Onnit T+ Ingredient Red Clover
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Onnit T+ Ingredient Red Clover

Onnit T+ Ingredient Red Clover

Red Clover

Red Clover (Trifolium pratense) is known to contain fair amounts of an isoflavone (flavonoid) known as Biochanin A (BCA) which is also found in soy and other legumes.  Biochanin A is also known as a phytoestrogen as it is a plant-derived nonsteroidal molecule that has estrogen-like activity as measured in 'in vivo' and 'in vitro' experiments.  Red Clover also contains small amounts of the isoflavones genistein, daidzein and formononetin (methoxy daidzein).  These flavonoids are in glycoside form in the intact plant, however when the plant is crushed to make extracts, the glycosides are broken down by enzymatic hydrolysis and an extract will contain the aglycones.   A glycoside is a simple sugar that is attached to the flavonoid and when the sugar moiety is removed it is referred to as an aglycone.  Onnit's T-Plus formula includes Red Clover due to its testo boosting and estrogen blocking properties.     

Biochanin A may have antioxidant properties as well as an anti-cancer, anti-plaque and anti-osteoporosis (due to estrogen effect) ability.  Animal studies indicate that BCA is absorbed through the small intestine and enters the lymphatics before it goes into the systemic circulation.  When it enters the liver it a number of modifications occur generating a number of metabolites.  BCA and formononetin as proestrogens are converted by a demethylation enyzme into the more potent phytoestrogens genistein and daidzein in the liver by cytochrome P450.  Research also indicates that BCA and formononetin can be broken down to genistein and daidzein by gut flora as well.  Onnit's T-Plus formula contains all of the above phytoestrogens which are reported to act as testo boosters and estrogen blockers.       

Red Clover has been used to treat symptoms of menopause, osteoporosis and cardiovascular issues.  As estrogen receptor-targeted therapies have been demonstrated to be successful in treating breast cancer and various metabolic disorders, phytoestrogens have been reported to be agonists on estrogen-related receptors.  There are a number of mechanism involved here including modifying enzymatic activities that result in a decrease of carcinogenicity of xenobiotics.  Xenobiotics are molecules that are not produced by the body but can be found in the body.  Flavonoids have also been demonstrated to modulate cytochrome P450 system (CYP gene).  Isoflavones have been demonstrated to inhibit the activity of aromatase (CYP19) which has the effect of decreasing estrogen synthesis, in other words an estrogen blocker, thereby generating antiestrogenic effects.  This is important when treating breast and prostate cancer or if you want to maintain testosterone levels .  Biochanin A also inhibits phosphodiesterase (PDE) activity specifically PDE4.  It is also known that genistein and daidzein selectively inhibit PDE2 and PDE3, respectively.  Some PDEs are involved with inflammation and bronchoconstriction.  Inhibition of some PDEs allows for anti-inflammatory effects as well as bronchodilation. 

Xenoestrogens have become of interest due to their effects on the reproductive system.  A study on male goat kids and how low-dose dietary phytoestrogen exposure such as genistein, daidzein, Biochanin A and formononetin affect testosterone production during puberty has been done.  Male goat kids at the age of three months received either low-dose (3-4 mg/kg/day) phytoestrogens or a standard diet for approximately 3 months.  Plasma levels of testosterone as well as total and free thyroid hormone (T3) levels were measured weekly.  At the end of the 3 month period, testicular testosterone levels and cAMP were measured.  

By the 2nd month, male goat kids that received phytoestrogen supplementation were found to have significantly higher testosterone levels than control animals.  The increase in testosterone levels was preceded by an increase in T3 plasma levels.  It was also observed that cAMP levels were significantly lower in phytoestrogen fed animals.

These researchers concluded that phytoestrogens such as genistein, daidzein, formononetin and Biochanin A have the ability to stimulate testosterone biosynthesis during puberty in male goats by increasing the secretion of T3.  Thyroid hormone T3 is known to stimulate Leydig cell steroidogenesis (testosterone production) in the testes.  Lower cAMP levels are due to phytoestrogen inhibition of phosphodiesterases.  The Red clover in Onnit's T-Plus contains these phytoestrogens and therefore may increase testosterone levels (testo booster) and act as an estrogen blocker.

Biochanin A and Asthma

Biochanin A has been demonstrated to attenuate airway resistance and improve lung function while decreasing inflammatory cells, neutrophils, eosinophils, levels of cytokines (interleukins 2, 4, 5) and tumor necrosis factor in the bronchi and alveoli of mice.  Biochanin A also reduces levels of ovalbumin (OVA) specific immunoglobulin E in serum and lungs.  It has also been demonstrated that levels of IgG are enhanced as well.  This isoflavone reduces cumulative OVA induced contractions in isolated guinea pig trachealis, suggesting that Biochanin A inhibits degranulation of mast cells.  This suggests that Biochanin A may be used to treat allergic asthma and COPD.

Red Clover has been used as a tea or tincture as an antispasmodic (involuntary muscle spasms) for bronchitis, laryngitis, tuberculosis, measles, whooping cough and asthma since the 1800s.    Research is bringing to light how this occurs.  Biochanin A has been demonstrated to inhibit phosphodiesterase (PDE) activity specifically PDE4.  It is also known that genistein and daidzein selectively inhibit PDE2 and PDE3, respectively.    

The classification of phosphodiesterases (PDEs) is oriented around their protein and complementary DNA sequences, cofactors, what they act on and their pharmacological activities.  Currently PDEs are grouped into eleven enzyme families that hydrolyze cAMP and/or cGMP.  PDE1 group (calcium/calmodulin-dependent), PDE2 group (cGMP-stimulated), PDE3 group (cGMP-inhibited), PDE4 group (cAMP-specific) and PDE5 group (cGMP-specific) have been found in canine trachea, guinea pig lung and human bronchi.  Phosphodiesterases 3 and 4 have been found in guinea pig airways.  Rolipram, which is a prototype PDE4 selective inhibitor and anti-inflammatory, is a drug that has both high and low affinity for PDE4.  A PDE4 inhibitor is a drug used to block the degradative action of PDE4 on cAMP (cyclic adenosine monophosphate.  PDE4s are most commonly found in immune cells and the central nervous system.  One of the best studied PDE4 inhibitors is rolipram.  It was initially used in research as a potential treatment for depression and Parkinson's.  As a therapeutic agent it has been abandoned due to adverse side-effects, however it is still used in research to get a better understanding of  PDE4 inhibitors.  In general, other PDE4 inhibitors have a wide range of therapeutic potential for COPD, asthma, depression, Alzheimer's and Parkinson's such as Biochanin A.  More recent studies are demonstrating that some PDE4 inhibitors have antipsychotic effects, improve long-term memory,  increase alertness and provide neuroprotection and repair.       

Research suggests that inhibition of high affinity PDE4 is linked to adverse side effects such as nausea, vomiting and gastric hypersecretion.  Inhibition of the low affinity PDE4 is linked to anti-inflammatory and bronchodilating effects.  Given this, the therapeutic ratio of selective PDE4 inhibitors to treat asthma and COPD (chronic obstructive pulmonary disease) is defined as a high to low PDE4 ratio.  Biochanin A has been demonstrated to have a higher PDE4 ratio then the selective PDE4 inhibitor known as AWD 12-281.  This suggests that Biochanin A has great potential in treating asthma and/or COPD.  A schematic of the physiological changes is below.  Schematic was taken from Wun-Chang Ko et.al.  http://www.hindawi.com/journals/ecam/2011/635058/ .

What is of interest here in Biochanin A's ability to treat asthma and COPD and its ability to open airways and inhibit inflammation may suggest that it may do the same in normal individuals.  If this is the case, bringing more oxygen into your system during the process of body building will allow for increased ATP production which can assist in maintaining normal blood glucose levels.  This would allow for greater strength and stamina during exercise.  Workouts may become easier to do as well as prolong the amount of time you can exercise and in turn increase lean muscle mass while it maintains testosterone levels by acting as an estrogen blocker.  This is not unlike Cordyceps and its ability to reduce inflammation and open airways.  Cordyceps has been demonstrated to increase oxygen utilization by up to 40 percent.  This in turn increases ATP production and stabilizes blood glucose levels as well.  The Red Clover in Onnit's T-Plus may be able to increase your oxygen utilization thereby increasing stamina and strength.

Summary

Red clover and a number of legumes contain the isoflavone known as Biochanin A which is a phytoestrogen.  This phytoestrogen has been demonstrated to interact with a certain type estrogen receptor and inhibit it.  Excess estrogen has been demonstrated to develop breast cancer.  Biochanin A inhibits a cytochrome P450 enzyme known as aromatase that converts androgen into estrogen.  It also is involved with CYP19 gene regulation decreasing the amount of message RNA produced which codes for aromatase.  You not only inhibit aromatase, you make less of it as well.  This suggests that red clover supplementation may be an effective estrogen blocker. Furthermore, Biochanin A has been demonstrated to inhibit PDE activity specifically PDE4.  This isoflavone has anti-inflammatory and bronchodilating properties.  This may be useful for bodybuilders as this may increase oxygen uptake from the lungs and increase the production of ATP while stabilizing blood glucose levels.  This would have the effect of increasing strength and stamina.  Onnit's T-Plus contains Red clover that may act as a testo booster by acting as an estrogen blocker.     

Suggested Reading:

The red clover (Trifolium pratense) isoflavone biochanin A inhibits aromatase activity and expression.  http://www.ncbi.nlm.nih.gov/pubmed/17761019

Gotoh T, Yamada K, Yin H, et al. Chemoprevention of N-nitroso-N-methylurea-induced rat mammary carcinogenesis by soy foods or biochanin A. Jpn J Cancer Res. 1998; 89:137-142.

Lee YS, Kim TH, Cho KJ, Jang JJ. Inhibitory effects of biochanin A on benzo[a]pyrene induced carcinogenesis in mice. In vivo. 1992; 6:283-286.

Moon YJ, Shin BS, An G, Morris ME. Biochanin A inhibits breast cancer tumor growth in a murine xenograft model. Pharm Res. 2008;25(9):2158-2163.

Siddiqui MT, Siddiqui M. Hypolipidemic principles of Cicer Arietnum: biochanin A and formononetin. Lipids. 1976; 11:243-246.

Yanagihara K, Ito A, Toge T, Numoto M. Antiproliferative effects of isoflavones on human cancer cell lines established from the gastrointestinal tract. Cancer Res. 1993; 53:5815-5821.

Wun-Chang Ko et.al., Biochanin A, a Phytoestrogenic Isoflavone with Selective Inhibition of Phosphodiesterase 4, Suppresses Ovalbumin-Induced Airway Hyperresponsiveness. Evidence-Based Complementary and Alternative Medicine. Vol 2011(2011), Article ID 635058, 13 pages, doi:10.1155/2011/635058.  http://www.hindawi.com/journals/ecam/2011/635058/

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