Category Archives: Antioxidants

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Piperine Enhances the Serum Concentration, Extent of Absorption and Bioavailability of Curcumin

The consumption of curcumin powder, a very lipophilic (fat soluble) substance, which has been obtained from the tumeric root (Curcuma longa L.), has poor bioavailability due to the following factors:

  • low intestinal absorption rate
  • rapid metabolism in the liver and intestinal wall due to glucuronidation
  • rapid systemic elimination

Because of this poor bioavailability, even with large amounts of consumed curcumin, there is low levels in the blood plasma and tissues.  The majority of consumed curcumin is excreted via the feces. This is why consuming large amounts of the curcumin powder may lead to diarrhea.

Glucuronidation

Glucuronidation is a Phase II process in metabolic detoxification which consists of the transfer of the glucuronic acid component of uridine diphosphate glucuronic acid to a toxic substrate resulting in substances known as glucuronides which are water-soluble.  These water-soluble glucuronides are subsequent eliminated from the body through urine or feces (via bile from the liver).

In the case of curcumin (without augmenting absorption), it is rapidly metabolised by glucuronic acid in the liver and intestinal wall and made water-soluble and mostly excreted via the feces. 

There are a number of ways in which to improve the bioavailability of curcumin by augmenting its absorption.  Some of the approaches that have been taken are:  1

  • adjuvant like piperine that interferes with glucuronidation
  • curcumin nanoparticles
  • curcumin phospholipid complex
  • liposomal curcumin
  • structural analogues of curcumin

Piperine

Piperine, which is derived from Black pepper (Piper nigrum) and a number of different varieties of pepper species, has many physiological effects.   Piperine, by favorably stimulating the digestive enzymes of the pancreas, enhances the digestive capacity and significantly reduces the gastrointestinal food transit time. Piperine has been demonstrated in in vitro studies to protect against oxidative damage by inhibiting or quenching free radicals and reactive oxygen species.  2

For more in-depth information on the current research into Piperine, read this article from Healthy But Smart entitled:  Does Piperine Have Health Benefits? The Current Research Examined

Piperine has been documented to enhance the bioavailability of curcumin by modifying the rate of glucuronidation by lowering the endogenous UDP-glucuronic acid content and strongly inhibiting hepatic and intestinal aryl hydrocarbon hydroxylase and UDP-glucuronyl transferase.  Piperine’s bioavailability enhancing property is also partly attributed to increased absorption as a result of its effect on the ultrastructure of intestinal brush border.  3

A study published in 1998, researchers examined the effect of combining piperine, a known inhibitor of hepatic and intestinal glucuronidation, on the bioavailability of curcumin in rats and healthy human volunteers. 

Humans were administered a dose of 2 grams of curcumin by itself and serum levels were either undetectable or very low. They then administered the same dosage of curcumin (2 grams) with a concomitant administration of piperine at 20 mg.  The result was a much higher concentrations from 0.25 to 1 h post drug (P < 0.01 at 0.25 and 0.5 h; P < 0.001 at 1 h), and an increase in bioavailability of 2000% or a 20-fold increase in bioavailability.

The study shows that in the dosages used, piperine enhances the serum concentration, extent of absorption and bioavailability of curcumin in humans with no adverse effects.  4

This study may lead to the conclusion to add some ground-up black pepper kernals with your curcumin powder.  Unfortunately, the consumption of black pepper directly with curcumin will not help achieve enhanced nutrient absorption, as was found in the above referenced study. 

In fact, one would have to consume large quantities of black pepper to achieve even a modest amount of piperine bioavailability, which is impractical.  The reason for this is that piperine remains captive in the form of raw black pepper and it takes time for its bioavailability enhancing property to be released.

Therefore, a purified extract of piperine is necessary to get the increased absorption.  This is where BioPerine® is useful. 

BioPerine®, a natural bioavailability enhancer from Sabinsa Corporation, received Generally Recognized As Safe (GRAS) status after a comprehensive review of safety and toxicology data by an independent panel of scientists with international repute.  Based on scientific procedures and available comprehensive scientific literature, including human and animal data determined the safety-in-use for black pepper extract (BioPerine®).

BioPerine® significantly improved the uptake of Curcumin—the healthful extract from turmeric roots with clinically validated efficacy in a wide range of health conditions ranging from inflammation to cancer.

Bioavailability of Curcumin (2000 mg) when co-administered with BioPerine® (20 mg) was enhanced by 20-fold or 2000% compared to bioavailability of Curcumin alone at doses that were devoid of adverse side effects.

piperinegraph

BioPerine® also increases the bioavailability of other natural substances:

Applications of BioPerine®

The nutritional materials which may be co-administered with BioPerine® are as follows:

Herbal Extracts   Curcuma longa, Boswellia serrata, Withania somnifera, Ginkgo biloba and Capsicum annuum
Water-soluble Vitamins    Vitamin B1, Vitamin B2, Niacinamide, Vitamin B6, Vitamin B12, Folic acid and Vitamin C
Fat-­soluble Vitamins   Vitamin A, Vitamin D, Vitamin E and Vitamin K
Antioxidants   Vitamin A, Vitamin C, Vitamin E, alpha-carotene, beta-carotene, beta-cryptoxanthin, lycopene, lutein/zeaxanthin, pine bark bioflavonoids complex, germanium, selenium and zinc
Amino Acids   Lysine, isoleucine, leucine, threonine, valine, tryptophan, phenylalanine, and methionine
Minerals   Calcium, iron, zinc, vanadium, selenium, chromium, iodine, potassium, manganese, copper and magnesium

Source:  BioPerine®

Informational References:

Health But Smart:  Does Piperine Have Health Benefits? The Current Research Examined

Cover Photo:  Black Pepper tree (piper nigrum)

Syzygium cumini: A Tree from the Indian Subcontinent with Multiple Health Benefits

Syzygium cumini, also known as jambul, jambolan, jamblang, or jamun, is an evergreen tropical tree in the flowering plant family Myrtaceae.  Syzygium cumini is native to the Indian Subcontinent and adjoining regions of Southeast Asia. The species ranges across India, Bangladesh, Pakistan, Nepal, Sri Lanka, Malaysia, the Philippines, and Indonesia.  

Syzygium_cumini_Tree_3

Syzygium cumini Tree

The name of the fruit is sometimes mistranslated as blackberry, which is a different fruit in an unrelated family.  In southern Asia, the tree is venerated by Buddhists, and it is commonly planted near Hindu temples because it is considered sacred to Lord Krishna.

The compounds in the tree, including the leaves, fruit, seeds and bark, include:  1

  • Anthocyanins
  • Glucoside
  • Ellagic acid
  • Isoquercetin
  • Kaemferol
  • Myrecetin

The fruit contains:

  • Raffinose
  • Glucose
  • Fructose
  • Citric acid
  • Mallic acid
  • Gallic acid
  • Anthocyanins
  • Delphinidin-3-gentiobioside
  • Malvidin-3-laminaribioside
  • Petunidin-3-gentiobioside
  • Cyanidin diglycoside
  • Petunidin
  • Malvidin

The seeds of the fruit contain:

  • Jambosine
  • Glycoside jambolin

The plant has been considered an anti-diabetic medicinal remedy throughout the Indian and Asian populations.  During the last four decades, numerous folk medicinal reports on the anti-diabetic effects of this plant have been cited in the literature. 

The Table below lists the various folk medicine uses of Syzygium cumini:

Folk medicinal uses of S. cumini (L.) Skeels.
Ethnic group used and their origin Plant part used, mode of preparation, administration and ailments treated References
Local people in southern Brazil Either infusions or decoctions of leaves of jambolan in water at an average concentration of 2.5 g/L and drank it in place of water at a mean daily intake of about 1 liter are used in the treatment of diabetes. [74]
Lakher and Pawi in North east India Infusion of fruit or mixture of powdered bark and fruit is given orally to treat diabetes. [75]
  Juice obtained from the seeds is applied externally on sores and ulcers.  
  Powdered seeds are mixed with sugar are given orally 2–3 times daily in the treatment of dysentery.  
  The juice of leaves is given orally as antidote in opium poisoning and in centipede bite.  
  The juice of ripe fruits is stored for 3 days and then is given orally for gastric problems.  
  The juice obtained from the bark is given orally for the treatment of women with a history of repeated abortion.  
Local informants in Maharastra, India Fruit and stem bark are used in the treatment of diabetes, dysentery, increases appetite and to relieve from headache [76]
Nepalese, Lepchas and Bhutias in northeast India Decoction of stem bark is taken orally three times a day for 2–3 weeks to treat diabetes [77]
Native amerindians and Quilombolas in North eastern Brazil Leaves are used in the treatment of diabetes and renal problems. [78]
Kani tribals in Southern India Two teaspoon of juice extracted from the leaf is mixed with honey or cow’s milk and taken orally taken twice a day after food for 3 months to treat diabetes. Fresh fruits are also taken orally to get relief from stomachache and to treat diabetes. [79]
  Young leaf is ground into a paste with goat’s milk and taken orally to treat indigestion.  
Malayalis in South India Paste of seeds is prepared with the combination of leaves of Momordica charantia and flowers of Cassia auriculata and taken orally once a day for 3 months to treat diabetes. [80]
Traditional medical healers in Madagascar Seeds are taken orally for generations as the centerpiece of an effective therapy for counteracting the slow debilitating impacts of diabetes. [35]
Local population in Andhra Pradesh, India Shade dried seeds are made into powder and taken orally thrice a day in the treatment of diabetes. [81]
Siddis in Karnataka, India The juice obtained from the leaves is mixed with milk and taken orally early in the morning, to treat diabetes. [82]
  The juice obtained from the stem bark is mixed with butter milk and taken orally every day before going to bed to treat constipation. The same recipe, when taken early in the morning on an empty stomach, is claimed to stop blood discharge in the faeces.  
Rural population in Brazil Leaves of jambolan are taken orally in the treatment of diabetes. [64]
Traditional healers in Brazil


Tea prepared from the infusion or decoction of leaves is taken orally to treat diabetes.


[83]


Tribal people in Maharastra The tender leaves are taken orally to treat jaundice. It was claimed that the eyes, nails and urine turned yellow. The treatment was followed for 2–3 days by adults and children as well. [84]

(Source:  Asian Pac J Trop Biomed. 2012 Mar; 2(3): 240–246.  doi:  10.1016/S2221-1691(12)60050-1)

The fruits, seeds and stem bark of Syzygium cumini possess promising activity against diabetes mellitus which has been confirmed by several experimental and clinical studies and considered its primary health benefit.

There are additional important health benefits of Syzygium cumini that have been studied and published.  They are listed in the Table below:

Health Benefits of Syzygium cumini (Jamun)

SystemConditionBenefitReferences
Gastrointestinal
Gastroprotective
A dose which consisted of 20.0 g tannins/kg rat weight showed significantly lower stomach free radical concentrations. These findings suggest that tannins extracted from S. cumini have gastroprotective and anti-ulcerogenic effects.1
Immunity
Anti-Inflammatory
These observations established the anti-inflammatory effect of S. cuminii seed extract in exudative, proliferative and chronic stages of inflammation along with an anti-pyretic action. Antiinflammatory and related actions of Syzigium cumini seed extract 2
The study concluded that S. cumini exhibits inhibitory role on inflammatory response to histamine, 5-HT and PGE2.3
The present study demonstrated that S. cumini bark extract has a potent anti-inflammatory action against different phases of inflammation without any side effect on gastric mucosa.4
Anti-bacterial and Anti-fungal
The water and methanolic extracts of Syzygium jambolanum seeds were examined for antibacterial and antifungal activity in vitro using the disc diffusion method, minimum inhibitory concentration, minimum bactericidal concentration and minimum fungicidal concentration. 5
The leaf essential oils of Syzygium cumini and Syzygium travancoricum were tested for their antibacterial property. The activity of S. cumini essential oil was found to be good, while that of S. travancoricum was moderate.6
Radioprotective
The radioprotective activity of the hydroalcoholic extract of jamun seeds (SCE) was studied in mice exposed to different doses of gamma radiation. The mice were injected with 0, 5, 10, 20, 40, 60, 80, 100, 120, 140 or 160 mg/kg body weight of SCE, before exposure to 10 Gy of gamma radiation, to select the optimum dose of radiation protection.
The mice treated with 80 mg/kg body weight SCE intraperitoneally before exposure to 6, 7, 8, 9, 10 and 11 Gy of gamma radiation showed reduction in the symptoms of radiation sickness and mortality at all exposure doses and caused a significant increase in the animal survival when compared with the concurrent double distilled water (DDW) + irradiation group. The SCE treatment protected mice against the gastrointestinal as well as bone marrow deaths and the DRF was found to be 1.24.
7
Syzygium cumini Linn. and Eugenia cumini (SCE) provided protection against the radiation-induced bone marrow death in mice treated with 10-60 mg/kg b.wt. of SCE. However, the best protection was obtained for 30 mg/kg b.wt. SCE, where the number of, survivors after 30 days post-irradiation was highest (41.66%) when compared with the other doses of SCE.8
Metabolism
Antioxidant
These data showed that in addition to 5 anthocyanidins, jamun contains appreciable amounts of ellagic acid/ellagitannins, with high antioxidant and antiproliferative activities.9
The leaves, bark and fruits of Terminalia arjuna, Terminalia bellerica, Terminalia chebula and Terminalia muelleri, the leaves and fruits of Phyllanthus emblica, and the seeds of Syzygium cumini were found to have high total phenolic contents (72.0-167.2 mg/g) and high antioxidant activity (69.6-90.6%).10
From the results, using different free radical-scavenging systems, it can be said that the fruit skin of S. cumini have significant antioxidant activity. In each case, lower antioxidant values, in comparison to tea, might be due to drying condition; through which some of antioxidants are presumably degraded. The antioxidant property of the fruit skin may come in part from antioxidant vitamins, phenolics or tannins and/or anthocyanins. Consumption of S. cumini fruit may supply substantial antioxidants which may provide health promoting and disease preventing effects.11
The present study reveals the efficacy of Eugenia jambolana seed kernel in the amelioration of diabetes, which may be attributed to its hypoglycemic property along with its antioxidant potential. The antioxidant effect of Eugenia jambolana seed kernel was also compared with glibenclamide, a standard hypoglycemic drug.12
Diabetes/Blood glucose
The present study reveals the efficacy of Eugenia jambolana seed kernel in the amelioration of diabetes, which may be attributed to its hypoglycemic property along with its antioxidant potential. The antioxidant effect of Eugenia jambolana seed kernel was also compared with glibenclamide, a standard hypoglycemic drug.13
In view of the knowledge summarized here, a successful clinical study should use S. cumini seeds, seed kernels or fruit from India in fairly high doses. Reductions on blood sugar levels by about 30% seem reasonably to be expected. Adverse effects to be expected comprise gastrointestinal disturbances.14
Study shows that S. cumini seed extracts reduce tissue damage in diabetic rat brain.15
Treatment with 400 mg per day of aqueous extracts of Momordica charantia (MC) and Eugenia jambolana (EJ) for 15 days substantially prevented hyperglycemia and hyperinsulinemia induced by a diet high in fructose (63.52+/-2.9 and 66.46+/-2.2 vs. 75.46+/-2.4, respectively).16
The oral antihyperglycemic effect of the water and ethanolic extracts of the fruit-pulp of Eugenia jambolana (EJ) was investigated in alloxan-induced diabetic with fasting blood glucose between 120 and 250 mg/dl as well as severely diabetic rabbits (fasting blood glucose above 250 mg/dl). Water extract was found to be more effective than the ethanolic extract in reducing fasting blood glucose and improving blood glucose in glucose tolerance test.
After treatment of diabetic and severely diabetic rabbits daily once with 25mg/kg, body weight with F-III for 7 and 15 days, respectively, there was fall in fasting blood glucose (38% diabetic; 48% severely diabetic) and improvement in blood glucose during glucose tolerance test (48%) in diabetic rabbits.
17


Resources:

Deep Foods – Frozen Jamun Fruit

Jamun Powder (Syzygium cumini)

Vedic Juices Organic Jamun Indian BlackBerry Juice 1 Liter 12 Packs

Basic Ayurveda – Jamun Juice

 

F2-Isoprostanes: A Major Aging Marker of Lipid Peroxidation and Risk Marker for Developing Coronary Heart Disease

Arachidonic acid

Arachidonic acid (AA) is a polyunsaturated omega-6 fatty acid (20:4(ω-6)) and is converted from linoleic acid, which is an essential fatty acid, known as omega-6 fatty acid.

In the body, arachidonic acid is present in the phospholipids of cell membranes and mostly abundant in the:

  • brain
  • muscles (accounting for roughly 10-20% of the phospholipid fatty acid content on average)
  • liver

Only animals and not plants can convert linoleic acid to arachidonic acid.  Arachidonic acid can also be obtained endogenously from the diet by consuming primarily animal foods, such as:

  • meat
  • poultry
  • eggs

Physiologically, the body requires a certain level of AA.  However, when that level is outside the accepted reference range, this can progress into a pro-inflammatory environment.  AA is actually considered to produce various pro-inflammatory eicosanoids. 

Image result for Arachidonic acid

Figure 1.  Arachidonic Acid cascade  (Source)

One measure of cellular inflammation is the AA:EPA Ratio.  The AA: EPA ratio provides a more specific indicator of the balance between omega-6 and omega-3 fatty acids in circulation. When this ratio is higher, there is preferred incorporation of AA into cell membranes over EPA, leading to a pro-inflammatory environment.

While both of these fatty acids are essential to human health, the optimal ratio of AA:EPA is around 1.7.  1 

Isoprostanes

Isoprostanes are prostaglandin-like compounds formed in the body from the free radical-catalyzed peroxidation of arachidonic acid.  Isoprostanes acts as inflammatory mediators and possess potent biological activity.  They are accurate markers of lipid peroxidation of oxidative stress.  2

Image result for lipid peroxidation

Figure 2.  Harmful Effects of Lipid Peroxidation  (Source)

Lipid peroxidation occurs in the cell membrane when free radicals oxidize or degrades the lipids contain the the cell membranes.  This ultimately results in cell damage.  Polyunsaturated fatty acids (mostly AA) are particularly vulnerable to lipid peroxidation due to the numerous double bonds in their structure.

F2-Isoprostanes

F2-Isoprostanes are produced by the reaction of free radicals with arachidonic acid.

Image result for F2-Isoprostanes

Figure 3.  Metabolism of F2-Isoprostanes  (Source)

The damage done by F2-Isoprostanes can be widespread, since they can generally cause:

  • blood vessels to constrict
  • blood pressure to raise
  • promotion of blood clots
  • promotion of the clumping of platelets

Numerous studies carried out over the past decade have shown that these compounds are extremely accurate measures of lipid peroxidation and have illuminated the role of oxidant injury in a number of human diseases including atherosclerosis, Alzheimer’s disease and pulmonary disorders.  3

Measuring and Testing for F2-isoprostanes

The F2-isoprostanes test is considered the gold standard for oxidative stress and is measured in a urine specimen. 

Elevated F2-isoprostanes levels are at a more than 30-fold risk for developing coronary heart disease compared with those with normally low levels.  4

According to the Cleveland HeartLab, Inc., your F2-isoprostanes risk is low when your level is less than 0.86 ng/mg; at or above that level places you at high risk.  5

 

Cleveland HeartLab, Inc.

Reference Range for F2-isoprostanes

Age                                                                ng/mg creatinine

All Ages                                                                  <0.86

 

 

Informational References:

Cleveland HeartLab, Inc. offers the F2-isoprostanes Test through the Know Your Risk Program®

Cleveland HeartLab, Inc. F2-isoprostanes Handout

Video:  Marc Penn – Trials and Tribulations of Assessing CVD Risk in 2013 (Cleveland HeartLab)

 

Puerarin, a Potent Bioactive Ingredient from Kudzu, Shows Promise as a Neuroprotective Agent

Kudzu, also called Japanese arrowroot, is a group of plants in the genus Pueraria, in the pea family Fabaceae.  It is native to Asia and the Pacific Islands.  The name is derived from the Japanese name for the plants, kuzu (クズ or 葛?).  It tends to be a very invasive plant and grows as a vine.

Image result for Kudzu root

Figure 1.  Kudzu root  (Source)

 

Figure 2.  Flowers of Pueraria montana var. lobata  (Source)

The Chinese derived the traditional medicine called Gegen (Ge Gen) from Pueraria lobata (Willd.) Ohwi, a specieis of Pueraria.

Image result for puerarin

Figure 3.  Puerarin molecule  (Source)

One of the major bioactive ingredients of Kudzu is puerarin and is its is most abundant secondary metabolite.  Since its isolation in the 1950’s, puerarin has been extensively investigated for its pharmacological properties.  It has been widely used in the treatment of:

  • cardiovascular and cerebrovascular diseases
  • diabetes and diabetic complications
  • osteonecrosis
  • Parkinson’s disease
  • Alzheimer’s disease
  • endometriosis
  • cancer

The beneficial effects of puerarin on the various medicinal purposes may be due to its wide spectrum of pharmacological properties such as:

  • vasodilation
  • cardioprotection
  • neuroprotection
  • antioxidant
  • anticancer
  • antiinflammation
  • alleviating pain
  • promoting bone formation
  • inhibiting alcohol intake
  • attenuating insulin resistance

Recent studies have revealed that puerarin can be neuroprotective in the following areas:

  • learning and memory impairment induced by D-galactose  1
  • protected neurons against apoptosis in the cortex and hippocampus of Alzheimer’s diseased rats caused by Aβ25–35 through downregulating Aβ1–40 and Bax expression in brain tissues, therefore alleviating the spatial learning and memory impairment of diseased animals.  2 
  • ischemic brain injury.  Puerarin could improve the learning-memory ability after global cerebral ischemia and reperfusion in rats. The protective mechanism might be related to the effect of inhibiting or delaying the cell apoptosis through up-regulating the expression of Bcl-2 after ischemia and reperfusion.  3 

The anti-Alzheimer’s disease effects of puerarin were also suggested to be related to its abilities in decreasing the lipid peroxidase levels and increasing superoxide dismutase levels in brain tissues, enhancing cerebral blood flow, and improving brain microcirculation   4  

Freezing Broccoli Sprouts Increases Sulforaphane Yield

Three-day old broccoli sprouts are concentrated sources of glucoraphanin, which is the precursor to sulforaphane.  Fresh broccoli sprouts contain 10 to 100 times more glucoraphanin by weight than mature broccoli plants. 1  Fresh broccoli sprouts can contain at least 73 mg of glucoraphanin (also called sulforaphane glucosinolate) per 1-oz serving.

A study from 2015 published in the journal RSC Advances by researchers from the College of Food Science and Technology, Nanjing Agricultural University, Nanjing, People’s Republic of China and the College of Food Science and Engineering, Qingdao Agricultural University, Qingdao, People’s Republic of China, investigated whether freezing broccoli sprouts would have an effect on glucoraphanin and ascorbic acid content, myrosinase activity, sulforaphane and sulforaphane nitrile formation.  2

The researchers froze broccoli sprouts at −20 °C (DF-20), −40 °C (DF-40) and −80 °C (DF-80) or stored at −20 °C (LN-20), −40 °C (LN-40) and −80 °C (LN-80) after being frozen in liquid nitrogen for 5 min or always frozen in liquid nitrogen (LN).

The results showed the following:

  • glucoraphanin content was not significantly affected by freezing
  • myrosinase activity was enhanced
  • sulforaphane yield  was increased by 1.54–2.11 fold
  • sulforaphane nitrile formation decreased
  • ascorbic acid content was decreased

By freezing fresh broccoli sprouts, sulforaphane can be increased by on average 1.825 times its original value when fresh and not frozen. 

Eating frozen broccoli sprouts may not be very appetizing.  Instead it is recommended to use the frozen broccoli sprouts in a smoothie.  Make sure you use the broccoli sprouts straight from the freezer and do not allow them to thaw.  

Increasing Nrf2: A Master Regulator of the Aging Process

Nuclear factor (erythroid-derived 2)-like 2, also known as NFE2L2 or Nrf2, is a transcription factor. The Nrf2 pathway is “the primary cellular defense against the cytotoxic effects of oxidative stress.”

Activation of Nrf2 results in the induction of many cytoprotective proteins. These include, but are not limited to, the following:

  • NAD(P)H quinone oxidoreductase 1 (Nqo1)
  • Glutamate-cysteine ligase, catalytic (Gclc) and glutamate-cysteine ligase, modifier (GCLM)
  • Heme oxygenase-1 (HMOX1, HO-1)
  • The glutathione S-transferase (GST) family
  • The UDP-glucuronosyltransferase (UGT) family
  • Multidrug resistance-associated proteins (Mrps)

A wide variety of dietary components have been shown in vitro or cell culture to activate Nrf2 and directly increase activity of phase II enzymes; these include:

  • epigallocatechin gallate (EGCG)
  • resveratrol
  • curcumin and its metabolite tetrahydrocurcumin, which has greater phase II activity
  • cinnamaldehyde
  • caffeic acid phenyethyl ester
  • alpha lipoic acid
  • alpha tocopherol
  • lycopene
  • apple polyphenols (chlorogenic acid and phloridzin)
  • gingko biloba
  • chalcone
  • capsaicin
  • hydroxytyrosol from olives
  • allyl sulfides from garlic
  • chlorophyllin
  • xanthohumols from hops

The beneficial effects of these phytochemicals have been demonstrated in numerous animal and human studies, particularly their chemopreventative and antioxidant abilities; these effects may be explained by their indirect stimulation of antioxidant enzyme production and phase II detoxification through Nrf2 signaling. (Source: Life Extension)


References:

Yuan JH, Li YQ, Yang XY. Inhibition of epigallocatechin gallate on or- thotopic colon cancer by upregulating the Nrf2-UGT1A signal path- way in nude mice. Pharmacology 2007; 80: 269 – 78

Hsieh TC, Lu X, Wang Z, Wu JM. Induction of quinone reductase NQO1 by resveratrol in human K562 cells involves the antioxidant response element ARE and is accompanied by nuclear translocation of tran-scription factor Nrf2. Med Chem 2006; 2: 275 – 85

Nayak S and Sashidhar RB. Metabolic intervention of aflatoxin B1 toxicity by curcumin. J Ethnopharmacol 2010;127 (3) : 641-4

Osawa T. Nephroprotective and hepatoprotective effects of curcuminoids. Adv Exp Med Biol 2007;595 : 407-23

Liao BC, Hsieh CW, Liu YC, Tzeng TT, Sun YW, Wung BS. Cinnamaldehyde inhibits the tumor necrosis factor-alpha-induced expression of cell adhesion molecules in endothelial cells by suppressing NF-kap- paB activation: Effects upon IkappaB and Nrf2. Toxicol Appl Pharmacol 2008; 229: 161 – 71

Lii CK, Liu KL, Cheng YP et al. Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation. J Nutrition 2010;140 (5) : 885-92

Feng Z, Liu Z, Li X, et al. α-Tocopherol is an effective Phase II enzyme inducer: protective effects on acrolein-induced oxidative stress and mitochondrial dysfunction in human retinal pigment epithelial cells. J Nutr Biochem 2010;21 (12) : 1222-31

Wang H and Leung LK. The carotenoid lycopene differentially regulates phase I and II enzymes in dimethylbenz[a]anthracene-induced MCF-7 cells. Nutrition 2010;26 (11-12) : 1181-7

Veeriah S, Miene C, Habermann N et al. Apple polyphenols modulate expression of selected genes related to toxicological defence and stress response in human colon adenoma cells. Int J Cancer 2008;122 (12) : 2647-55

Liu XP, Goldring CE, Wang HY, Copple IM, Kitteringham NR, Park BK. Extract of Ginkgo biloba induces glutathione-S-transferase subunit-P1 in vitro. Phytomedicine 2009; 16(5):451–455

Liu YC, Hsieh CW, Wu CC, Wung BS. Chalcone inhibits the activation of NF-kappaB and STAT3 in endothelial cells via endogenous electrophile. Life Sci 2007; 80: 1420 – 30

Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK et al. Capsaicin in- duces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxid Redox Signal 2007; 9: 2087 – 98

Zhu L, Liu Z, Feng Z et al. Hydroxytyrosol protects against oxidative damage by simultaneous activation of mitochondrial biogenesis and phase II detoxifying enzyme systems in retinal pigment epithelial cells. J Nutr Biochem 2010;21 (11) : 1089-98

Gong P, Hu B, Cederbaum AI. Diallyl sulfide induces heme oxygenase-1 through MAPK pathway. Arch Biochem Biophys 2004; 432: 252 – 60

Zhang Y, Guan L, Wang X, Wen T, Xing J, Zhao J. Protection of chloro- phyllin against oxidative damage by inducing HO-1 and NQO1 ex- pression mediated by PI3K/Akt and Nrf2. Free Radic Res 2008; 42: 362–71

Dietz BM, Kang YH, Liu G et al. Xanthohumol isolated from Humulus lupulus Inhibits menadione-induced DNA damage through induction of quinone reductase. Chem Res Toxicol 2005;18 (8) : 1296-305

Surh YJ, Kundu JK, Na HK. Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Med 2008;74 (13) : 1526-39


Informational Reference:

Nrf2.com  

Inhibiting the Destructive Effects of arNOX (ENOX3)

The Aging-Related Cell Surface NADH Oxidase (arNOX) enzyme is one in a class of newly-identified ECTO-NOX (external NADH oxidase or ENOX (Ectos is Greek for outside) ) proteins that are located on external cell membranes.  arNOX is also known as ENOX3.

As the cells mitochondria age and produce less energy, arNOX becomes increasingly active.  arNOX is present in all cells tested, and in particular in the serum and saliva as well as the dermis and epidermis of the skin. 

ArNOX activity increases with age between 30 and 50–65 years and generates the destructive superoxide free radical.  arNOX transmits cell surface oxidative changes to surrounding cells and circulating lipoproteins. 

arNOX promotes tissue aging, especially in the vascular walls and the skin and the structural components of the skin’s extracellular matrix, such as collagen and elastin. arNOX is shed from the cell surface and is found in saliva, urine, perspiration, and interstitial fluids that surround the collagen and elastin matrix underlying dermis.

There is a strong correlation with the level of arNOX in the blood or saliva and a persons age.  The older one looks, apparently the more arNOX is in the blood and saliva.  arNOX is inactive in youth and can vary among individuals after age 30.  arNOX activity correlates with age and reaches a maximum at about age 65 in males and 55 in females.

Inhibiting arNOX by exogenous (dietary) natural substances is the only way to lessen and mitigate the destrucitve effects of arNOX.

Inhibiting arNOX activity

There are a number of natural substances that have been shown to inhibit arNOX activity and reduce oxidative damage caused by the superoxide free radical.  The following natural substances are able to inhibit arNOX:

Co-enzyme Q10 (CoQ10)

Co-enzyme Q, especially CoQ10 is capable of inhibiting arNOX.  1  The generation of superoxide by arNOX proteins is inhibited by Coenzyme Q10 as one basis for an anti-aging benefit of CoQ10 supplementation in human subjects.  arNOX activity was reduced between 25 and 30% by a 3 x 60 mg daily dose Coenzyme Q10 supplementation. Inhibition was the result of Coenzyme Q10 presence. 2

Tyrosol and Hydroxytyrosol

Tyrosol and Hydroxytyrosol are capable of inhibit arNOX activity.  3

Herbes de Provence

Based on the scientific research of James and Dorothy M. Morré, they demonstrated that natural compounds from French culinary seasonings – “Herbes de Provence” inhibit arNOX activity.  4

Herbes de Provence typically comprise:

  • basil (Ocimum basilicum)
  • fennel seed (Foeniculum vulgare)
  • marjoram (Origanum majorana)
  • oregano (Oreganum vulgare)
  • rosemary (Rosmarinus officinalis)
  • sage (Salvia officinalis)
  • summer savory (Satureja hortensis)
  • tarragon (or estragon, dragon’s-wort, Artemisia dracunculus)
  • thyme (Thymus vulgaris)

The ratio of these herbs that make up Herbes de Provence vary with personal or regional choice.

Of the herbs listed, the following are particularly active as arNOX inhibitors:

  • basil
  • tarragon (especially French tarragon)
  • rosemary
  • marjoram
  • sage
  • savory (especially summer savory)

Figure 1.  Summer Savory

Summer savory was the herb that had the highest arNOX activity inhibition at 89%.

Figure 2:  arNOX activity % inhibition.  (Source:  U.S. Patent 20120207862 A1)

According to U.S. Patent 20120207862 A1 entitled ORAL INHIBITORS OF AGE-RELATED NADH OXIDASE (arNOX), COMPOSITIONS AND NATURAL SOURCES, by the inventors, D. James Morré, Dorothy M. Morré, Thomas Shelton, components can be incorporated in the following proportions:

  • basil, 0-95%
  • thyme, 0-50%
  • oregano, 0-90%
  • tarragon, 0-95%
  • rosemary, 0-95%
  • lavender, 0-50%
  • sage, 0-95%
  • savory, 0-95%
  • marjoram, 0-95%

The U.S. Patent recommends the following dosages.  By formulating the herbal preparations as sustained-release preparations, 24 h of protection were attained with just two 400-mg capsules/day (one in the morning and one before bedtime) A preferred total daily dose is from about 200 mg to about 600 mg of a combination of herbs and/or natural products as described herein.

Free E-Book: The Health and Medicinal Benefits of Ashitaba

Ashitaba, which is the common name used in Japan, is botanically known as Angelica keiskei or Angelica Keiskei Koidzumi. The English translation of the Japanese word “Ashitaba” (アシタバ or 明日葉) is “Tomorrow’s Leaf”. Ashita means ‘tomorrow and ba means ‘leaf.’ The name stems from the plant’s ability to quickly regenerate new leaves after taking cuttings. This give an indication of its potential for longevity of life.

asitab_5

Ashitaba plant

There are two separate substances (products) that are derived from the Ashitaba plant.

The first is the hot-air dried powder of Ashitaba from the leaves and stems. The color of this powder is bright green. The leaves of the Ashitaba plant contain approximately 0.25% to 0.35% chalcones.

The second is the powder made from the unique yellow sap which is collected from the Ashitaba’s stem. It is commonly called Ashitaba Chalcone Powder which consists up to 8% chalcones. The color of Ashitaba Chalcone Powder is bright yellow and is a fat-soluble substance.

Although the green Ashitaba powder from the leaves and stems provide nutritional and health benefits, it is the Ashitaba Chalcone Powder (bright yellow powder from the sap of the stem) that is the Chalconoids are natural phenols related to chalcone. They form the central core for a variety of important biological compounds.

997422_orig

Chalcone sap from Ashitaba stem

Chalcones are the active factors in Angelica Keiskei Koidzumi. At least 20 chalcones have been identified in Angelica Keiskei.

Ashitaba contains a thick, sticky yellow sap, which is not found in other celery plants, and are unique to this strain of angelica. This yellowish element in Ashitaba contain the chalconoids.

 

Download the Free E-Book (PDF): The Health and Medicinal Benefits of Ashitaba

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Astaxanthin and Other Natural Substances Increase the Activity of the FOXO3 Longevity Gene

The gene FOXO3a codes for a human protein called Forkhead box O3, also known as FOXO3.

FOXO3 belongs to the family of transcription factors which are characterized by a distinct fork head DNA-binding domain. There are three other FoxO family members in humans:

  • FOXO1
  • FOXO4
  • FOXO6

Protein FOXO3 PDB 2K86.png

Structure of protein FOXO3. Based on PyMOL rendering of PDB 2K86  (Source: Pleiotrope – Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=15989699)

This important protein has many vital functions in the human body and is primarily associated with human longevity, which is why it is often referred to as the “longevity gene”.  1  2 

Among the many functions and roles that this protein plays in the human body, the most important have been identified:

  • functions as a trigger for apoptosis through upregulation of genes necessary for cell death  3
  • upregulates antioxidants such as catalase and MnSOD  4
  • suppresses tumorgenesis in cancer  5
  • functions in DNA repair mechanisms  6  7
  • promotes resistance to oxidative stress  8

These important functions of the FOXO3 protein will only happen when the FOXO3 gene is activated and increased to encode the protein. 

Researchers have identified certain natural substances that activate and increase the FOXO3 gene:  These natural substances include:

  • Astaxanthin 9
  • Baicalein (from the Scutellaria baicalensis root or Baikal skullcap)  10
  • Butyrate (as Calcium Magnesium Butyrate) 11
  • R-Lipoic Acid 12
  • Selenium 13
  • Vitamin D  14

A Closer Look at Astaxanthin

Astaxanthin is a keto-carotenoid which belongs to a larger class of chemical compounds known as terpenes.  Astaxanthin is usually classified as a xanthophyll.

Astaxanthin can be found in:

  • microalgae
  • yeast
  • salmon
  • trout
  • krill
  • shrimp
  • crayfish
  • crustaceans
  • feathers of some birds (e.g., flamingos)

A recent study published in 2017 and co-authored by the The University of Hawaii John A. Burns School of Medicine (“JABSOM”) and Cardax, Inc. (“Cardax”), a Honolulu based life sciences company, demonstrated that the Astaxanthin compound (CDX-085 (developed by Cardax)) is able to switch on the FOX03 ‘longevity gene’ in mice.  15

Researchers of the study stated that all humans have the FOXO3 gene, which protects against aging in humans, but about one in three persons carry a version of the FOXO3 gene that is associated with longevity. By activating the FOXO3 gene common in all humans, researchers stated that they can make it act like the “longevity” version. This important study has shown that Astaxanthin “activates” the FOXO3 gene.

The study used mice which were fed either normal food or food containing a low or high dose of the Astaxanthin compound CDX-085 provided by Cardax. They witnessed a significant increase in the activation of the FOXO3 gene in the heart tissue of those mice that were fed the higher amount of the Astaxanthin compound.  In fact, they found a nearly 90% increase in the activation of the FOXO3 gene in the mice fed the higher dose of the Astaxanthin compound CDX-085. 

The researchers concluded that their hope is that these findings will lead to a highly effective anti-aging therapy that extends the lifespan of human beings.  

7,8-dihydroxyflavone (7,8-DHF): An Flavone With Remarkable Health Benefits

7,8-Dihydroxyflavone (7,8-DHF) is a naturally-occurring flavone found in:

  • Godmania aesculifolia
  • Tridax procumbens
  • Primula tree leaves

Flavones are a class of flavonoids which are a class of plant secondary metabolites.

Natural flavones include:

  • Apigenin (4′,5,7-trihydroxyflavone)
  • Luteolin (3′,4′,5,7-tetrahydroxyflavone)
  • Tangeritin (4′,5,6,7,8-pentamethoxyflavone)
  • Chrysin (5,7-hydroxyflavone)
  • 6-hydroxyflavone
  • Baicalein (5,6,7-trihydroxyflavone)
  • Scutellarein (5,6,7,4′-tetrahydroxyflavone)
  • Wogonin (5,7-dihydroxy-8-methoxyflavone)

Synthetic flavones include:

  • Diosmin
  • Flavoxate
  • 7,8-dihydroxyflavone (7,8-DHF)

7,8-Dihydroxyflavone (7,8-DHF) has been determined and studied to be a potent and selective agonist of the TrkB receptor, which is the main signaling receptor of brain-derived neurotrophic factor (BDNF). It is able to penetrate the blood-brain-barrier after oral consumption.

7,8-DHF has been very therapeutically efficient in various central nervous system disorders including:

  • Depression [1]
  • Alzheimer’s disease [2]
  • Schizophrenia [3]
  • Parkinson’s disease [4]
  • Huntington’s disease [5]
  • Amyotrophic lateral sclerosis [6]
  • Traumatic brain injury [7]
  • Cerebral ischemia [8]

7,8-DHF has also been found to be a potent antioxidant [9] and provides neuroprotection against glutamate-induced excitotoxicity.

The authors of the study concluded that:

Our data demonstrate that 7,8-DHF protects against hydrogen peroxide and menadione-induced cell death, suggesting that 7,8-DHF has an antioxidant effect. In summary, although 7,8-DHF is considered as a selective TrkB agonist, our results demonstrate that 7,8-DHF can still confer neuroprotection against glutamate-induced toxicity in HT-22 cells via its antioxidant activity.” [10]


References:

[1] Liu X, Chan CB, Jang SW, Pradoldej S, Huang J, He K et al. (2010). “A synthetic 7,8-dihydroxyflavone derivative promotes neurogenesis and exhibits potent antidepressant effect”. J. Med. Chem. 53 (23): 8274–86. doi:10.1021/jm101206p. PMC 3150605. PMID 21073191

[2] Castello NA, Nguyen MH, Tran JD, Cheng D, Green KN, LaFerla FM (2014). “7,8-Dihydroxyflavone, a small molecule TrkB agonist, improves spatial memory and increases thin spine density in a mouse model of Alzheimer disease-like neuronal loss”. PLoS ONE 9 (3): e91453. doi:10.1371/journal.pone.0091453. PMC 3948846. PMID 24614170.

Chen C, Li XH, Zhang S, Tu Y, Wang YM, Sun HT (2014). “7,8-dihydroxyflavone ameliorates scopolamine-induced Alzheimer-like pathologic dysfunction”. Rejuvenation Res 17 (3): 249–54. doi:10.1089/rej.2013.1519. PMID 24325271.

Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP et al. (2014). “7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease”. Neuropsychopharmacology 39 (3): 638–50. doi:10.1038/npp.2013.243. PMID 24022672.

[3] Yang YJ, Li YK, Wang W, Wan JG, Yu B, Wang MZ et al. (2014). “Small-molecule TrkB agonist 7,8-dihydroxyflavone reverses cognitive and synaptic plasticity deficits in a rat model of schizophrenia”. Pharmacol. Biochem. Behav. 122: 30–6. doi:10.1016/j.pbb.2014.03.013. PMID 24662915.

[4] Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y et al. (2010). “A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone”. Proc. Natl. Acad. Sci. U.S.A. 107 (6): 2687–92. doi:10.1073/pnas.0913572107. PMC 2823863. PMID 20133810.

[5] Jiang M, Peng Q, Liu X, Jin J, Hou Z, Zhang J et al. (2013). “Small-molecule TrkB receptor agonists improve motor function and extend survival in a mouse model of Huntington’s disease”. Hum. Mol. Genet. 22 (12): 2462–70. doi:10.1093/hmg/ddt098. PMC 3658168. PMID 23446639.

[6] Korkmaz OT, Aytan N, Carreras I, Choi JK, Kowall NW, Jenkins BG et al. (2014). “7,8-Dihydroxyflavone improves motor performance and enhances lower motor neuronal survival in a mouse model of amyotrophic lateral sclerosis”. Neurosci. Lett. 566: 286–91. doi:10.1016/j.neulet.2014.02.058. PMID 24637017

[7] Wu CH, Hung TH, Chen CC, Ke CH, Lee CY, Wang PY et al. (2014). “Post-injury treatment with 7,8-dihydroxyflavone, a TrkB receptor agonist, protects against experimental traumatic brain injury via PI3K/Akt signaling”. PLoS ONE 9 (11): e113397. doi:10.1371/journal.pone.0113397. PMC 4240709. PMID 25415296.

[8] Wang B, Wu N, Liang F, Zhang S, Ni W, Cao Y et al. (2014). “7,8-dihydroxyflavone, a small-molecule tropomyosin-related kinase B (TrkB) agonist, attenuates cerebral ischemia and reperfusion injury in rats”. J. Mol. Histol. 45 (2): 129–40. doi:10.1007/s10735-013-9539-y. PMID 24045895.Uluc K, Kendigelen P, Fidan E, Zhang L, Chanana V, Kintner D et al. (2013). “TrkB receptor agonist 7, 8 dihydroxyflavone triggers profound gender- dependent neuroprotection in mice after perinatal hypoxia and ischemia”. CNS Neurol Disord Drug Targets 12 (3): 360–70. PMC 3674109. PMID 23469848.

[9] Flavonoids, Coumarins, and Cinnamic Acids as Antioxidants in a Micellar System. Structure−Activity Relationship†

[10] Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity.