.)
Sarsasapogenin has been used as a starting material for the synthesis of other steroids and sex hormones. (130)
Sarsasapogenin has been used in breast creams as a volume-enhancing, firming and reshaping agent. It has a progressive, intense, anti-sagging action which can restructure and give support to the breast.
Sarsasapogenin interacts with adipose cells and triggers them to divide and grow, thus increasing the amount of fat in the breast. (131), (132)
Beware! Long term use of sarsasapogenin and smilagenin can cause unacceptable cholinergic side effects and can damage GI tract, liver and kidney.
Direct contact of the material with the eye may result in excessive tearing and conjunctival redness.
Handling the material containing sarsasapogenin and smilagenin can cause contact dermatitis.
Inhalation of the dust containing sarsasapogenin and smilagenin can cause allergic rhinitis, bronchospasm, bronchitis and pulmonary edema. (133)
Tigogenin
Molecular formula: C27H44O3
Structural formula: Tigogenin is a crystalline steroidal sapogenin found in fenugreek and can be obtained by hydrolysis tigonin. (134)
It has anti-inflammatory, analgesic, anti-diabetic and immune enhancing properties. (135)
It is used as starting raw material in the production of corticosteroids.
Neotigogenin
Molecular formula: C27H44O3
Structural formula:
 (136)
Neotigogenin is the isomer of tigogenin. They are the simplest sapogenins having correct configuration from which to make steroids and steroidal hormones. (137)
When administered orally, glycosides having neotigogenin aglycone moieties inhibit absorption of cholesterol in the GIT. These compounds are useful in the treatment of hypercholesterolemia. (138)
Gitogenin
Molecular formula: C27H44O4
Structural formula:
Gitogenin is a crystalline, steroidal glycoside found in the seeds of fenugreek and in many other plants. It is soluble in chloroform, hot alcohol and ether; sparingly soluble in cold ethyl acetate and insoluble in water.
It is used in medicine for treating coronary artery disease. (139), (140)
Neogitogenin
Molecular formula: C27H44O4
Structural formula:
 (141)
Its pharmacological actions are similar to gitogenin.
Yuccagenin
Molecular formula: C27H42O4
Structural formula:
 (142)
Yuccagenin markedly lowers the cholesterol and triglyceride content in the blood serum of healthy animals and animals with experimental hyperlipidemia. (143)
Phytosterols
Sitosterol
Molecular formula: C29H50O
Structural formola:
Beta-Sitosterol is one of several phytosterols (plant-sterols) with chemical structure similar to that of cholesterol. Beta-Sitosterol is a white, waxy powder with a characteristic odor. It is hydrophobic and soluble in alcohol.
Beta-Sitosterol is found in fruits, vegetables, nuts, and seeds. It is found in pumpkin seeds, cashew, rice bran, wheat germ, corn oils, soybeans and dandelion coffee.
It inhibits absorption of cholesterol from the intestine and reduces total cholesterol and LDL cholesterol. After absorption from the intestine it is incorporated in the cellular membrane.
One small study shows a positive effect on male hair loss in combination with Saw palmetto. In Europe Beta-Sitasterol is used in herbal therapy for benign prostatic hyperplasia (BPH). It is also used for boosting the immunity; prevent colonic cancer, gallstones, rheumatoid arthritis, tuberculosis, psoriasis, allergies, bronchial asthma, bronchitis, chronic fatigue syndrome and erectile dysfunction.
Beta-Sitosterol should be avoided during pregnancy and breast-feeding.
Beta-Sitosterol should be avoided by individuals with sitosterolemia, a rare inherited fat-storage disorder. This condition is correlated with increased risk of heart disease (even heart attacks) and worsening existing heart disease.
Beta-Sitosterol is a precursor of anabolic steroid boldenone undecyclate that is used in veterinary medicine to induce growth in cattle but commonly absued anabolic steroid in sports. (144), (145)
A study conducted in the Department of Urology, Ruhr-University, Bochum, Germany showed significant improvement in symptoms of the patients of benign prostatic hyperplasia treated with beta-sitosterol. (146)
Flavonoids
The Flavone C- glycosidesMolecular formula: C30H26O12 (147)
A glycoside is a molecule in which a sugar is bound to another functional group. The sugar group is known as the glycone and the non-sugar group as the aglycone or genin. The glycone can consist of a single sugar group (monosaccharide) or several sugar groups (oligosaccharide). Many plants store glycosides in the inactive form. These can be activated by enzyme-hydrolysis which causes the sugar part to be broken off making the chemical available for use. Glycosides play numerous important roles in living organisms. Many plant glycosides are used as medications. In animals and humans poisons are often bound to sugar molecules as part of their elimination from the body. (148)
Recently apigenin and luteolin are the two flavone C-glycosides isolated from seeds of fenugreek. (149)
Molecular formula: C21H20O10 Structural formula:  Vitexin is an apigenin flavone glucoside found in fenugreek and many other plants. (150)
Vitexin is goitrogenic and has antithyroid activity. (151)
Pentylenetetrazole (90 mg/kg, intraperitoneally) induce seizure in rats. Vitexin administered intracerebroventricularly (I. C. V.) has anticonvulsant effects possibly through interaction at the benzodiazepine site of the gamma-aminobutyric acid (GABA) type A receptor complex. (152)
Scopolamine induces memory impairment in rats. Vitexin administered intracerebroventricularly (I.C.V.) showed a potential role in enhancing memory retrieval. A possible mechanism is modulation of cholinergic receptors. (153)
In the study on mice, vitexin administered orally at doses 10, 20, 30 mg/kg showed central and peripheral anti-nociceptive effect. The study showed that the effect was mediated via opiod-related mechanisms. (154)
In mice vitexin showed anti-depressant like effects. This activity is mediated through 5-HT (1A), noradrenergic alpha (2) and dopaminergic D (1), D (2) and (3) receptors. (155)
In one study, cardiac hypertrophy was induced by isoproterenol (ISO) in cultured neonatal rat ventricular myocytes in vitro and by transverse aortic constriction in mice in vivo. Vitexin dose-dependently attenuated cardiac hypertrophy induced by ISO and prevented it induced by transverse aortic constriction as assessed by heart weight/body weight, LV weight/body weight and lung weight/body weight ratios, cardiomyocyte cross-sectional area, echocardiographic parameters and gene expression of hypertrophic markers.
These results indicate that vitexin has the potential to protect the heart against cardiac hypertrophy. (156)
Molecular formula: C21H20O10 Structural formula:  Other names: Homovitexin, Saponaretin
Vitexin and isovitexin are a pair of isomeric compounds. Isovitexin is a flavone. It can be found in passion flower. It is antioxidant. (See also Vitexin, the 8-C-glucoside of apigenin).
In the study on mice, vitexin administered orally at doses 10, 20, 30 mg/kg showed central and peripheral anti-nociceptive effect. The study showed that the effect was mediated via opiod-related mechanisms. (157)
In mice vitexin showed anti-depressant like effects. This activity is mediated through 5-HT (1A), noradrenergic alpha (2) and dopaminergic D (1), D (2) and (3) receptors. (158)
In a study, cardiac hypertrophy was induced by isoproterenol (ISO) in cultured neonatal rat ventricular myocytes in vitro and by transverse aortic constriction in mice in vivo. Vitexin dose-dependently attenuated cardiac hypertrophy induced by ISO and prevented it induced by transverse aortic constriction as assessed by heart weight/body weight, LV weight/body weight and lung weight/body weight ratios, cardiomyocyte cross-sectional area, echocardiographic parameters and gene expression of hypertrophic markers.
These results indicate that vitexin has the potential to protect the heart against cardiac hypertrophy. (159)
It is alpha glucosidase inhibitor. It is a speciality product for proteomics research. (160)
Molecular formula: C15H10O7 Sttrucural formula: 
Quercetin is a flavonoid (plant pigment).
Quercetin is found in fruits, vegetables, leaves, grains and various types of honey. It is found in red wine, onions, green tea, apples, berries, Ginkgo biloba and St. John’s wort.
It is used in beverages and as a food supplements.
Quercetin is anti-inflammatory (hence used in fibromyalgia rheumatoid arthritis and gout). It is anti-oxidant, anti-microbial and anti-viral. It inhibits reverse transcriptase, part of the replication process of retrovirus. It is anti-allergic hence is used in hay fever, bronchial asthma and eczema. It is used to treat diabetes and metabolic syndrome. It is Monoamine-Oxidase (MAO) inhibitor. It is used in treating dyslipidemia and atherosclerosis. It is also used to boost immunity, increase endurance and improve athletic performance.
Quercetin competitively binds to bacterial DNA gyrase. Hence it is contraindicated with some antibiotics especially fluoroquinolones.(161), (162)
Apigenin Molecular formula: C15H10O5 Structural formula:  Apigenin a pale yellow crystalline solid is an aglycone glycoside found in fenugreek and many plants.
Apigenin induces autophagy in leukemia cells but the autophagy simultaneously induces resistance against vincrystine. Apigenin is a potent inhibitor of CYP2C9, an enzyme responsible for the metabolism of many drugs in the body.
In vitro studies have shown that apigenin may be toxic to RBCs.
In rats apigenin has been shown to prevent renal damage caused by cyclosporine.
In the CNS apigenin acts as a monoamine transporter activator. It inhibits the binding of flunitrazepam exerting anxiolytic and sedative effect. It may also stimulate neurogenesis in adults which may be useful for the treatment of neurological diseases, injuries, and degenerative neurological disorders. (163)
Apigenin appears in the blood 24 hours after ingestion. It has a half life of 91.8 hours. It is rapidly metabolized and released into the serum as glucuroside (glucuronide) and sulfate conjugates. It is mostly excreted in the urine but there is some fecal excretion as well due to enterohepatic ejection.
Apigenin can reduce oxidative stress, induce cell cycle inhibition and increase hepatic detoxification enzyme efficacy.
By inhibiting NO-synthase and COX2 enzymes in macrophages apigenin exerts anti-inflammatory effects. It also has inhibitory effects on Interleukin-4 and TNF alpha.
Though it has anxiolytic effect (Dose: 3-10 mg/kg body weight) it has no muscle relaxant effects. Its sedative effects are observed at doses 30-100mg/kg bodyweight.
By calcium build-up in neural mitochondria it exerts neuroprotective effect against excitotoxicity.
Apigenin has interactions with cortisol, estrogen and testosterone. (164)
Apigenin displays hypotensive and antispasmodic properties in vivo. It activates both the intrinsic and extrinsic apoptotic pathways and exhibits antiproliferative activity in human breast cancer cells. (165)
Apigenin has significant promises as a chemopreventive agent against skin cancer. (166)
Luteolin:
Molecular formula: C15H10O6Structural formula:  Luteolin a flavonoid found in fenugreek is a yellow crystalline compound. It is also found in many plants having medicinal and food values. It is antioxidant, anti-inflammatory, free radical scavenger, immune-modulator and promoter of carbohydrate metabolism. It may inhibit cancer, has potential effects on septic shock and is suggested to be useful for the treatment of multiple sclerosis.
In basic research luteolin is a PDE4 inhibitor, phosphodiesterase inhibitor and interleukin 6 inhibitor. Luteolin also acts as a monoamine transporter activator. (167)
For detailed information on Luteolin please visit: http://luteolin.com/beneficial_effects.html (168)
Because luteolin induces apoptosis in squamous carcinoma cells, it can be an effective chemotherapeutic agent for the treatment of oral squamous cell carcinoma. Combination treatment of luteolin with paclitaxel enhances the cytotoxic effect of paclitaxel. (170)
Luteolin (5-10mg/kg) improves memory and learning process; increases the level of glutathione (GSH) in the cerebral cortex and hippocampus and reduces the oxidative stress in the brain. (171), (172)
Anti-inflammatory activity of luteolin exerts neuroproprotective, disease modifying effects in various neurodegenerative disorders including Alzheimer’s disease (AD). (173)
Some researchers have identified several novel luteolin-regulated genes. Their findings provide a molecular basis to understand the versatile effects of luteolin on microglial homeostasis. The data suggests that luteolin can be a promising candidate to develop immune-modulatory and neuroprotective therapies for the treatment of neurodegenerative disorders. (174)
Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells.(175)
In one study on the effect of lutiolin on cell cycle regulation in human nasopharyngeal carcinoma (NPC) cells, it was found that luteolin inhibited cell cycle progression at G1 phase and prevented entry into S phase in a dose and time dependent manner. The data from this study suggests that luteolin can be useful as a chemotherapeutic and chemo-preventive agent in human cancer. (176)
[Note: The cell cycle or cell division cycle consists of four distinct phases. G1phase, S phase (synthesis), G2 phase (collectively known as interphase) and M phase (mitosis). Cells that have temporarily or reversibly stopped dividing are said to have entered a state of quiescence called G0 phase.
Quiescent/Senescent state; Gap 0 or G0 phase: This is a resting phase where the cell has left the cycle and has stopped dividing.
Interphase state; Gap 1 or G1 phase: In this phase, cells increase in size. The G1 checkpoint control mechanism ensures that everything is ready for DNA synthesis.
Interphase state; Synthesis phase: During this phase DNA replication occurs.
Interphase state; Gap 2 or G2 phase: During this phase, the cell will continue to grow. The G2 checkpoint control mechanism ensures that everything is ready to enter the M (mitosis) phase and divide.
Cell division state; Mitosis or M phase: At this stage the cell growth stops and cellular energy is focused on the orderly division into two daughter cells. A checkpoint in the middle of mitosis (Metaphase Checkpoint) ensures that the cell is ready to complete cell division.]
Errors in mitosis can either kill a cell through apoptosis or cause maturations that may lead to cancer. (177)
The data of one study conducted on mice in “Graduate Institute of Chinese Pharmaceutical Science” suggests that, by blocking NF-kappa B and AP-1 activation, luteolin suppresses the LPS-elicited inflammatory events in alveolar macrophages. This effect was mediated via inhibition of generation of reactive oxygen species. This suggests that luteolin may be a therapeutic agent for treating inflammatory disorders in lung. (178)
Flavonoids have been found to possess pro-oxidant and anti-oxidant actions. Researchers of the Department of Radiation Oncology, Chi Mei Hospital, Liouying, Taiwan, found that the effects of luteolin on human lung squamous carcinoma CH27 cell apoptosis resulted from anti-oxidant rather than pro-oxidant action of luteolin. (179)
Luteolin protects myocardium against LPS-induced TNF-alpha expression via inhibition of the NF-kB signaling pathway. This suggests that luteolin may be a potential therapeutic agent for the treatment of inflammation-related myocardial diseases. (180)
Myocardial ischemia damages the structure of the heart muscle which results in alteration of its function. Reperfusion can restore both in most cases. However, reperfusion itself can exacerbate myocardial injury beyond that caused by ischemia. In recent years, anti-inflammatory and antioxidant activities of luteolin have been shown to play an important role in the cardio-protection against ischemia reperfusion injury. However its mechanism in cardio-protection has not been clearly elucidated. (181)
Researchers from “Institute of Cardiovascular Disease Research,” Xuzhou Medical College, PR China, investigated the mechanism of cardio-protection by luteolin in ischemia-reperfusion-injury. Their results showed that luteolin inhibits apoptosis and improves cardio-myocyte contractile function at least partly through the PI3K/Akt pathway.
[Note: The PI3K/Akt/mTOR pathway is an intracellular signaling pathway important in apoptosis. It contributes to hypertrophic muscle growth.) (182), (183]
One study in diabetic rats shows that luteolin preserves cardiac function, reduces infarct size, and cardio-myocyte apoptotic rate after ischemia-reperfusion injury. It exerts its action by up-regulating anti-apoptotic proteins FGFR2 and LIF expression and activating PI3K/AKT pathway while increasing BAD phosphorylation and decreasing ratio of Bax to Bcl-2. (184)
[Note: Leukemia inhibitory factor (LIF) is an interleukin 6 class cytokine that affects cell growth by inhibiting differentiation. When LIF levels drop, the cells differentiate.] (186)
A study was designed to investigate the direct effect of luteolin against necrosis and apoptosis following ischemia-reperfusion in cardio-myocytes. Sprague-Dawley rats were selected for the study. Researchers tested the contractile function of left ventricular cardio-myocytes with different concentrations of luteolin: 0.5, 1.5, 2.5 and 5.0 microgram/ml after simulation of ischemia-reperfusion injury. They also observed the function of isolated hearts subjected to ischemia-reperfusion with or without 10.0 microgram/ml luteolin pretreatment. At 2.5 microgram/ml, luteolin distinctly reduced the necrosis and apoptosis of cardio-myocytes. Furthermore, in the study on isolated hearts, at 10.0 microgram/ml luteolin improved ischemia-reperfusion induced damaged myocardial function by normalizing the heart rate, limiting the decline of left ventricular systolic pressure and elevation of left ventricular end-diastolic pressure to some extent. (187)
Although the exact mechanisms of the development of atherosclerosis are uncertain, the balance of vascular smooth muscle cells (VSMCs) proliferation and apoptosis appears to play a pivotal role in the pathogenesis and progression of atherosclerosis. Some researchers have indicated that inhibiting VSMCs proliferation is involved in attenuating atherosclerosis. Luteolin can reduce VSMCs proliferation and hence prevent and arrest the progression of atherosclerosis. It appears that luteolin can also be useful for the treatment of atherosclerosis. (188)
Luteolin suppresses H2O2 (hydrogen peroxide)-directed migration and proliferation in VSMCs partially due to down-regulation of Akt and Src signaling pathways, which are important participants in the processes of migration and proliferation of VSMCs. (189)
Periodontal disease comprises of infective gingivitis, periodontal tissue destruction, in severe cases alveolar bone loss with tooth exfoliation. Luteolin inhibits the growth of bacteria in the gingival fibroblasts. (190)
TNF alpha (Tumor Necrosis Factor-alpha) activates both cell death and cell survival pathways, which renders most cancer cells resistant to cytotoxic, chemotherapeutic agents. Pretreatment with luteolin sensitizes TNFalpha-induced apoptotic cell death in a number of human cancer cell lines such as colorectal cancer COLO205, HCT116 cells and cervical cancer HeLa cells. The molecular mechanisms responsible for this sensitization are complicated. But the data from the study reveals a novel function of luteolin and its value as an anticancer agent. (191)
In the study by “Biogeron Research Group,” Korea, luteolin strongly induced apoptosis in HepG2 hepatocarcinoma cells. It also dramatically reduced the tumor volume in a tumor xenograft model. Both effects were accompanied by AMPK activation by luteolin. AMPK or 5’ adenosine monophospahte-activated protein kinase is an enzyme that plays an important role in cellular energy homeostasis. The Study by Xu Huang et al on mice led them to hypothesize that activation of AMPK would suppress tumorogenesis. (192), (193)
Luteolin inhibits proliferation of HepG2 human hepatocellular carcinoma cells. (194)
The flavonoid luteolin blocks the growth factor receptor tyrosine kinase activity which leads to inhibition of the growth and apoptosis of the tumor cells of the pancreas. (195)
Luteolin inhibits angiogenesis in human pancreatic carcinoma cells. This activity of luteolin induces apoptosis in pancreatic cancer cells.(196)
Human Epidermal Growth Factor Receptor 2 (HER 2) also known as Neu, ErbB-2, CD340 (Cluster of Differentiation 340) or p185 is a protein that in humans is encoded by the ERBB2 gene. Over-expression of this gene has been shown to play an important role in the pathogenesis and progression of certain types of breast cancer. In recent years it has become an important biomarker and target of therapy for about 30% of breast cancer patients. (197)
Luteolin inhibits cell proliferation and induces apoptosis in HER-2 over-expressing cancer cells. (198)
Luteolin induces apoptosis in human myloid leukemia HL-60 cells. This result of the study conducted in Korea suggests that luteolin may be used as a chemo-protective and chemotherapeutic agent for human myloid leukemia. (199)
By down regulating androgen receptor expression, luteolin inhibits cell proliferation and induces apoptosis in human prostate cancer cells and xenografts. Therefore luteolin may be useful for the prevention and treatment of prostate cancer. (200)
Cisplatin, a well-known anti-cancer agent is nephrotoxic. Luteolin ameliorates cisplatin-induced nephrotoxicity. (201)
Multiple biological effects of luteolin could be functionally related to each other. For instance, the anti-inflammatory activity is linked to its anticancer property which is associated with the induction of apoptosis, inhibition of cell proliferation, metastasis and angiogenesis. Luteolin also sensitizes cancer cells to cytotoxicity of the anticancer chemotherapeutic agents. Furthermore, recent epidemiological studies have attributed a cancer-prevention property to luteolin. (202)
Many cancer cells have acquired resistance to apoptosis. SMAC (second mitochondria-derived activator of capsase) was identified as an important signal amplifier for the intrinsic apoptosis pathway. SMAC is an apoptosis-regulating molecule and can lower the threshold of cancer cells to apoptosis. Recently researchers have developed many SMAC-mimetics which are potential anticancer agents killing cancer cells through autocrine TNF-mediated apoptosis pathway. Combination of SMAC- mimetic compound 3 (SMC3) and luteolin is an effective approach for improving the anticancer value of SMC3 which has implications in cancer prevention and therapy. (203)
TNF-related apoptosis-inducing ligand (TRAIL) has a great potential in cancer therapy. Luteolin sensitizes TRAIL-induced apoptosis.(204)
In one study, the flavonoid luteolin inhibited tumor growth and angiogenesis in a murine xenograft model. Furthermore, luteolin inhibited vascular endothelial growth factor (VEGF)-induced in vivo angiogenesis in the rabbit corneal assay. Luteolin also showed antimitotic activity. These results suggest that luteolin can be a useful anticancer agent. (205)
Luteolin enhances the anticancer activity of cisplatin. More studies reveal a novel molecular mechanism involved in the anticancer effect of luteolin and support its potential clinical application as a chemo-sensitizer in cancer therapy. (206)
Tumor metastasis is a complicated, multi-step process which requires the conversion of polarized epithelial cells to mesenchymal, Epithelial-Mesenchymal transition (EMT). Hypoxia-induced epithelial mesenchymal transition (EMT) is an essential step in cancer metastasis. Cells grown under hypoxic condition also migrate faster and show reduced adhesion to extracellular matrix.
In one study conducted by the Department of Clinical Pharmacy, College of Pharmacy, Nanjing PR China, luteolin inhibited hypoxia-induced EMT in human non-small cell lung cancer cells in culture. In addition, luteolin also inhibited hypoxia-induced proliferation, motility and adhesion in the cells. (207), (208)
Toxicity of luteolin
Luteolin does have adverse effects such as nausea, vomiting and gastric hyper-secretion.
Vicenin-1
Molecular formula: C26H28O14
Strucrural formula:
 209
Vicenin 1 is antioxidant and protects against radiation injury.
Kaempferol
Molecular formula: C15H10O6
Structural formula:
 (210)
Kaempferol is a type of flavonoid. It is a yellow crystalline solid. It is slightly soluble in water but soluble in hot ethanol or diethyl ether.
Kaempfeerol is found in tea, broccoli, grapefruit, cabbage, kale (a type of cabbage), beans, tomato, strawberries, grapes, sprouts and apples.
Kaempferol is anti-oxidant, anti-inflammatory, anti-microbial and anti-allergic. It has anxiolytic, analgesic, neuroprotective, cardioprotective, antidiabetic, anti-osteoporotic and anti-cancer activity.
Regular consumption of kaempferol containing foods lowers the risks of cardiac problems, dibetes and cancer especially pancreatic cancer and lung cancer.
Kaempferol is a potent prophylactic agent against NOX-mediated neurodegeneration.
Kaempferol is now said to be a longevity promoting agent. (210), (211)
Naringenin:
Not to be confused with naringin
Molecular formula: C15H12O5
Structural formula:
 (211)
Naringenin a flavon is colorless crystalline substance.
Naringenin is found in grapefruits, oranges and tomatoes. It has an inhibitory effect on the human cytochrome P450 which can change pharmacokinetics in a human host of several popular drugs in an adverse manner.
Naringenin is antioxidant, free radical scavenger, antiinflammatory, promoter of carbohydrate metabolism and modulator of immune system. It helps the muscle uptake more glucose. It protects mice fed a high fat diet from developing obesity.
Narigenin lowers plasma and hepatic cholesterol by suppressing HMG-CoA reductase in rats fed a high cholesterol diet.
Narigenin has also been shown to reduce hepatitis C production by infected hepatocytes in liver cell culture. This seems to be secondary to narigenin’s ability to inhibit the secretion of very-low-density lipoprotein by the cells. The antiviral effects of narigenin are currently under clinical investigation.
Narigenin also produces BDNF-dependent (Brain-Derived Neurotrophic Factor- dependent) antidepressant-like effects in mice. (211)
Arabinoside
Arabinoside is a glycoside that yields arabinose on hydrolysis. (212)
Arabinoside is being investigated for its activity against leukemia.
Orientin
Molecular formula: C21H20O11
Structural formula:
 (213)
Orientin is also known as Lutexin, luteolin 8-C-glucoside. It is a water soluble flavone. It is found in barley, millets and passion flower. It has anti-nociceptive properties. (213), (214)
Isoorientin
Molecular formula: C21H20O11
Structural formula:
Isoorientin or Homoorientin a flavone is the luteolin-6-C-glucoside. Apart from fenugreek it is also found in passion flower, Vitex negundo, Terminalia negundo, Swertia japonica and Acai palm. (215)
Isoorientin is a light yellow crystalline solid. It is sensitive to light and moisture. The physical, chemical and toxicological properties of isoorientin have not been thoroughly investigated.
According to directive 67/548/EEC and Regulation (EC) No.1272/2008, it is not a hazardous and dangerous substance. However the experience of the industry workers tells a different tale.
If inhaled, isoorientin may cause respiratory tract irritation, may cause skin irritation if it comes in contact with skin or may be harmful if absorbed through skin, may cause eye irritation and may be harmful if swallowed.
First Aid Measures: If inhaled, move the person into fresh air, give oxygen; if nor brearhing, start CPR (Cardiopulmonary resuscitation).
In case of skin contact, wash the skin with plenty of soap and water.
In case of eye contact, flush eyes with plenty of plain water. Contact eye specialist if required.
If swallowed, NEVER give anything by mouth, rinse mouth with water. (216), (217)
Pharmacological Properties: Isoorientin shows anti-inflammatory, potent antioxidant, anti-allergic, anxiolytic and sedative, anti-nociceptive, anti-proliferative and gastro-protective activities. It has inhibitory effect on LDL oxidation, protective effect against neurodegenerative diseases and effect on the regulation of antioxidative gene expression. (218), (219)
Coumarins
Coumarins
Molecular formula: C9H6O2
Structural formula:
 (220)
Coumarin is a colorless, fragrant and crystalline organic chemical compound in the benzopyrone class. The name comes from a French term for the tonka bean coumarou (Indian name: Kumaru). Coumarin was first isolated in 1820 by A. Vogel of Munich, who mistook it for benzoic acid. Also in 1820, Nicolas Jean Baptiste Gaston Guibourt of France independently isolated and named it “coumarin”. Coumarin was first synthesized in 1868 by the English chemist William Henry Perkin.
Apart from fenugreek it is found naturally in many plants e.g. tonka bean (Dipteryx odorata), vanilla grass, (Anthoxanthum odoratum), sweet woodruff (Galium odoratam), mullein (Verbascum spp.), sweet grass (Hierochloe odorata), cassia cinnamon (Cinnamomum cassia), sweet-clover (Meliotus ssp.), and deertongue (Dichanthelium clandestinum).
Coumarin is presumed to be produced by plants as a defense chemical in order to discourage predation. Though it has a pleasant sweet odor, it has a bitter taste, and animals tend to avoid it. It has appetite-suppressing properties, which in plants may reduce the impact of grazing animals.
Coumarin itself has no anticoagulant properties; it is transformed into the natural anticoagulant dicoumarol by a number of species of fungi.
Coumarin is used in the pharmaceutical industry as a precursor molecule in the synthesis of many synthetic anticoagulants like warfarin and some even more potent rodenticides that work by the same anticoagulant mechanism.
Coumarin has clinical medical value by itself as an edema modifier. It stimulates macrophages to degrade extracellular albumen, allowing faster resorption of edema-fluids.
Coumarin has many biological activities, but its approved medical uses are few. It has anti-inflammatory, anti-septic, analgesic, anti- HIVand anti-hypertension, anti-arrhythmia and anti-osteoporosis activity. It is used in the treatment of bronchial asthma and lymphedema.
Some evidences from modern research:
Naturally occurring coumarins and their synthetic analogues show antioxidant property. (221), (222)
Natural and synthetic coumarins have cytotoxic-antitumor activity. (223)
Toxicity:
Humans metabolize it mainly to 7-hydroxycoumarin, a less toxic compound. In larger doses however coumarin is moderately hepatotoxic and nephrotoxic. (LD50 =275mg/kg). (224)
Side Effects
Loss of appetite, nausea, diarrhea, breathlessness, blurred vision, headache, unusual bleeding (blood in the urine or stool), allergic skin rash, itching, swelling. (225)
Trimethylcoumarin, Methyl coumarin, Trigocoumarins have properties and actions similar to ‘coumarin’.
Aminoacids
Isoleucine/ 4-Hydroxyisoleucine
Molecular formula: C6H13NO3
Structural formula:
 (226)
Isoleucine/ 4-Hydroxyisoleucine is a light yellow, hygroscopic powder. It has a characteristic odor and slightly bitter taste. It is moderate to severe irritant to the skin and eyes.
In one study on rats, 4-Hydroxyisoleucine at 50mg/kg per day for eight weeks normalized the elevated levels of liver enzymes (AST, ALT) and improved HDL cholesterol levels. Thus it showed hepatoprotective activity. (227)
HIL (4-Hydroxyisoleucine) has insulinotropic and anti-obesity effects. Researchers think HIL may be a novel orally active drug for the simultaneous treatment of type 2 diabetes and obesity. (228)
4-Hydroxyisoleucine (4-HIL) decreased elevated levels of plasma glucose, total cholesterol and triglyceride in a hamster model of diabetes. It also reduced body weight in diet-induced obese mice. It seems 4-HIL can be an attractive new candidate for the treatment of metabolic syndrome. (229)
In the dyslipidemic hamster model, 4-Hydroxyisoleucine decreased plasma triglyceride levels by 33%, total cholesterol by 22% and free fatty acids by 14%. It increased HDL-C/TC ratio by 39%. This shows that 4-HIL, an unusual amino acid isolated from Trigonella foenum-graecum can be a good adjuvant to the drug therapy for dyslipidemia. (230)
In various studies, the amino acid 4-Hydroxyisoleucine increased glucose-induced insulin secretion by the beta cells of the pancreas in humans and rats. It also inhibited the activities of alpha-amylase and sucrase, the intestinal enzymes, involved in the regulation of carbohydrate metabolism.
This amino acid acts specifically on the beta cells since the levels of glucagon and somatostatin were unaltered. (231)
4-Hydroxyisoleucine is a secrtogogue antidiabetic agent. When administered at 50mg/kg for eight weeks to diabetic rats, it restored the elevated liver enzymes to normal levels. It also elevated the level of HDL cholesterol by 31%. This shows that 4-Hydroxyisoleucine is useful for the treatment of type 2 diabetes and dyslipidemia and also is a hepatoprotective agent. (232)
In experiments on mice, 4-Hydroxyisoleucine stimulated glucose-dependent insulin secretion by a direct effect on the beta cells of the pancreas. It also reduced insulin resistance in muscles and liver by activating insulin receptor substrate-associated phosphoinositide 3 (PI3) kinase activity. It also reduced body weight in diet-induced obese mice. The decreae in body weight was associated with a marked decrease in both, plasma insulin and glucose levels. It corrected dyslipidemia i. e. decreased elevated levels of total cholesterol and triglyceride in a hamster model of diabetes.
This study shows that 4-Hydroxyisoleucine is very useful for the treatment of key components of metabolic syndrome. (233)
4-Hydroxyisoleucine has significant anti-diabetic activities that are independent of insulin. Hence it is useful for the treatment of type 1 and type 2 diabetes. (234)
Histidine
Molecular formula: C6H9N3O2
Structural formula:
Histidine is a basic amino acid essential for human development. It was initially thought that it was only essential for infants, but recent studies established that it is also essential for adult humans. It is involved in a wide range of metabolic processes in the body. It is a precursor of histamine. It is needed for growth and repair of the tissues, as well as the maintainance of the myelin sheaths. It is required for the manufacture of both RBCs and WBCs. It assists in stabilizing oxyhemoglobin and destabilizing carboxyhemoglobin. It helps to protect the body from damage caused by radiation. It also helps to remove heavy metals from the body. In the stomach it is helpful in producing gastric juice. (235), (236)
Leucine
Molecular formula: C6H13NO2
Structural formula:
 (236)
Leucine is a white crystalline powder. It is odorless and has slightly bitter taste.
Leucine (abrieviated as Leu or L) is classified as a hydrophobic amino acid. It is an essential amino acid. It cannot be synthesized by animals. Therefore it must be ingested, usually as a component of proteins. In plants and microorganisms, leucine is synthesized from pyruvic acid by a series of enzymes. Leucine is a white crystalline powder. It is odorless and has slightly bitter taste.
Food sources of leucine are: Soybeans, peanuts, beans, oats, lentils, wheat germ, yellow corn, almonds, cow milk, human milk, meat, chicken, pork, fish and egg yolk.
Leucine is utilized in the liver, adipose tissue, and muscle tissue. In adipose and muscle tissue it is used in the formation of sterols, and the combined usage of leucine in these two tissues is seven times greater than its use in the liver.
Leucine is the only amino acid that has the capacity to stimulate muscle protein synthesis. Leucine has been found to slow the degeneration of muscles by increasing the synthesis of muscle proteins in aged rats. More studies are needed to show the benevolent effects in elderly men. (236), (237)
Leucine, isoleucine and valine make up about one-third of muscle protein. Leucine stimulates protein synthesis in muscles and is closely associated with the release of gluconeogenic precursors, such as alanine, from muscles. Significant decreases in plasma or serum levels of leucine occur folloing aerobic (11 to 33%), anaerobic lactic (5 to 8%) and strength exercise sessions (30%). The current recommended daily dietary intake of leucine is 45mg/kg body weight for sedentary individuals and more for those participating in intensive physical training. Consumption of 30 to 35% leucine before or during endurance exercise may prevent or decrease the net rate of protein degradation, may improve both physical and mental performance and may have a sparing effect on muscle glycogen degradation and depletion of muscle glycogen stores. Furthermore, supplementation of 76% leucine in combination with moderate energy restriction has been shown to induce significant and preferential losses of visceral fat and to allow maintainance of a high level of performance. (238)
Leucine has been suggested to be ergogenic (nutritional aid that enhances performance in high-intensity exercises) for both for endurance and strength/power performance. In one study on thirteen (three males, ten females) competitive outrigger canoeists (aged 31.6 years) dietary supplementation of leucine for six weeks significantly improved endurance performance and upper body power in outrigger canoeists. (239)
Lysine
Molecular formula: C6H14N2O2
Structural formula:
Lysine (abbreviated as Lys or K) is an essential amino acid for humans. It is a white to yellow colored powder, freely soluble in water.(241), (242)
Lysine was first isolated from casein in 1889. In the US it was used to fortify bread to target populations with lysine-poor diets. However, the FDA refused to modify the standards of identity for white bread. Since 1970, lysine has been commonly added to animal food. (243)
Dietary sources of lysine are: nuts, soybeans and other beans, lentils, peas, fenugreek seeds, cow milk, cheese, yeast, spirulina, eggs, red meat and fish.
Lysine is required for proper growth, development of bones, maintaining the correct nitrogen balance, production of antibodies, hormones, enzymes, for the production of carnitine which converts fatty acids into energy to lower cholesterol. It helps the body absorb calcium. It plays an important role in the formation of collagen.
Lysine deficiency can cause fatigue, nausea, loss of appetite, anemia, reproductive disorders, growth retardation and osteoporosis.
Lysine blocks the replication of HSV and can prevent HSV outbreak. Lysine has been investigated for its effects on increasing muscle mass, lowering blood sugar and improving anxiety and ameliorating angina.
For adults the daily requirement of lysine is 12mg/kg.
High intake of lysine may cause diarrhea, gastric pain, hepatic dysfunction, gall stone, Fanconi’s syndrome and renal failure. Lysine and arginine share a common pathway in the body. High levels of arginine may lower lysine levels in the body. (244), (245), (246)
L-Tryptophan
Molecular formula: C11H12N2O2
Structural formula:
 (247)
The way to a peaceful blissful life is through tryptophan. A cup of warm milk before bedtime imparts a reposeful, freshening sleep. Thanks to tryptophan contained in it.
Tryptophan is an essential amino acid occurring in isomeric forms.It is an odorless, white to off-white crystalline, powder with a bland taste and slightly soluble in water. L-tryptophan has slight bitterness, while D- tryptophan and
DL-tryptophan have slight sweetness. (248), (249)
Tryptophan was isolated by Frederick Hopkins in 1901 through hydrolysis of casein (milk protein).
Its dietary sources are: chocolate, oats, banana, peanuts, sesame, sunflower seeds, pumpkin seeds, dates, milk and milk products, red meat, eggs and fish.
Tryptophan functions as a biochemical precursor for serotonin, niacin and melatonin.
Tryptophan is sleep augmenter, anti-depressant and has been suggested for the treatment of epilepsy.
Eosinophilia-Myalgia Syndrome (EMS):
EMS is an incurable and sometimes fatal flu-like neurological condition, believed to have been caused by ingestion of L-tryptophan supplements. Clinically it is similar to regular eosinophilia.
There was a large tryptophan-related outbreak of “Eosinophilia-Myalgia Syndrome” (EMS) in 1989 in America. As many as 60,000 individuals became ill, 1500 became permanently disabled and atleast 37 died from using L-tryptpphan. The outbreak was traced to L-tryptophan supplied by a Japanese manufacturer, Showa Denko K. K. It was hypothesized that impurities produced during the manufacture of tryotophan may have been responsible for the outbreak. Showa Denko used genetically engineered bacteria to produce L-tryptophan which gave rise to speculation that genetic engineering was responsible for such impurities. An alternative explanation for the 1989 EMS outbreak is that large doses of tryptophan produce metabolites that inhibit the normal degradation of histamine and excess histamine in turn has been proposed to cause EMS. Tryptophan was banned from sale in the US and other countries in 1991.
Turky meat and drowsiness: A common assertion is that heavy consumption of turkey meat results in drowsiness due to high levels of tryptophan contained in turkey. However, the amount of tryptophan in turkey is comparable to that contained in most other meats.
On November 18, 2012 episode of the Discovery Channel series ‘Myth Busters’ Build Team members Tory Belleci, Kari Byron and Grant Imahara investigated the claimed link between turkey consumption and drowsiness. They found that the amount of food eaten had a much larger effect on the result than whether or not turkey was part of the meal. (250), (251)
Tryptophan is now used for insomnia, sleep apnea, depression, anxiety, facial pain, a severe form of PMS (premenstrual syndrome) called premenstrual dysphoric disorder (PMDD), smoking cessation, grinding teeth during sleep (bruxism), attention deficit- hyperactivity disorder (ADHD), Tourette’s syndrome and to improve athletic performance. (252)
Side effects of tryptophan:
Serious side effects include:
· Severe myalgia (most often in the shoulders, back, legs),
· Weakness, numbness, tingling or burning pain (especially at night),
· Tremors or twitching muscle movements,
· Dryness, yellow discoloration and hardening of the skin (seen especially workers handling commercial tryptophan),
· Swelling in any part of the body,
· Breathlessness or irregular heart beats
Less serious side effects include:
· Dryness of mouth, loss of appetite, nausea, vomiting, heartburn, burping
(belching aloud) and diarrhea,
· Light headedness, head ache and drowsiness,
· Blurring of vision (253)
Arginine
Molecular formula: C6H14N4O2
Structural formula:
 (254)
Arginine abbreviated as Arg or R is an alpha amino acid which was first isolated in 1886 by the Swiss chemist Ernst Schultze. Premature infants are unable to synthesize it internally making it nutritionally ‘essential’ for them. However, adults are able to synthesize arginine in the urea cycle. Because of these differences, in mammals, arginine is classified as semiessential or conditionally essential amino acid.
Shaped like a prism, arginine is a crystalline solid, soluble in water.
Its dietary sources are: milk, yogurt, whey protein drinks, cottage cheese, whole wheat, fenugreek, brown rice, corn, oats, peanuts, raisins, walnuts, cashews, soybeans, seeds of pumpkin, sesame, seeds of sunflower, chocolate, beef, pork, lobster, shrimp, salmon.
On a whole body-basis, synthesis of arginine occurs principally via the intestinal-renal axis. Epithelial cells of the small intestine produce citrulline from glutamine and glutamate; collaborate with cells of the proximal tubules of the kidney which convert citrulline into arginine. As a consequence, impairment of small bowel or renal function can reduce endogenous synthesis of arginine, thereby increasing the dietary requirement.
In the body arginine is converted to an amino acid ornithine which stimulates the anterior pituitary gland to produce growth hormone. Thus arginine (especially L-arginine) plays an important role in the growth of the body. It plays an important role in cell division, the healing of wounds, removing of ammonia from the body, immune function and the release of various hormones. It quickens repair time of damaged tissues particularly the bones. It reduces blood pressure in normal as wall as hypertensive subjects.
Arginine (8%) in toothpaste provides effective relief from sensitive teeth by depositing a dentine-like mineral forming a protective layer on teeth.
An unproven claim is that a low ratio of arginine to lysine may be of benefit in the treatment of herpes simplex.
Supplementation of L-arginine and antioxidant vitamins may help to combat abnormally high blood pressure during high risk pregnancies such as pre-eclamcia.
In combination with proanthocyanidins or yohimbin it is used for the treatment of erectile dysfunction (ED).
L-arginine taken in combination with L-lysine has been shown to be effective for relieving anxiety states.
The malate salt of arginine is used during the treatment of alcoholic hepatitis and advanced cirrhosis. (254)
Recommended daily dose of arginine is 3g. Deficiency of arginie is rare; but signs may include impaired insulin production as well as possible hair loss.
Some interesting points: Arginine proglutamate, in addition to having cognitive enhancing effects, is an excellent growth hormone releaser because it is carried more efficiently across the blood- brain barrier than arginine alone. Arginine alone does not produce cognitive enhancing effects. In Italy, arginine proglutamate is used to treat senility, mental retardation and alcoholism.
Key benefits of arginine: Promoting protein synthesis and anabolic activity, endothelial support for circulatory health and building up of immunity. (255)
Hazards of arginine:
· Inhalation of L-arginine can cause bronchitis and worsen bronchial asthma
· May cause skin irritation, allergic dermatitis, erythema and edema with crusting and scaling
· May cause allergic conjunctivitis
· Ingestion may cause GI irritation with nausea, vomiting and diarrhea as well as increasing the activity of some viruses. For this reason people suffering from herpes, pregnant and lactating women and people suffering from schizophrenia should avoid high dosages of L-arginine.
· Laboratory experiments have resulted in mutagenic effects. (256), (257)
Molecular formula: C6H12N2O4S2 Structural formula: 
Cystine is a sulphur containing aminoacid. It is a white solid, slightly soluble in water. Human hair, skin, bones and connective tissues are rich in cystine.
Presence of cystine is called cystinuria. In humans the excretion of high levels of cystine crystals is indicative of cystinosis a rare genetic disorder. (258)
Molecular formula: C9H11O3 Structural formula: 
Tyrosine (abbreviated as Tyr) is one of 22 amino acid used by cells to synthesize proteins. It is non-essential amino acid. It can be synthesized in the body from phenylalanine.
Tyrosine is found in chicken, turkey, fish, milk, yoghurt, cottage cheese, fenugreek, peanuts, almonds, pumpkin seeds, sesame seeds, beans, oats, wheat and banana.
In plants it has an important role in photosynthesis.
Tyrosine plays an important role in signal transduction process. It is a precursor to neurotransmitters and increases plasma levels of neurotransmitter levels (particularly dopamine and nor-epinephrine).
A number of studies have shown that tyrosine is useful during conditions of stresses, cold, fatigue; deprivation of sleep, loss of loved one. In such conditions it reduces the levels of stress hormones, improves cognitive function and physical performance and prevents weight-loss in chronic stressful conditions. However tyrosine does not have significant effect on mood, cognitive or physical performance in normal circumstances.
In medical practice it used for mental depression, attention deficit disorder (ADD), attention deficit-hyperactive disorder (ADHD), sleep deprivation, premenstrual syndrome (PMS), Parkinsonism, Alzheimer’s disease, chronic fatigue syndrome (CFS) and erectile dysfunction (ED). It is useful in phenylketonuria, a rare genetic disorder. Some dermatologists apply tyrosine to skin to reduce age related wrinkles.
There is no enough information about its side effects. It is prudent not to use it during pregnancy and lactation and pediatric practice. It should not be used in hyperthyroidism.
Tyrosine interacts with levodopa and thyroid hormones.
A daily dosage (as reported in the literature on clinical trials) is 100mg/kg for an adult. The usual dosage suggested by experts amounts to 500 to 1500 mg per day. (259), (260)
The author does not find extra information regarding vitamins A (Carotene), B1, B2, B3 (Niacin), B6 (Pyridoxin), C, D, E, Folic acid than hitherto known to any inquisitive reader.
Vitamin B15 (Pangamic acid)Molecular formula: C10H19NO8 Structural formula:  (261)
Pangamic acid once termed as “vitamin B15” because of its wide range of medicinal usage is not a true vitamin, has no nutritional value, has no acceptable medicinal value in the treatment of diseases and has now been called a: “quack remedy”.
Natural sources of pangamic acid include brewre’s yeast, whole brown rice, sesame seeds and pumpkin seeds.
Originally pangamic acid was patented by Krebses as a detoxifying agent, as well as for the treatment of asthma, skin conditions, joint pain and nerve pain. However clinical trials do not support any of these claims. One review noted that it meets the “criteria of a quack remedy”!!
The US FDA disapproves it as a drug!
Recent research also warns that pangamic acid is mutagenic. (261)
Natural sources of pangamic acid include brewre’s yeast, whole brown rice, sesame seeds and pumpkin seeds.
Pangamic acid is used for the treatment of asthma, eczema and other skin conditions, joint pain, neuralgias, fatigue, alcoholism, dyslipidemia and even cancers.
Pangamic acid should not be used during pregnancy and lactation. It is not to be used in children. Pangamic acid can cause kidney stones. It is contraindicated in chronic kidney diseases.
Pangamic acid interacts with digoxin, amlodipin, diltiazem, verapamil and diuretics. (262)Vitamin B17 (Amygdalin) Molecular formula: C20H27NO11 Structural formula: 
Amygdalin must not be confused with laevomandelonitrile, also called as laetrile (vitamin B 17). Amygdalin and laetrile are different chemical compounds.
Amygdalin is is a glycoside initially isolated from bitter almonds (Prunus dulcus). Several species in the genus of Prunus including apricot (Prunus armeniaca) and black cherry (Prunus serotena) also contain amygdalin.
In 1950 a modified form of amygdalin was named as laetrile or vitamin B17. As mentioned above they are different chemical compounds and in reality neither is vitamin in any sense. But some experts still recognize them as “vitamins”. They are sometimes sold as “Vitamin B17”
The metabolism of amygdalin produces hydrogen cyanide (HCN), a potent toxin. The enzyme that catalyzes the release of cyanide from amygdalin is present in human small intestine. It is this property that was thought to be useful in treating cancers. In Russia, in 1845, amygdalin was used to treat cancer. World wide trials however do not support this view. Now it is confirmed that amygdalin is not an anticancer agent. U.S. FDA does not approve it for cancer therapy. (263)
Molecular formula: C7H7NO2 Structural formula:  (264)
4-Aminobenzoic acid also known as PABA is a white grey crystalline substance, slightly soluble in water.
Food sources of PABA include liver, brewer’s yeast, unfiltered beer, kidney, molasses, mushrooms, fenugreek and whole grains.
PABA is an intermediate in the bacterial synthesis of folate. PABA is sometimes called as Vitamin Bx. Some bacteria in the human intersinal tract such as E. coli generate PABA. Humans lack the enzyme to convert PABA into folate and therefore need folate supplementation. In humans PABA is considered nonessential and is not recognized as a vitamin.
Potassium salt is used as a drug aginst fibrotic skin disorders, such as Peyronie’s disease. It is also used in irritable bowel syndrome, and in nutritional epidemiological studies to assess the completeness of 24-hour urine collection for the determination of urinary sodium, potassium or nitrogen levels. (264)
Minerals Magnesium
Magnesium is a mineral that is present in large amounts in the body about 25 grams; about half of which is in the bones. People get magnesium from their diet.
Dietary sources of magnesium include fenugreek, legumes, whole grains, vegetables, seeds and nuts.
Magnesium is used as laxative. It is also used for bowel preparation for surgical and diagnostic procedures. It is also used as antacid for acid indigestion. It is used in diseases of heart and blood vesselsand cardiac arrhythmias.
Magnesium is also used to treating attention deficit-hyperactivity disorder (ADHD), chronic fatigue syndrome, anxiety, Lyme disease, fibromyalgia, leg crams during pregnancy, PMS, kidney stones, asthma, hay fever.
Athlets sometimes use magnesium to increase energy and endurance.
Magnesium is used to treat infected skin ulcers, boils, carbuncles, as a cold compress and to speed up wound healing. (265)
Trace elements
Trace elements also called Micronutrients, are required by living organisms in minute amounts, usually as part of vital enzymes. Micronutrients include copper, boron, zinc, manganese and molybdenum. (266)
Crude fiber
Originally, fiber was defined to be the components of plants that resist human digestive enzymes. The definition included lignin and polysaccharides. The definition was later changed to also include nondigestible starches, along with inulin and other oligosaccharides. In day to day practice dietary fiber is known as roughage or ruffage.
The name is derived from the fact that it has a naturally fibrous structure. Its primary purpose in plants is to form part of the structure in the cells. Crude fiber is little-used distinction to differentiate the types of fibers.
Dietary fibers act by changing the nature of the contents of the gastrointestinal tract.
Deitary fiber is characterized by low or no nutritional value. It is thought to lower elevated levels of sugar and cholesterol in the blood.
There are two main components:
1. Soluble fiber dissolves in water. It is readily fermented in the colon into gases and physiologically active byproducts and can be prebiotic and/ or viscous. Soluble fiber slows down the movement of food through the system.
2. Insoluble fiber does not dissolve in water. It can be metabolically inert and provide bulking or prebiotic, metabolically fermenting in the large intestine. Inert fibers absorb water as they move through the GI tract. By adding bulk to stools they ease defecation. Fermentable insoluble fibers can be readily fermented in the colon into gases and physiologically active byproducts. They accelerate the movement of food through the system.
The disadvantage of a diet high in fiber content is the potential for significant production of gas in the GIT and bloating. Constipation can occur if insufficient fluid is consumed with a high-fiber diet. (267), (268)
Soluble fiber
In type 2 diabetic rats the soluble dietary fiber (SDF) fraction of fenugreek lowers the elevated postprandial blood sugar.
The soluble dietary fibre of fenugreek has a beneficial effect on dyslipidemia and can inhibit platelet aggregation in Type 2 diabetic model rats. (269)
In one study, daily administration of soluble dietary fibre fraction (SDF) of fenugreek seeds to type 2 diabetic rats for 28 days decreased elevated serum glucose, increased liver glycogen content, and enhanced total anti-oxidant status. Serum insulin levels and insulin secretion were not affected by the SDF fraction. Glucose transport in 3T3-L1 adipocytes and insulin action were increased. These effects were mediated through inhibition of carbohydrate digestion, carbohydrate absorption and enhancement of peripheral action of insulin. (270)
Galactomannan, a soluble fibre found in fenugreek, has been reported to reduce post prandial blood sugar. The inhibitory effect of galactomannan was found to be in parallel with the degree of viscosity of the fibre in solutions. Because of its viscous property, galactomannan reduces intestinal absorption of glucose. (271)
The mucilagenous fiber of the fenugreek seed is hydrated. This forms a colloidal suspension in the stomach and intestines that affects gastrointestinal transit of glucose, slowing its absorption. This prevents postprandial elevation of blood sugar, exerting indirectly antidiabetic effect. (272)
Mucilage
Mucilage is a thick gummy substance produced by nearly all plants. It is a polar glycoprotein; exopolysaccharide (high-molecular-weight polymer that is composed of sugar residues). In plants mucilage plays a role in the storage of water and food, seed germination and thickening membranes.
Mucilage is edible. It is used in medicine for its demulcent properties. Mucilages cover the mucous membranes and prevent irritation of the nerve endings. Therefore mucilages can be used in inflammatory bowel disease. (273)
Mucilage from fenugreek exerts antioxidant and anti-inflammatory effects in adjuvant induced arthritis in rats. (274)
Galactomannans are polysaccharides consisting of a mannose backbone with galactose sidegroups.
Fenugreek gel consists chiefly of galactomannans characterized by their high water-holding capacity. These galactomannans have a unique structure and may be responsible for some of the characteristic therapeutic properties attributed to fenugreek. (275)
There is no limit for the intake of fenugreek gum because it is harmless. But according to clinical trials, 1.25 g of gum (5g fenugreek seeds) is enough to lower the blood sugar, cholesterol and triglyceride.
Animal experiments have proved that galactomannan blocks the absorption of glucose from the intestine. However, it is not clear why intake of indigestible galactomannan lowers the blood cholesterol and also lowers biosynthesis of cholesterol in the liver. It is said that, the dietary fiber increases intestinal viscosity, adsorbs cholesterol and excreats it. Thus reduced absorption of the cholesterol from the gut lowers the blood level of cholesterol. Some say, galactomannan is aliment (food, nourishment) to intestinal bacteria which decompose glucose into volatile fatty acid. This reduces the absorption of sugar and prevents elevation of the blood sugar. The fatty acid is absorbed in to the blood that prevents the biosynthesis of cholesterol in the liver. Others say that galactomannan causes intestinal wall to secrete more hormones and enzymes, thus affecting the absorption of sugar and biosynthesis of cholesterol in the liver. Though the mechanism has not been fully understood, the bacteria bred by galactomannan may unravel the knot.
Galactomannan has an effect as bulk cathartic.
Some testimonials from modern researchGeneral PharmacologyIn chemistry, a vanadate is a compound containing an oxoanion of vanadium generally in its highest oxidation state of +5.
An oxyanion or oxoanion is a chemical compound with the generic formula AxOyz- where A represents a chemical compound and O represents oxygen atom. (277), (278)
Oral administration of vanadate to diabetic animals restores the altered metabolic pathways and stabilizes the glucose homeostasis. However low dose of vanadate is ineffective and high dose has several toxic effects. In one study, alloxan-diabetic rats were treated with a combination of fenugreek seed powder and low dose of vanadium for three weeks. The treatment restored euglycemia, lipidperoxidation and membrane fluidity suggesting that synergism of fenugreek and low dose of vanadium exerts better control on diabetes than the monotherapy. (279)
Oral administration of low dose of sodium orthovanadate and fenugreek seed powder ameliorated the altered mitochondrial enzyme activities during experiments on type-1 diabetes. This study conclusively proved to be a possible method to minimize potential vanadate toxicity without compromising its positive effects in the therapy of experimental type-1 diabetes. (280)
Oral administration of fenugreek seed powder to diabetic rats prevented and restored the histopathological abnormalities in the liver and kidney. (281)
Liver pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) are key enzymes involved in glycolysis and gluconeogenesis respectively. Along with skeletal muscle glucose transporter (GLUT4) these enzymes play a key role in glucose homeostasis. In the diabetic state this balance is disturbed owing to deficiency or absence of insulin. Treatment with fenugreek seed powder partially restored the altered expression of liver pyruvate kinase (PK) and phosphoenolpyruvate carboxykinase (PEPCK) in alloxan-diabetic rats. The treatment also corrected the alterations in the distribution of GLUT4 in the skeletal muscle in the experimental animals. (282)
Oral administration fenugreek seed powder to alloxan induced diabetic rats improves glucose homeostasis in the tissues by reversing the altered glycolytic, gluconeogenic and lipogenic enzymes. (283)
Diets rich in fat and sucrose culminate in obesity. The researchers from Josai University, Japan (muraki@josai.ac.jp) used high fat and high sucrose (lard 50% kcal and sucrose 25% kcal) to induce obesity and other metabolic disorders in experimental rats. They were then fed with different doses of fenugreek. Fenugreek dose-dependently reduced the levels of hepatic triglyceride and total cholesterol and increased excretion of cholesterol and total bile acids into the feces. However, the glucose tolerance, L and VL levels showed no significant change by fenugreek administration. The effective, safe and tolerable dose of fenugreek was found to be around 2.5% (W/W). (284)
Purified steroid saponins from fenugreek mixed with food and administered chronically to rats (12.5 mg/ 300 kg body weight) enhance food consumption and motivation to eat and reduce the blood levels of cholesterol. (285)
The ethanol extract of fenugreek has the ability to inhibit taurocholate and deoxycholate absorption in a dose dependent manner. (286)
The mucilage derived from Fenugreek retards the absorption of various substances from the intestine. This property of the mucilage is taken advantage of to formulate the controlled-release drugs. (287)
Antioxidant and Detoxification Activity
Type II diabetes is the result of chronic oxidative stress. Fenugreek is traditionally used in Indian folk medicine to treat diabetes. Many bioactive molecules found in fenugreek reduce oxidative stress. Treatment of experimental rats with fenugreek seed powder apart from normalizing blood glucose level, exhibits antioxidant activity and protects pancreas and liver tissues of normal and diabetic rats against the oxidative stress. (288)
In a study on streptozotocin-induced diabetic rats, fenugreek leaf powder supplementation significantly lowered lipid peroxidation and reduced oxidative stress. At the dose of 1g/kg of body weight, the effect of fenugreek leaf powder was similar to that of glibenclamide. (289)
In one study fenugreek and vanadate seeds showed antioxidant property. On the basis of this study, researchers feel vanadate and fenugreek seeds can be useful in the treatment of the reversal of the complications of diabetes. (290)
A group of researchers found that lower doses of vanadate could be used in combination with fenugreek seed powder to effectively counter oxidative stress and altered carbohydrate metabolism in alloxan-induced diabetic rats. (291)
In Departments of Biochemistry and Toxicology, CSIR, Central Drug Research Institute, New Delhi, India; researchers studied the effect of alcoholic extract of fenugreek seeds on oxidative stress and dyslipidemia. They found that long term feeding of fenugreek seed extract (200 mg/kg body weight), countered oxidative stress, lowered plasma and hepatic lipid levels. Thus the data demonstrated that fenugreek seed extract has both antioxidant and antidyslipidemic properties. (292)
Apart from controlling the blood glucose levels, fenugreek seeds also have antioxidant activity to protect the organs such as liver and pancreas against the oxidative damage induced by diabetes. (293)
The protective effect of aqueous extract of fenugreek seeds was studied in aloxan-diabetic rats. The diabetic rats exhibited enhanced lipid peroxidation and increased susceptibility to oxidative stress associated with depletion of antioxidants in liver, kidney and pancreas. The study showed that the liver was protected by the aqueous extract to nearly 80%. According to researchers the antioxidant property of the soluble portion of the seeds of fenugreek could have been responsible for this effect. (294)
The quantity of flavonoid and phenolic compounds is much more in germinated seeds of fenugreek than in the seed powder. This explains why germinated seeds show more antioxidant activity than that of the seed powder. (295)
Anti-Inflammatory Activity
The alkaloid and flavonoid contained in fenugreek show anti-inflammatory and antinociceptive activity. (296)
Researchers of Kanazawa University, Japan, prepared the methanolic extract of the seeds of fenugreek. From the extract they isolated three active constituents. These were identified as the steroidal saponins. Compounds 1 and 2 strongly suppressed the production of inflammatory cytokines, whereas compound 3 was weaker in this regard. Melanogenesis in B16F1 cells was significantly suppressed by 1 and 3, and weakly suppressed by 2. All three compounds showed moderate cytotoxicities. These results show that fenugreek could protect against skin damage. (297)
Immunomodulatory activity
Fenugreek has a stimulatory effect on immune functions in mice. The study validates its use in Ayurveda for medicinal purpose and its immunostimulatory effect. (298)
In Animal Ecophysiology Laboratory, Tunisia, alloxan- induced diabetic rats treated with fenugreek oil showed reversal in inflammatory activity in the pancreatic beta cells, normalized elevated glucose levels, improved glucose intolerance and increased insulin sensitivity. The altered architecture of pancrease and kidney was restored to normal. The increased levels of lipid peroxidation, creatinine and urea decreased significantly. These effects were attributed to immunomodulatory and antioxidant potential of fenugreek oil. (299)
Antimicrobial Activity
Phenolics present in fenugreek seeds show potent antimicrobial activity especially against Helicobacter pylori. Fenugreek sprouts therefore can be included as a dietary supplement in anti-Helicobacter regimen. (300)
Fenugreek extract derived via solid-state bioconservation inhibits alpha-amylase and Helicobacter pylori. These results suggest that fenugreek should be included in diet for the treatment of diabetes and peptic ulcer. (301)
Extracts of leaves fenngreek (Trigonella foenum graecum) in chloroform, hexane, methanol, ethanol and water showed antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. (302)
Actions on the Skin
The Korean researchers investigated the antiallergic activity of fenugreek extract using trimellitic anhydride (TMA)-induced allergic dermatitis in BALB/c mice. BALB/c mice were administered 250mg/kg of body weight, fenugreek extract for seven days after sensitization with 2-5% TMA challenge. The treatment with fenugreek extract cured T helper 2- induced allergic inflammation by enhancing T helper 1 differentiation. (303)
Actions on Nervous System
Treatment of diabetic rats with fenugreek seed powder can revert back the hyperglycemia induced changes to normal in rat brain. Fenugreek ameliorates ffects of hyperglycemia induced lipid peroxidation, restores membrane fluidity thereby reversing the diabetic complications. (304)
Hyperglycemia in diabetics induces demyelination of nerves. Ultrastructural observation of the sciatic nerve in alloxan-induced diabetic rats showed extensive demyelination and axonal loss. The treatment of these rats with fenugreek seed powder, and with a combination of fenugreek seed powder and low dose vanadium prevented the activation of polyol pathway and sugar accumulation. The sciatic nerves were also protected against the structural abnormalities found in diabetes. (305)
That fenugreek extract exerts anti-inflammatory, analgesic and antipyretic effects was proved in different experimental models. A group of researchers decided to investigate the site and mechanism of the analgesia induced by different doses of Trigonella foenum-graecumleaf extract. This study confirmed the central action of Trigonella foenum-graecum leaf extract and that spinal 5-HT system is partially involved in the analgesia induced. They also suggest co-existence of other mechanisms of analgesia. The effective dose was found to be 1-3 mg/ rat. (306)
To evaluate the effects of the standardized extract of fenugreek seed (IND 01) in animal models of peripheral neuropathy a study was undertaken in the Department of Pharmacology, Poona College of Pharmacy, Bharati Vidyapeeth Deemed University, Pune, India. The effects of daily oral administration of IND 01 (50, 100, 200 mg/kg) were studied in rats after partial ligation of the sciatic nerve and sciatic nerve crush injury during 30-days period. The results showed that IND 01 offered sustained protection against thermal hyperalgesia and deranged motor function test scores in both models from seven day onwards. (307)
That chronic hyperglycemia is accompanied with a significant increase in the neurolipofuscin deposition and Ca2+ levels with decreased activities of membrane linked ATPases and antioxidant enzymes in diabetic brain is wellknown.
The researchers of School of Life Sciences, Jawaharlal Nehru University, New Delhi, India confirmed these facts in experimemts on diabetic rats.
These diabetic rats showed increased monoamine oxidase activity with correlated increase in genomic DNA degradation in the brain, supporting the hypothesis that catecholamine oxidation is an important source of oxidative stress, causing loss of membrane fluidity, increased neurolipofuscin deposition and decrease of GLUT4 expression in the brain. Treatment with fenugreek seed powder showed reversal of these changes to near normal levels in diabetic rat brain. (308)
[Note: Lipofuscin is the name given to finely granular yellow- brown pigment composed of lipid containing residues of liposomal digestion. It is considered tobe one of the ‘aging’ pigments, found in the liver, kidney, heart muscle, retina, adrenals, nerve cells and ganglion cells. It is specifically arranged around the nucles.
Lipofuscin is the product of oxidation of unsaturated fatty acids and may be symptomatic of membrane damage.
Abnormal accumulation of lipofuscin is associated with neurodegenerative disorders called lipofuscinoses. Lipofuscin accumulation is a major risc factor implicated in macular degeneration. Pathological accumulation of lipofuscin is implicated in Alzheimer’s disease, Parkinsonism, amyotrophic lateral sclerosis, acromegaly and certain lysosomal diseases, denervation atrophy, lipid myopathy, COPD and centronuclear myopathy. Accumulation of lipofuscin in the colon is the cause of the condition melanosis coli.] (309)
Effects on the Eye
Ultrastructure of the diabetic retina shows disintegration of the inner nuclear layer cells with reduction in rough endoplasmic reticulum and swelling of mitochondria in the bipolar cells. Treatment with fenugreek seed powder effectively restores these histopathological changes and other biochemical abnormalities to near normal states. (310)
Cataract is the opacification in the lens of the eye and leads to 50% of blindness worldwide. Fenugreek seed powder protects against experimental cataract. This effect is attributed to antioxidant activity of fenugreek seeds. To explore its role in human cataract further studies are necessary. (311)
Alcoholic extract of fenugreek seeds at the dose of 2g/kg/day given to alloxan-induced diabetic rats prevented the developmentment of cataract. (312)
Actions on Behavior
Chronic oral administration of the fenugreek extract significantly increases food intake and the motivation to eat in rats and also induces hyperinsulinemia as well as hypocholesterolemia. The treatment with fenugreek does not prevent the anorexia or the decreased motivation to eat induced by d-fenfluramine (2mg/kg. IP) (313)
Fenugreek seeds have been used for treating metabolic and nutritive dysfunction. They have been shown to modulate feeding behavior in animals. Researchers have recently observed a selective decrease in fat consumption in healthy normal weight volunteers treated with hydro-alcoholic extract of fenugreek seeds. (314)
Actions on the Endocrine system
Two growth- hormone release stimulators isolated from methanolic extract of fenugreek seeds were: saponin l and dioscin. In rats fenugreek saponin caused 12.5-fold and dioscin caused 17.7-f old stimulation of release of rat growth hormone from rat pituitary cells.(315)
Actions on the Musculoskeletal System
A study was designed to investigate the beneficial outcome of fenugreek by researchers of the Department of Pharmacology, St. Peter’s Institute of Pharmaceutical Sciences, Warangal, AP, India. In the study ethanol extract of Trigonella foevonum-graecum seeds was tested against Freund’s complement adjuvant-induced arthritis in albino rats. There was a marked improvement at the dose 400mg/kg of bod y weight. This improvement was due to anti-inflammatory and antioxidant activities of fenugreek. (316)
Addition of fenugreek extract to high oral dose of dextrose enhances the glycogen resynthesis after exercise. (317)
Actions on CVS
The researchers of the Department of Medicine, R. T. N. Medical College, Udaipur, India, investigated the effect of fenugreek on blood sugar, blood lipids, platelet aggregation, fibrinogen and fibrinolytic activity. The subjects included in the study were healthy individuals, patients with coronary artery disease (CAD) and patients with non-insulin-dependent diabetes mellitus (NIDDM) who either had CAD or were without CAD. Fenugreek was given in the dose of 2.5 g twice a day for 3 months. There were no changes in the blood chemistry of healthy individuals. However fenugreek decreased significantly the blood lipids and triglycerides without affecting HDL-c in CAD and NIDDM patients. Fenugreek also reduced significantly fasting and postprandial blood sugar in NIDDM patients. Fenugreek did not affect platelet aggregation, fibrinolytic activity and fibrinogen in all the individuals. (318)
A study was aimed to investigate the effect of fenugreek (Trigonella foenum-graecum) on antioxidant status and lipid peroxidation in heart tissue of normal and alloxan induced diabetic rats by researchers of the Department of Biochemistry, University of Lucknow, Lucknow; India. The result of the study demonstrated that administration of fenugreek seed powder (9g/kg body weight) could exert beneficial effects against the diabetes and associated free radicals complications in the heart tissue. (319)
Actions on GI System
The aqueous extract and the gel fraction isolated from fenugreek seeds shows cytoprotective effects on the gastric mucosa and prevents ulceration. This effect seems to be not only due to anti-secrerory action but also to the effects on mucosal glycoproteins. The soluble gel fraction derived from the seeds is more effective than omeprazole in preventing ulcer formation. (320)
Fenugreek seed powder included in the diet significantly decreases the activity of beta-glucosidase in all the tissues. Fenugreek inhibits colon carcinogenesis by modulating the activities of beta-glucosidase and mucinase. The beneficial effect of fenugreek may be attributed to the presence of fibre, flavonoids and/ or saponins. (321)
Heart burn, a burning sensation in the chest, is caused by hyperacidity and acid reflux from the stomach into the esophagus (GERD). Fenugreek not only reduces gastric acid secretion but also relieves GERD. (322)
Actions on the Liver
Trigonella foenum graecum seed powder (TSP) administered for three weeks to alloxan induced diabetic rats stabilized glucose homeostasis and free-radical metabolism in the liver and kidney. It normalized the histological structures of the liver and kidney altered due to diabetes. It also reversed the diabetic state at the cellular level. (323)
Chang liver cell is a human cell line with epithelial morphology that will grow to high density. This cell line is extensively used in virology and biochemistry. Subsequently it was shown to be a subline of HeLa cells. (324)
A HeLa cell is a cell type in an immortal cell line used in scientific research. It was derived from cervical cancer cells. The cell line was found to be remarkably durable and prolific as illustrated by its contamination of many other cell lines used in research. (325)
The protective effect of a polyphenolic extract of fenugreek seeds (FPEt) against ethanol-induced toxicity was investigated in human Chang liver cells by the researchers of the Department of Biochemistry, Annamalai University, Tamil Nadu; India. The extract reduced the formation of thiobarbituric acid reactive substances in the dose-dependent manner. FPEt reduced liver cell apoptosis. The findings suggest that the phenolic compounds of fenugreek seeds have cytoprotective effect on ethanol-induced liver damage. The cytoprotective effects of FPEt were comparable with those of sylimarin, a known hepetoprotective agent. (326)
Fenugreek contains an unusual amino-acid, 4-hydroxyisoleucine which has insulinotropic property. In one study, streptozotocin-induced diabetic rats were treated with 4-hydroxyisoleucine at 50mg/kg per day for 8 weeks. This prolonged exposure did not show signs of side effects or liver damage. The treatment improved HDL cholesterol levels. The researchers concluded that 4-hydroxyisoleucine can be useful for the treatment of insulin resistance and can be a hepatoprotective agent. (327)
Cypermethrin (CM) an important type 2 pesticide used extensively in pest control is hepatotoxic and nephrotoxic. Fenugreek is well-known for its antitoxic and antioxidant potential. In one study hepatotoxicity was induced in male Wister rats by treating them with 25mg/kg body weight of CM. They were then treated with 10% aqueous extract of fenugreek for 60 days. CM treatment caused increase in thiobarbituric acid reactive substances, depletion in glutathione and reduction in the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione S-transferase in liver and kidneys. Treatment with 10% aqueous extract of fenugreek showed replenishment of antioxidant status and all values to near normal indicating the hepato-renal protective effects of fenugreek. This study shows that phytochemicals present in fenugreek could ameliorate the pesticide-induced hepato-renal toxicity. (328)
Dieldrin, an insecticide is hepatotoxic, nephrotoxic and induces alterations in hematological parameters. In one study on male Wister rats, dieldrin poisoning resulted in (1) perturbations of several hematological parameters, (2) an oxidative stress on hepatic and renal tissue evidenced by an increase of lipid peroxidation level associated with an increase of superoxide dismutase (SOD) activity and decrease of glutathione peroxidase and catalase activities, (3) increased levels of sugar, total cholesterol, triglycerides, creatinine, urea, uric acid and proteins in blood, (4) increased activities of lactate dehydrogenase, alkaline phosphatase and transaminases in blood. However previous administration of fenugreek was found to hinder and prevent these dieldrin-induced damages. This protective effect is due to antioxidant properties of fenugreek. (329)
[Note on Aldrin and Dieldrin:
 
Aldrin Dieldrin
Aldrin and dieldrin are insecticides. Dieldrin was developed as an alternative to DDT. Dieldrin proved to be a highly effective insecticide was widely used during the 1950s to early 1970s.
Aldrin was used to control soil pests namely termites on corn and potato crops. Dieldrin was used as an insectide on fruit, soil and seed.
Both have been banned in most developed countries.] (330), (331)
Dietary supplementation of fenugreek reducess the accumulation of triglyceride in the liver, a hallmark fearure of hepatic steatosis without affecting the plasma insulin or glucose levels in Zucker obese rats suggesting that TNF-alpha may play an important role in this process. (332)
Chronic alcoholism is associated with fatty liver which culminates into fibrosis characterized by accumulation of collagen. To investigate the effects of fenugreek seed polyphenol extract on liver lipids and collagen, hepatotoxicity was induced in male albino Wister rats by administering ethanol (6g/kg/day) for 30 days. Administration of fenugreek ployphenol extract (200mk/kg/day) for 30 days significantly improved lipid profile and reduced collagen content. The positive effect was attributed to bioactive phytochemicals in fenugreek seeds. (333)
Effects on the Biliary System
The etiology of cholesterol gall stone disease is multi-factorial. Alteration in hepatic and biliary cholesterol homeostasis, stasis of bile in the gall bladder and infection or inflammation are some important ones. Lipid lowering, anti-inflammatory and some other hitherto un-understood activities of fenugreek can prevent the formation of cholesterol stones in the gall bladder. (334)
Further experimental study on mice by Reddy R. L. R. and Srinivasan K showed that fenugreek seeds not only regress existing cholesterol gallstones but also can prevent their possible recurrence. (335)
Formation of cholesterol gall stones in the gallbladder is controlled by crystallizing and anti-crystallizing factors in bile. Dietary fenugreek reduces the cholesterol content in the bile, modulates the nucleating and anti-nucleating proteins which in turn affect cholesterol crystallization. (336)
Effects on Metabolism
Diabetes is a multi-metabolic disorder. Its control can be achieved by inhibiting key digestive enzymes related to carbohydrate and lipid digestion. Trigonelline found in fenugreek seeds significantly decreases intestinal alpha amylase and maltase by 36 and 52% respectively. This leads to significant decrease in post-prandial blood glucose by 46%. Trigonelline also inhibits lipase activity in the small intestine by 56%. This leads to significant decrease in serum triglyceride (TG) and total cholesterol (TC) and increase in HDL cholesterol levels.
Trigonelline also protects liver and kidney functions effectively as was evidenced by decrease in serum aspartate transaminase (AST), alanine transaminase (ALT), gamma-glutamyl transpeptidase (GGT), lactate dehydrogenase (LDH) and creatinine and urea levels. Histological studies show positive effects of trigonelline on the tissues of pancreas, liver and kidney. Trigonelline prevents or retards the apoptosis of the beta cells of the pancreas. It seems trigonelline is a molecule of choice for the holistic treatment of diabetes. (337)
By enhancing insulin sensitivity, by improving disturbed lipid metabolism in the liver and the plasma, dietary supplementation of fenugreek seeds improve high fat, high sucrose diet-induced metabolic disorders. (338)
Recently, in Canada, flour supplemented with 8%-10% dietary fibre of fenugreek has been used in the production of baked products such as bread, pizza, muffins and cakes. This admixture allows the production of functional foods that may be widely acceptable to consumers observing western diets. In the West the potential of fenugreek as a functional food and nutraceutical and its benevolent effects on metabolism are very much admired.
[Note: A functional food is a food given an additional function by adding new ingredients or more of existing ingredients. The function of the functional food is often one related to health promotion or disease prevention.
Please compare this term to the concept of ‘Rasaayana’ mentioned in Ayurveda.] (339), (340)
That the action of fenugreek in lowering blood sugar levels is almost equivalent to that of insulin has been investigated and documented by many researchers. However recent research shows that combination of fenugreek, manganese and vanadium has better anti-diabetic (insulin mimetic) effect. (341)
Anti-metabolic syndrome effects of fenugreek are now very well accepted in modern medicine. Recently immunomodulatory activity of fenugreek seed powder (0.5 amd 1.0 g/kg body weight) in alleviating experimentally induced immunosupression and delay in burn healing in cyclophosphamide-treated rats was evaluated. The results showed that the fenugreek seed powder (FSP) has a more potent immunostimulant activity than anti-metabolic syndrome activity. Thus FSP may be useful not only as an adjunct for the control of metabolic syndrome but also as an immunostimulant in immunocompromised patients such as those on anti-cancer chemotherapy. (342)
In an experimental study on diabetic rats majority of the mitochondrial enzymes in their tissues had significantly higher activities compared to the control rats. Similsrly, the activities of mitochondrial and cytosolic aminotransferases and arginase were significantly higher in liver and kidney tissues of the diabetic rats.
Oral administration of fenugreek seed powder and sodium orthovanadate restored the activities of these enzymes to normal values.(343)
The data of research on fenugreek suggests that 4-hydroxyisoleucine; a simple plant derived-amino acid may be an attractive candididate for the treatment of type 2 diabetes, obesity and dyslipidemia, all key components of metabolic syndrome. (344)
Fenugreek leaves also show a significant antidiabetic activity. The effect is similar to that of glibenclamide. Supplementation of fenugreek leaves also lower elevated lipids in streptozotocin-induced diabetic rats. (345), (346)
The disrupted free radical metabolism in diabetic animals may be normalized by fenugreek seed supplementation in the diet. (347)
Incorporation of 50g of fenugreek seed powder during lunch and dinner in the diet of type 1 diabetics for 10 days significantly reduced fasting blood sugar and improved glucose tolerance (GTT). There was 54% reduction in 24 hour urinary excretion of sugar. Serum levels of total cholesterol, LDL and VLDL cholesterol and triglyceroids were also significantly reduced. However the HDL cholesterol level remained unchanged. (348)
Trigonella foenum-graecum extract can lower kidney/body weight ratio, blood glucose, blood lipid levels and improve hemorheological properties in experimental diabetic rats following treatment for 6 weeks in dose dependent manner. (349)
Daily fat consumption was significantly reduced in healthy volunteers by repeated consumption of fenugreek seed extract. (350)
By reversing the altered glycolytic, gluconeogenic and lipogenic enzymes fenugreek seed powder administered to type-1 and type-2 diabetics, stabilizes glucose and lipid homeostasis. Fenugreek also stabilizes glucose homeostasis in the liver and kidney. Thus various biochemical effects exerted by fenugreek seed powder make it a valued therapeutic agent in type-1 and type-2 diabetes. (351)
Consumption of alcohol causes increase in plasma and liver lipids, together with alterations in collagen content. Administration of fenugreek seed polyphenol extract to alcohol-fed rats significantly improved lipid profile and reduced collagen content, cross linking, aldehyde content and peroxidation. These effects were comparable with those of silymarine. The protective effects were attributed to bioactive phytochemicals in fenugreek seeds. (352)
The lipid lowering effects of fenugreek may be due to sapogenins, which increase biliary cholesterol excretion. This effect might also be attributed to estrogenic constituent, indirectly increasing the thyroid hormone T4. (353)
Administration of fenugreek to diabetic rats restored the decreased activity of creatine kinase in heart, skeletal muscles and liver to almost control levels in experimental diabetic rats. This activity of fenugreek was comparable to insulin and vanadate also used in the study.(354)
Antidiabetic activity
Fenugreek seeds produce hypoglycemic effect in both normal and diabetic rats. The hypoglycemic effect is related to dose. (355)
To study effects of the hydro-alcoholic extract of fenugreek seeds (TFG seeds) in diabetic mice; the extract (2g/kg daily) was administered orally for about 20 weeks. Fenugreek reduced fasting plasma glucose, plasma insulin and insulin resistance. The extract also caused significant reduction in triglycerides and total cholesterol levels and increase in HDL cholesterol levels. The extract had no effect on calorie intake or body weight. (356)
An unusual amino acid (2S, 3R, 4S) 4-hydroxyisoleusine (4-HO-IIe) has anti-diabetic properties. It enhances insulin secretion under hyperglycemic conditions. In diabetic rats it also lowered the high levels of lipids and uric acid. For details refer: (357)
Fenugreek stimulates the secretion of insulin from the beta cells of the pancreas and lowers blood sugar levels when administered for a short duration of about 30 days. However prolonged administration of fenugreek does lower fasting blood sugar but fasting serum insulin levels are much lower than expected; suggesting extra-pancreatic mode of action. It possibly increases the sensitivity of tissues to insulin. The hypoglycemic effect is slow but sustained without any risk of developing severe hypoglycemia. (358)
Hypoglycemic effect of fenugreek is mediated through insulinomimetic effect as well as inhibition of intestinal alpha-amylase activity.(359)
The fraction of fenugreek that contains the testa (a hard protective outer layer of the seeds of flowering plants) with the peculiar smell and bitter taste and the endosperm of the defatted seeds (i. e. the subfraction “A”) are said to be associated with the hypoglycemic effects of fenugreek. These effects have not been observed in studies of lipid extracts. Fenugreek lowers lipids because it contains saponins that are transformed in the GI-tract into sapogenins. The fibre contained in fenugreek seeds slows the rate of postprandial glucose absorption. All these properties of fenugreek exert hypoglycemic effect.
In humans, fenugreek increased the number of insulin receptors, although the mechanism underlying this effect unclear. (360)
Actions on Urinary System
Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Oxidative stress is the key factor involved in the development of diabetic nephropathy. Prevention and prompt control of this complication can give a good quality of life to the patients. Administration of fenugreek seeds to these patients can restore the kidney function of diabetics via its anti-inflammatory and anti-oxidant activities. Recent data shows the efficacy of fenugreek to attenuate the progression of diabetic nephropathy and production of interlukin-6. Fenugreek significantly reduces the high levels of glucose, urea, creatinine, sodium and potassium. Furthermore, all the ultramorphologic abnormalities in the kidney of diabetic rats, including the uneven thickening of the glomerular base membrane, were markedly ameliorated by treatment with Trigonella seed extract. (361), (362)
Cyclophosphamide (CP) a common anti-cancer drug causes nephrotoxicity by its reactive metabolites acrolein and phosphoramide mustard. A study was conducted by the Department of Medical Elementology and Toxicology, New Delhi, India; to evaluate modulation of toxicity caused by concomitant exposure to cyclophosphamide and l-buthionine-SR-sulfoximine (BSO) by fenugreek extract. Fenugreek showed protective effect on kidney against cyclophosphamide toxicity. Fenugreek may be a promising protective herb for consideration in complementary therapy in cancer patients undergoing chemotherapy. (363)
Etiology, pathology, prevention and treatment of nephrolithiasis are grey areas in the realm of medicine. In one study fenugreek was found to prevent the formation of calcium oxalate stone. (364)
Actions on Male Reproductive System
For many years, in the past fenugreek was used to improve male libido and treat erectile dysfunction (ED) in males. According to a recent study conducted in Australia, fenugreek significantly improved male libido. Hence fenugreek is now christened as “Natural Viagra”! The research performed by the Centre for Integrative Clinical and Molecular Medicine, showed that fenugreek extract taken twice a day for six weeks did improve sex life (libido) of men aged 25 to 52. Researchers however are unclear how, fenugreek used as a spice in curry and other dishes, works to improve libido. Researchers know for sure that saponins contained in fenugreek do increase the production of sex hormones. (365)
Fenugreek increases the serum levels of free testostrerone in males, improves the blood supply to corpora cavernosa and increases the levels of NOS which improves the ED.
Actions on Female Reproductive System
Fenugreek has been used by lactating mothers to increase the volume of breast milk they produce. (366)
Fenugreek seeds exert mastogenic effect resulting in enhanced breast size. This suggests that fenugreek has estrogenic effects. In one in vitro study chloroform extract of fenugreek seeds stimulated the proliferation of MCF-7 cells, showed binding to ER and acted as an agonist for ER mediated transcription via ERE. It also induced the expression of estrogen responsive gene pS2 in MCF-7 cells. (367)
MCF-7 is a breast cancer cell line isolated in 1970 from a 69-year-old Caucasian woman. Prior to MCF-7, it was not possible for cancer researchers to obtain a mammary cell line that was capable living longer than a few months. The patient, Frances Mallon, whose name is unknown to the vast majority of cancer researchers, died in 1970. Her cells were the source of much current knowledge about breast cancer. At the time of sampling she was a nun in the convent of Immaculate Heart of Mary in Monroe, Michigan under the name of Sister Catherine Frances.] (368)
Anti-tumor Activity
Recent research by Indian researchers shows that fenugreek seeds protect against cancer of the breast (Amin et al. 2005) and cancer of the colon (Raju et al. 2006). (369)
Hepatoma cells previously cultured with a reactive oxygen species generating system showed increased invasive activity. Trigonellin suppressed this activity. Thus trigonellin acts against cancer cells. (370)
Fenugreek shows antitumor activity against the Ca755 mouse mammary carcinoma and the Guerin’s carcinoma in rats. Fenugreek powder inhibits the growth of certain tumors, decreases the level of malondialdehyde in the liver, heart and kidney. Consumption of fenugreek is accompanied with decreased polyamines (spermine, spermidine and putrescine) content in tumor tissue. Inclusion of fenugreek to allowance improves certain blood value. (371)
Intra-peritoneal administration of the alcohol extract of fenugreek seed both before and after inoculation of Ehrlic ascites carcinoma cell in experimental mice produced more than 70% inhibition of tumor cell growth with respect to control. Treatment with the extract of fenugreek seed was found to enhance both the peritoneal exudates cell and macrophage cell counts. The extract also showed a significant anti-inflammatory effect. (372)
DMH (1, 2- dimethylhydrazine) is a carcinogen. It undergoes oxidation in the liver and induces colonic carcinoma. Antioxidant activity of fenugreek modulates DMH- induced hepatic oxidative stress during colon carcinogenesis. (373)
By inhibiting arachidonic acid metabolism fenugreek may prevent tumerogenesis. (374)
Culinary Uses
Methee or fenugreek is one of the commonest spices used in India. It is used for the preparation of pickles, curry powders, pastes and is often encountered in the cuisine of the Indian subcontinent. The young, tender leaves and sprouts of fenugreek are eaten as greens and dried leaves are used to flavor other dishes. In India methee or fenugreek is used in a variety of dishes and sweets as Methee Paraathaa, Methee vegetables, Methee Laddu and Methee sweets.
It is used used in injera/taita, a type of bread unique to Ethiopian and Eritean cuisine. In Yemen it is the main condiment and an ingredient added to the national dish called saltah.
In Egypt, fenugreek seeds are used to prepare tea. This is a popular winter drink served in coffee shops. In some parts of the Middle East it is used in a variety of sweet confections. (375)
Medicinal Actions and UsesTraditional Uses
Methee or fenugreek seeds are used in flatulent dyspepsia, intestinal colic, diarrhea, dysentery, chronic cough, hepato-splenomegaly, rickets, gout and diabetes. It is also used as carminative, tonic and aphrodisiac.
It is used in the manufacture of hair oils and hair tonics. In middle ages, fenugreek was recommended as a cure for baldness in men. In Java, it is used in hair tonic preparations and as a cosmetic.
It has been in vogue for the treatment of (bronchial) asthma, headchce, heart burn and menstrual abnormalities. When taken with lemon juice and honey it reduces fever.
It has been utilized for centuries to promote woman’s health, to induce labour and to increase breast milk secretion during lactation. This ancient wisdom is made use of by farmers to help increase the cow milk production. (376)
Fenugreek does pass through breast milk. When used in moderation it is safe for both mother and baby. The U. S. FDA has rated it as ‘Generally Regarded as Safe’ (GRAS). Using fenugreek can cause breast milk, sweat and urine to smell like maple syrup. And since it passes to the baby it can also cause the baby’s urine and sweat to smell like maple syrup. The smell of maple syrup caused by fenugreek is not dangerous but there is a serious illness that is characterized by a maple syrup smell. Therefore it is very important to tell the pediatrician attending the baby that the mother feeding the baby with breast milk is taking fenugreek so the baby’s illness is not misdiagnosed. (377)
Fresh fenugreek leaves are beneficial in the treatment of indigestion, flatulence and a sluggish liver. An infusion of the leaves is used as a gargle for recurrent mouth ulcers and for ordinary sore throat.
Paste of fresh fenugreek leaves applied over the scalp regularly before bath helps hair grow, preserves natural color of hair, keeps hair silky and cures dandruff.
Topically, the gelatinous mucilage of fenugreek seed has some benefit for soothing irritation of the skin by eczema, prickly heat etc. It has also been applied as a warm poultice to relieve muscle aches and joint pains.
Fenugreek seeds reduce the amount of calcium oxalate in the kidneys and prevent oxalate-stone formation. (378)
Usages in Ayurveda
In Ayurveda, there are two different traditions which can be referred to as the Father lineage, the medicinal aspect based upon scriptures, sootras (doctrines and aphorisms) and traditions of vaidyas, and the Mother lineage based on the wisdom passed on from proverbial grandmothers to daughters through generations.
Usages according to the Father Lineage:
Internally Methee is used for madhumeha i.e. diabetes mellitus (Bhavprakash 2006), digestive disorders, fever, impotance, bronchial asthma and externally for mastitis, inflammations and as hair tonic.
According to Ayurvedic Pharmacopeia (1999) Methee seed powder is indicated for grahanee (various types of colitis) in the dosage of 3to 6grams. According to the textbook of Dravyaguna (2007), 1 to 3 grams of Methee seed powder soaked in freshly made yoghurt relieves prawaahikaa (diarrhea, dysentery). In addition to prawaahikaaBhishgratna (2002) recommends it to relieve flatulent dyspepsia, intestinal colic and bloody diarrhea.
Bhavprakash (2006) mentions that Methee is anabolic and galactogogue and recommends it to be used to increase milk volume in lactating mothers. Modern research supports this statement. Bhavprakash also recommends Methee for fevers and paste of Mehtee leaves to be applied over the eyes to relieve conjunctivitis.
Usages according to Mother Lineage:
Methee Laadoo is a traditional sweet in Rajasthan, Maharashtra and in many states of India; prepared from roasted Methee seeds added to wheet flour or gram flour, jaggery and ghee. It is predominantly used by lactating mothers to increase milk volume. The laadoo is mostly consumed as a nourishing tonic in winter season. It is also used to alleviate muscle and joint pains (Rheumatism and arthritis).
Methee tea has been used for rhinitis, sinusitis, bronchitis and bronchial asthma.
To get relief from sorethroat, decoction of Methee seeds and mint leaves is used for gargling.
Folks of Tamilnadu, India consume a teaspoonful of Methee powder with a glass of water every day as a cooling drink in summer. Yemenite Jews also consume similar drink. (379)
Usages in Modern Medicine
The Commission E approved internal use of fenugreek for loss of appetite and external use as a poultice for inflammation, as an emollient for treating boils, furuncles and eczema. However, the primary clinical applications of fenugreek are in the treatment of diabetes and hyperlipidemia. (380)
Toxicity
Major side effect of fenugreek is diarrhea. If diarrhea occurs, the dose should be reduced. A few minor side effects are nausea, vomiting, GI discomfort such as hyperacidity and gastritis if taken on empty stomach. When used topically skin irritation and rashes may be noticed.
Fenugreek should not be used during pregnancy since it has the potential to induce labor. (381)
Recently researchers have identified allergenic fenugreek proteins by immunoblotting, using sera from 29 patients with specific IgE to peanut and other legumes. In addition, 2 patients were evaluated by skin prick test and open food challenge with native fenugreek powder.
High levels of specific IgE to both peanut and fenugreek were seen in most sera. Fenugreek sensitization is believed to be a consequence of cross-reactivity in patients with peanut allergy. Primary fenugreek allergy was suspected in only one case. The dose of fenugreek eliciting symptoms was about 2mg in the open food challenge. Fenugreek contains several potential allergens. There is evidence for a high rate of cross-reactivity to peanut. (382)
Fenugreek can cause allergic rhinitis, hoarseness of voice, persistent coughing, wheezing, facial angioedema and shock.
Repeated external applications of fenugreek may lead to undesirable skin reactions.
Allergies to various legumes such as soybeans, peanuts and green peas may cause allergy to fenugreek.
Allergic reactions to fenugreek are possible in subjects who have asthma or who are allergic to peanuts and soya beans. (383)
Researchers of Norwegian Institute of Public Health also demonstrated cross allergic reactions to fenugreek. However the symptoms were milder than the primary allergic response. Differences in serolosical responses between primary allergy and cross-allergy might be due to mediation through different immune mechanisms. These differences need to be further investigated. (384)
Individuals allergic to pea nut may have serious allergy on exposure to fenugreek. Researchers of Norwegian Institute of Public Health noticed even anaphylactic reaction to fenugreek in previously sensitized mice. (385)
An allergy is a hypersensivity disorder of the immune system. A substance that causes allergy is protein in nature. Researchers of the National Veterinary Institute, Oslo, Norway, showed that fenugreek proteins ranging from 50 kDa to 66 kDa have high IgE- affinity. These proteins were homologous to proteins found in peanut causing allergy. Hence individuals, who are allergic to peanut, show allergy or cross-allergy to fenugreek. These observed homologies to major peanut allergens provide a molecular explanation for clinical cross-allergies.
[Note: Dalton (symbol: Da) is the standard unit unit that is used for indicating mass on an atomic or molecular scale (atomic mass). Masses of proteins are often expressed in daltons. For example, a protein with a molecular weight of 64000 g mol-1 has a mass of 64000 daltons or 64 kDa]. (386)
Ovine fenugreek stagger: Ovine are sheep or sheep like animals. Ovine fenugreek stagger is a nervous disorder affecting animals grazing on fenugreek. It commonly occurs in sheep in Victoria. It occurs both as an acute and a chronic syndrome. In acute syndrome edema of the brain and and spinal cord is found. Signs include quadriperesis, a high stepping fore limb gait and a ‘bunny-hopping’ hind limb gait i. e. hopping on hind limbs by putting them together (Kangaroo gait). In chronic syndrome changes of Wallerian degeneration and peripheral neuropathy are seen. Kangaroo gait occurs in lactating ewes in New South Wales. The clinical signs and pathological changes are remarkably similar to those of fenugreek staggers. Although the diet associated with each is different the causal agent may be the same. (387)
Fenugreek (injectable drug and oral drug alike) in large doses is teratogenic, can decrease the severity of bone marrow cell proliferation and increase foetal mortality rate. (388)
Contraindications
Use of fenugreek is contraindicated in subjects having history of hypersensitivity to fenugreek, peanut allergy and pregnancy.
Drug Interactions:
A number of medications can interact negatively with fenugreek.
Concomitant use of fenugreek with modern antidiabetic agents including acarbose, glipizide, glyburide, metformin, glitazones, insulin and others can lower blood sugar to a dangerous level of hypoglycemia.
Concomitant use of fenugreek with aspirin, clopidogrel, warfarin, statins, NSAIDs, dalteparin, enoxaparin, and heparin can initiate or induce minor bleeding such as brusing or induce serious internal bleeding because fenugreek contains coumarins.
Fenugreek can also interfere with corticosteroid drug activity, hormone therapy and monoamine oxidase inhibitors due to high content of mucilaginous fiber and high viscosity in the gut.
Other Safety Issues:
Use of fenugreek should be immediately stopped if the following side effects occur because it may indicate symptoms of allergic reactions. These symptoms include breathing distress, discomfort in the throat, chest pain, skin rashes or itching of the skin. Using fenugreek should be avoided during pregnancy and with impaired liver and kidney function. (389), (390)
Preparations and dosages
Capsules: Because Fenugreek seeds and powder taste bitter they are supplied in capsule form. Readymade capsules come in different doses.
For hyperglycemia, hyperlipidemia: 5 grams to 100 grams two times a day. 25 to 30 grams twice a day with meals is the dose most commonly used by experienced patients. It is used indefinitely.
In general, initially start taking one capsule three times a day, increasing slowly until sweat and urine smells of maple syrup.
Tea: Place 1 to 3 teaspoons (5 to 15 G) of fenugreek seeds in 1 US cup (250 ml) of boiling water, steep and strain. Tea can be consumed up to three times a day.
Fenugreek is thought to work well in combination with other herbs, such as blessed thistle (Cnicus benedictus, Carbenia benedicta), alfalfa (Medicago sativa) and fennel (Foeniculum vulgare). It is often one of the main ingredients found in nursing teas. When taken as directed, results can be seen within a week.
Method to prepare ‘cold tea’ (called as ‘Sheeta’ or ‘Hima’ in Ayurveda): It is prepared by steeping 500mg seed in 150 ml of cold water for three hours and then straining. One cup is taken several times a day.
Paste: To prepare paste mix 50 grams of seed- powder with 25 ml of water. Apply as needed to inflammed area, boils, furuncles etc.
Poultice: To prepare poultice mix 50 grams of seed-powder with 1 liter of water and apply as needed. (391)
Facial scrub: Soak 2 tablespoon seeds in a 1 tablespoon “live yoghurt” (Indian Fresh Dahee), then mix and blend well to make paste. Gently rub this on to the face and neck using circular movements and wash off after 15 minutes.
Sprouts: Soak 1 to 2 teaspoon seeds in adequate water overnight. (One can drink the excess water. It tastes bitter but contains valued water soluble ingredients of Methee in it). One can pour off that water. Then rinse seeds with clear water and wrap in a clean cloth or place seeds in in a sprouter. The sprouting process takes about five days. The sprouts are palatable like any other sropts. (392)
Swaras (Fresh juice): 10 to 20 ml
Choorna (Powder): 3 to 6 Gms
Some important Formulations: Siddhamethika, Methika Modaka, Methika Paak, Mehika Beeja Choorna (Special Methee Beeja Powder), Shuntyhaadi Paaka. (393)
Some important preparations:
In the Ayurvedic Pharmacopeia (1999) Methee constituted as an important ingredient in Mritasanjeewanee Suraa andMustakaarishta.
Ingredients of Mritasanjeewanee Suraa (Bhatat, 2010)
Puraana guda (Very old jiggery), Cinnamon, Pomegranate, Lajjalu (Touch me not), Ashwagandhaa, Dewadaaru, Bilwa, Shyonaka, Gokshura/u, Shaalaparnee/Shyaalaparnee, Prasnaparnee, Aruna, Paatala, Mocha, Brihatee, Kantakaaree, Indrawaarunee, Badaree, Chitraka, Punarnawaa, Swyanguptaa/Svyangupta, Dhustura (?Dhatura), Pooga, Kamala (Lotus), Chandana, Sandalwood, Usheera, Shatapushpee, Mareecha, Black pepper, Ajwayan, Krishna jeerak, Black cumin, Saariwaa, Elaa, Ilaayachee, Cardamom, Jatiphal, Nutmeg, Mustaka, Granthaparnee, Shunthee, Dry ginger, Methikaa, Fenugreek, Shatee.
Ingredients of Mustakaarishta (Bharat, 2010)
Mustaka, Guda, Jaggary, Mareecha (Black pepper), Dhatakee pushpa, Methika (Fenugreek), Jeeraka (Cumin), Shunthee (Dry ginger), Chitraka, Lawang (Clove), Ajwayan.
Suraa is a kind of medicinal wine, essentially an herbal wine called Aasawa. It is made from cold water without boiling the ingredients (Shaarangadhara).
Mritasanjeewanee Suraa is the drug of choice for kapha jjwara (Fever associated with cough with expectoration), sannipaata jjwara (Tridoshaja jjwara), dourbalya (Debility), krishataa (Emaciation), shwaasa (Dyspnea), and kaasa (Cough probably dry cough). It penetrates deep into the lungs and helps to clear the air passages. (Bharat, 2010)
Arishta is a medicinal herbal wine prepared by boiling the ingredients (Shaarangadhara). It is also useful in conditions whereMritasanjeewanee Suraa is used
Chaturbeeja: Methee is also a part of the formua Chaturbeeja. It contains:
1. Methee, Fenugreek (Trigonella foenum graecum),
2. Chandrashoora (Leptidium sativum),
3. Krishna jeeraka, Black cumin (Nigella sativa),
4. Yawaanee, Ajwaayan (Carum copticum)
Chaturbeeja is used for indigestion, bloating (flatulent dyspepsia), shoola (Intestinal colic?), and thoracic and pelvic pain (Bhavaprakash 2006).
Extracts of Methee nowadays are used in maple syrup imitations and cosmetic products. Due to antibacterial and antifungal properties of the seeds, Fenugreek- paper is shown to be suitable as packaging material to preserve food. For inventing this, a high school student from Maryland, in 2002, won an award (Turner, 2005) (394)
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