Category Archives: Inflammation

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The Multiple Health Benefits of Tributyrin, a Triglyceride Form of Butyrate

Short-Chain Fatty Acids

A considerable amount of scientific interest has been focused on short chain fatty acids (SCFAs) for improving colonic and systemic health, and specifically reducing the risk of inflammatory diseases, diabetes, and cardiovascular disease.

Researchers have shown that SCFAs have distinct physiological effects:  1

  • they contribute to shaping the gut environment
  • they influence the physiology of the colon
  • they can be used as energy sources by host cells and the intestinal microbiota 
  • they also participate in different host-signaling mechanisms

Prebiotics, which consist of primarily dietary carbohydrates such as resistant starch and dietary fibers, are the substrates in the large intestine for fermentation that produce SCFAs.  The other source of SCFA, although in smaller amounts than dietary carbohydrates, are amino acids.  Three amino acids:

  • valine
  • leucine
  • isoleucine

obtained from protein breakdown can be converted into isobutyrate, isovalerate, and 2-methyl butyrate, known as branched-chain SCFAs (BSCFAs), which contribute very little (5%) to total SCFA production.  2

There are seven short-chain fatty acids that are produced by the large intestine through the fermentation of dietary fiber and resistant starch.  Of these seven short-chain fatty acids, three of them are the most important and common:

  • acetate
  • propionate
  • butyrate

These three represent about 90–95% of the SCFA present in the colon.  The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time.

Butyrate is the major energy source for colonocytes. Propionate is largely taken up by the liver. Acetate enters the peripheral circulation to be metabolized by peripheral tissues and is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis.

Image result for Short-Chain Fatty Acids

Figure 1.  Fibers, specific oligosaccharides and resistant starch reach the colon intact, where they induce shifts in the composition and function of intestinal bacteria (shifts indicated by different colors). Intestinal bacteria use these compounds as substrates for the production of the short-chain fatty acids acetate, propionate and butyrate. These microbial metabolites are taken up by intestinal epithelial cells called enterocytes. Butyrate mainly feeds the enterocytes, whereas acetate and propionate reach the liver by the portal vein.  (Source:  You are what you eat,  Nature Biotechnology  32, 243–245 (2014) doi:10.1038/nbt.2845)

Butyrate (Butyric Acid)

The most important short-chain fatty acid is butyrate.

Butyrate is a primary energy source for colonic cells.  3 4   Butyrate also has demonstrated anti-inflammatory properties.  5  Butyrate may also have a role in preventing certain types of colitis. A diet low in resistant starch and fiber, which will result in a low production of SCFAs in the colon, may explain the high occurrence of colonic disorders seen in the Western civilization.  6

Studies have demonstrated that butyrate has anti-carcinogenic properties:

  • It inhibits the growth and proliferation of tumor cell lines in vitro.  7
  • It induces differentiation of tumor cells, producing a phenotype similar to that of the normal mature cell.  8
  • It induces apoptosis or programmed cell death of human colorectal cancer cells.  9 10
  • It inhibits angiogenesis by inactivating Sp1 transcription factor activity and down regulating VEGF gene expression. 11

Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification.

Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect.   12

Butyrate is mainly taken up by the colon epithelial cells, only small amounts reach the portal vein and the systemic circulation.  The primary beneficial effects of butyrate occurs at the intestinal level, yet there are additional benefits at the extra intestinal level:

Intestinal effects

  • Is the preferred energy source for the colon epithelial cells
  • Decreases the pH of the colon (which decreases bile salt solubility, increases mineral absorption, decreases ammonia absorption, and inhibits growth of pathogens)
  • Stimulates proliferation of normal colon epithelial cells
  • Prevents proliferation and induces apoptosis of colorectal cancer cells
  • Affects gene expression of colon epithelial cells
  • Plays a protective role against colon cancer and colitis
  • Improves the gut barrier function by stimulation of the formation of mucin, antimicrobial peptides, and tight-junction proteins
  • Interacts with the immune system and regulates immune function
  • Has anti-inflammatory effects
  • Stimulates the absorption of water and sodium
  • Reduces oxidative stress in the colon
  • Assists in ion absorption
  • Assists in proper intestinal motility
  • Induces cell cycle arrest, differentiation, and apoptosis in colon cancer cells

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Figure 2.  The multiple effects of butyrate at the intestinal level.  (Source:  Potential beneficial effects of butyrate in intestinal and extra intestinal diseases)

Extra intestinal effects  13

  • Insulin sensitivity
  • Cholesterol synthesis
  • Energy expenditure
  • Ammonia scavenger
  • Stimulation of β-oxidation of very long chain fatty acids and peroxisome proliferation
  • CFTR function
  • Neurogenesis
  • HbF production

Tributyrin

The major problem with butyrate is achieving high concentrations in the blood. Butyrate is metabolized rapidly as soon as it enters the enteroocytes via its active transport system, and its plasma concentrations are far below those required to exert its antiproliferative/differentiating actions.  14 

An alternative and more advantageous form of butyric acid is the triglycerine form called Tributyrin, also known as glyceryl tributyrate. Tributyrin is a triglyceride containing 3 molecules of butyric acid which are bound by a glycerol molecule. 

Tributyrin is naturally present in butter in trace amounts.  However, it is not recommended to consume butter as a means to obtain therapeutic amounts of tributyrin.  There is no point to recommend consuming butter to someone if the intention is to increase butyric acid consumption.

As an alternative to consuming butter, tributyrin can now be consumed in the form of a supplement or a food additive and can provide considerable amounts of butyrate to the intestine in addition to the endogenous production of SCFAs (butyrate) from the fermentation of dietary fibers.

Tributyrin is known to overcome the pharmacokinetic drawbacks of butyrate.  Because it is rapidly absorbed and chemically stable in plasma, tributyrin diffuses through biological membranes and is metabolized by intracellular lipases, releasing therapeutically effective butyrate over time directly into the cell. 

Ball-and-stick model of the butyrin molecule

Figure 3.  Ball-and-stick model of the tributyrin molecule, the triglyceride of butyric acid.  Source:  By Jynto (talk) – Own workThis chemical image was created with Discovery Studio Visualizer., CC0, https://commons.wikimedia.org/w/index.php?curid=20234384

The technique of attaching butyrate to a glycerol molecule turns the new molecule (tributyrin) into a fat. The attachment of a glycerol molecule to 3 butyric acid molecules is through an ester bond which can only be broken by a specific enzyme called pancreatic lipase.  

Pancreatic lipase is secreted from the pancreas into the small intestine (duodenum) and not in the stomach.  Because of this, tributyrin stays intact in the stomach but once it reaches the small intestine (duodenum), the 3 butyric acid molecules are released by the pancreatic lipase enzyme. 

After the pancreatic lipase action, two free butyric acid molecules and one monobutyrin molecule are formed where they are used in the intestine and taken up by the enterocytes. After transportation through the portal vein they are metabolized in the liver. 

chem formula

Figure 4.  Ester bond of glycerol and 3 butyric acid molecules.  (Source: Bioremediation of Fats and Oils)

The tributyrin form of butyrate ensures high bioavailability of butyrate in all the sections of the small intestine.  Because tributyrin is a delayed release source of butyrate, it achieves more sustained plasma levels. 

According the the U.S. Federal Drug Administration (FDA), tributyrin is a food substance affirmed as Generally Recognized As Safe (GRAS).  15

Multiple Health Benefits of Tributyrin 

Specific studies on tributyrin have demonstrated multiple benefits in a number of disease conditions by releasing therapeutically effective butyrate over time directly into the cell.  The advantage with tributyrin is that it has all the health benefits of butyrate, as evidenced above, as well as its own specific targeted health benefits.

Some of the more important and specific health benefits of tributyrin include:

  • Anticarcinogenic potential
    • Colon cancer
    • Leukemia
    • Melanoma
    • Liver cancer (apoptosis)
  • Alzheimer’s disease and Dementia
  • Antibiotic-associated diarrhea (AAD)
  • Lipopolysaccharide (LPS)-induced liver injury
  • Inflammation

Anticarcinogenic potential

In vitro and in vivo studies have shown that tributyrin acts on multiple anticancer cellular and molecular targets without affecting non-cancerous cells. The mechanisms of action of tributyrin as a anticarcinogenic agent include:  16

  • the induction of apoptosis
  • cell differentiation
  • the modulation of epigenetic mechanisms

Due to the minimum toxicity profile of tributyrin, it is an excellent candidate for combination therapy with other agents for the control of cancer. 

Colon cancer

Tributyrin was shown to be more potent in inhibiting growth and inducing cell differentiation than natural butyrate on growth, differentiation and vitamin D receptor expression in Caco-2 cells, a human colon cancer cell line.  17

Tributyrin provides a useful therapeutic approach in chemoprevention and treatment of colorectal cancer.   

In another in vitro study, tributyrin showed potent antiproliferative, proapoptotic and differentiation-inducing effects in neoplastic cells.  18

Leukemia

In this study monobutyrin (MB) and tributyrin (TB) were studied in vitro for their effects on inducing differentiation of human myeloid leukemia HL60 cells and murine erythroleukemia cells. On a molar basis TB was about 4-fold more potent than either BA or MB for inducing differentiation of HL60 cells. BA, MB, or TB induced erythroid differentiation of murine erythroleukemia cells.  19

Melanoma

A study from February 2011 sought to investigate a possibility to develop tributyrin emulsion as a potent anti-cancer agent against melanoma. Tributyrin emulsion was more potent than butyrate in inhibiting the growth of B16-F10 melanoma cells. Accumulation of cells at sub G(0)/G(1) phase and the DNA fragmentation induced by tributyrin emulsion treatment revealed that tributyrin emulsion inhibited the growth of B16-F10 cells by inducing apoptosis. Treatment with tributyrin emulsion suppressed the colony formation of melanoma cells in a dose-dependent manner.  20

The data from this study suggests that tributyrin emulsion may be developed as a potent anti-cancer agent against melanoma.

Liver cancer

Researchers in this study from November 1999 investigated whether butyrate could induce apoptosis in transformed human liver (Hep G2) cells. Hep G2 cells treated with butyrate displayed acetylated histones, increased DNA fragmentation and morphological features consistent with apoptosis. 

They also investigated whether butyrate present in tributyrin, a triacylglycerol more compatible for inclusion into colloidal lipid structures than butyrate, could also induce apoptosis in Hep G2 cells.

Tributyrin induced DNA fragmentation and morphological features characteristic of apoptotic cells in Hep G2 cells.

These results are a significant advance towards delivering butyrate via colloidal lipid particles to cancerous sites in vivo. This study showed that butyrate and tributyrin are potent apoptotic agents. 21

Alzheimer’s disease and Dementia

Recent research at MIT has determined that, in rodent models of Alzheimer’s dementia, the negative impact of amyloid beta exposure on neuronal function and new memory formation results largely from increased neuronal expression of an enzyme known as HDAC2 (histone deacetylase 2).

A study from March 2004 showed that tributyrin may have the most practical potential to inhibit HDAC by blunting microglial activation. Tributyrin is anti-inflammatory in primary, brain-derived microglial cells.  A blunting of microglial cytokine production might in itself have a favorable impact on progression of Alzheimer’s.  22  23  

Antibiotic-associated diarrhea (AAD)

In a recent study from November 2014, researchers hypothesized that antibiotic-induced changes in gut microbiota reduce butyrate production, varying genes involved with gut barrier integrity and water and electrolyte absorption, lending to AAD, and that simultaneous supplementation with the probiotic Lactobacillus GG  and/or tributyrin would prevent these changes.

Optimizing intestinal health with Lactobacillus GG and/or tributyrin may offer a preventative therapy for AAD.  24  Lipopolysaccharide (LPS)-induced liver injury

In this study from April 2015, researchers elucidated the protective effect of oral administration of tributyrin against LPS-mediated lipid metabolism disorder in rats.  Tributyrin suppresses lipopolysaccharide (LPS)-induced liver injury through attenuating nuclear factor-κB activity with an increased hepatoportal butyrate level.  25

Inflammation

Another study from May 2015 was carried out to investigate the effects of tributyrin (TB) on the growth performance, pro-inflammatory cytokines, intestinal morphology, energy status, disaccharidase activity, and antioxidative capacity of broilers challenged with lipopolysaccharide (LPS).

Taken together, these results suggest that the TB supplementation was able to reduce the release of pro-inflammatory cytokines and improve the energy status and anti-oxidative capacity in the small intestine of LPS-challenged broilers.  26

ELiE Health Solutions

Tributyrin is now available for purchase by consumers and professionals directly from ELiE Health Solutions as a product called BUTYCAPS.

ELiE Health Solutions, based in Sevilla, Spain, was formed through a project based on the science of the microbiota and probiotics.

ELiE Health Solutions is named after Elie Metchnikoff, famed microbiologist and the recipient of the 1908 Nobel Price in Physiology. A century ago he proposed the benefit of acid lactic bacteria to the human host and their role in health and longevity.

David Manrique, a pharmacist with ELiE Health Solutions describes the challenges of finding a more bio-available form of butyric acid:

“The challenge was to find a chemical form of enteric release of butyric acid, and also to ensure microencapsulated as slowly and delayed release possible. It has been a great innovative effort, but we are very satisfied with the results.”  27 

ELiE Health Solutions was successful in developing a delayed release form of butyric acid (tributyrin) using microencapsulation technology in their product BUTYCAPS.  The microencapsulation technology of BUTYCAPS allows a slower and gradual release along the intestine. 

BUTYCAPS contains 900 mg of Tributyrin equivalent to 787 mg of butyric acid in each sachet. Each box contains 30 sachets.  BUTYCAPS are non-chewable granules.

170126_3dbutycaps

Figure 5.  BUTYCAPS product from ELiE Health Solutions

BUTYCAPS can be purchased directly from ELiE Health Solutions. 

Figure 6.  Formulation process of microencapsulated tributyrin. (Source:  ELiE Health Solutions)

Resources:

Purchase BUTYCAPS

Cover photo:  Enterocytes were butyrate is taken up in the intestine (Source)

Delaying the Chronological Aging of the Yeast Saccharomyces cerevisiae by Six Plant Extracts

Researchers from Concordia University in Montreal, Quebec, Canada, in collaboration with the Quebec-based biotech company Idunn Technologies, published a study in the Journal Oncotarget on 29 March 2016, describing their discovery of six plant extracts that increase yeast chronological lifespan to a significantly greater extent than any of the presently known longevity-extending chemical compounds.  1

For the study, the researchers examined many plant extracts that would increase the chronological lifespan of yeast.  They finally found and used 37 plant extracts for this study.  These plant extracts are listed in the Table 1 below:

Table 1: List of plant extracts that have was used in this study

Abbreviated nameBotanical namePlant part used
PE1Echinacea purpureaWhole plant
PE2Astragalus membranaceousRoot
PE3Rhodiola rosea L.Root
PE4Cimicifuga racemosaRoot and rhizome
PE5Valeriana officinalis L.Root
PE6Passiflora incarnate L.Whole plant
PE7Polygonum cuspidatumRoot and rhizome
PE8Ginkgo bilobaLeaf
PE9Zingiber officinale RoscoeRhizome
PE10Theobroma cacao L.Cacao nibs
PE11Camellia sinensis L. KuntzeLeaf
PE12Apium graveolens L.Seed
PE13Scutellaria baicalensisRoot
PE14Euterpe oleraceaFruit
PE15Withania somniferaRoot and leaf
PE16Phyllanthus emblicaFruit
PE17Camellia sinensisLeaf
PE18Pueraria lobataRoot
PE19Silybum marianumSeed
PE20Eleutherococcus senticosusRoot and stem
PE21Salix albaBark
PE22Glycine max L.Bean
PE24Calendula officinalisFlower
PE25Salvia miltiorrhizaRoot
PE27Panax quinquefoliumRoot
PE28Harpagophytum procumbensRoot
PE29Olea europaea L.Leaf
PE30Gentiana luteaRoot
PE31Piper nigrumFruit
PE32Aesculus hippocastanumSeed
PE33Mallus pumila Mill.Fruit
PE34Fragaria spp.Fruit
PE35Ribes nigrumLeaf
PE36Dioscorea oppositaRoot
PE37Cinnamomum verumBark

Table source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes

The means by which these six plant extracts (PEs) delays the onset and decreases the rate of yeast chronological aging is by eliciting a hormetic stress response. The budding yeast Saccharomyces cerevisiae is a beneficial model organism for the discovery of genes, signaling pathways and chemical compounds that slow cellular and organismal aging in eukaryotes across phyla.  Yeast was chosen in this study because aging progresses similarly in both yeast and humans.

The six PEs that were identified include:  2

  • Black Cohosh (Cimicifuga racemosa) (PE4)
  • Valerian  (Valeriana officinalis L.)  (PE5)
  • Passion Flower  (Passiflora incarnata L.)  (PE6)
  • Ginko Biloba  (Ginko biloba)  (PE8)
  • Celery Seed  (Apium graveolens L.)  (PE12)
  • White Willow  (Salix alba)  (PE21)

 

The six identified PEs out of the thirty-seven PEs that were examined showed the highest percentage increase of lifespan, (also known as the chronological lifespan (CLS)), in the yeast,   The researchers determined both the mean (average) CLS and the maximum CLS of the six PEs.

Table 2 below list the six PEs and their mean and max. CLS:

Table 2: Percent increase of lifespan of S. cerevisiae by 6 PEs

Plant Extract (PE)Mean CLSMax CLS
PE4 (Black Cohosh)195%100%
PE5 (Valerian)185%87%
PE6 (Passion Flower)180%80%
PE8 (Ginko Biloba)145%104%
PE12 (Celery Seed)160%107%
PE21 (White Willow)475%369%
CLS - Chronological Lifespan

(Source:  Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

The researchers noted that PE21 appears to be the most potent longevity-extending pharmacological intervention presently known. It increases the mean and maximum CLS of yeast by 475% and 369%, respectively.  PE21 or White Willow bark represents a much greater effect than rapamycin and metformin, the two best drugs known for their anti-aging effects.

These findings by the researchers imply that these extracts slow aging in the following ways:  3

  • PE4 (Black Cohosh) decreases the efficiency with which the pro-aging TORC1 pathway inhibits the anti-aging SNF1 pathway;
  • PE5 (Valerian) mitigates two different branches of the pro-aging PKA pathway;
  • PE6 (Passion Flower) coordinates processes that are not assimilated into the network of presently known signaling pathways/protein kinases;
  • PE8 (Ginko biloba) diminishes the inhibitory action of PKA on SNF1;
  • PE12 (Celery Seed) intensifies the anti-aging protein kinase Rim15; and
  • PE21 (White Willow) inhibits a form of the pro-aging protein kinase Sch9 that is activated by the pro-aging PKH1/2 pathway.

The researchers showed that each of these six PEs decelerates yeast chronological aging and has different effects on several longevity-defining cellular processes, as illustrated in Figure 1.

An external file that holds a picture, illustration, etc. Object name is oncotarget-07-50845-g009.jpg

Figure 1.  A model for how PE4, PE5, PE6, PE8, PE12 and PE21 delay yeast chronological aging via the longevity-defining network of signaling pathways/protein kinases.  Activation arrows and inhibition bars denote pro-aging processes (displayed in blue color) or anti-aging processes (displayed in red color). Pro-aging or anti-aging signaling pathways and protein kinases are displayed in blue or red color, respectively.  (Source: Discovery of plant extracts that greatly delay yeast chronological aging and have different effects on longevity-defining cellular processes)

Each of the six PEs have different effects on cellular processes that define longevity in organisms across phyla. These effects include the following:

  • increased mitochondrial respiration and membrane potential;
  • augmented or reduced concentrations of reactive oxygen species;
  • decreased oxidative damage to cellular proteins, membrane lipids, and mitochondrial and nuclear genomes;
  • enhanced cell resistance to oxidative and thermal stresses; and
  • accelerated degradation of neutral lipids deposited in lipid droplets.

The researchers also revealed that certain combinations of the six PEs could markedly increase aging-delaying proficiencies of each other.

In conclusion, the study stated that the obvious challenge was to assess whether any of the six PEs can delay the onset and progression of chronic diseases associated with human aging.  Idunn Technologies is collaborating with four other universities for six research programs, to go beyond yeast, and work with an animal model of aging, as well as two cancer models.  4

This study and ongoing research reveals five features of the six PEs as potential interventions for decelerating chronic diseases of old age. These five features include:  5

  • the six PEs are caloric restriction (CR) mimetics that imitate the aging-delaying effects of the CR diet in yeast under non-CR conditions;
  • they are geroprotectors that slow yeast aging by eliciting a hormetic stress response;
  • they extend yeast longevity more efficiently than any lifespan-prolonging chemical compound yet described;
  • they delay aging through signaling pathways and protein kinases implicated in such age-related pathologies as type 2 diabetes, neurodegenerative diseases, cardiac hypertrophy, cardiovascular disease, sarcopenia and cancers; and
  • they extend longevity and delay the onset of age-related diseases in other eukaryotic model organisms.

High-mobility group protein 1 (HMG-1): A Marker of Chronic Inflammation

High-mobility group protein 1 (HMG-1) is a protein that in humans is encoded by the HMGB1 gene.

HMGB1 turns on the release of chemical signals called cytokines that generate inflammation in your body.

The molecule HMGB1 is responsible for initiating acute inflammation, which is a helpful reaction when your body is under attack by germs, or following an injury. Unfortunately, when a cell is damaged, its contents of HMGB1 leak out, leading to chronic inflammation.

When HMGB1 leaks out, it acts as a “danger signal” that triggers the release of chemical signaling molecules (called cytokines) that call in more white blood cells, which release still more cytokines, in a vicious cycle.

Inhibiting HMGB1 is a powerful means of slowing and reversing the processes involved in inflammation.

HMGB1 serves as a risk factor for memory impairment, chronic neuro-degeneration, and progression of neuro-inflammation. 1

The Table below lists the recognized and researched substances that may inhibit High-mobility group protein 1 (HMG-1):

Substances that Inhibit HMGB1

HMGB1  
CategoryNutraceuticals/Foods/HerbsReference(s)
Foods
Mung Bean Coat Extract1 2 vitexin, isovitexin
Herbs
Green Tea4 5 6 7
Angelica sinensis (Dong Quai)8
Lipids
Glycyrrhizin (Licorce)9


Resources:

Life Extension Cytokine Suppress with EGCG


 

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.  

Resistant Starch Produces Short-Chain Fatty Acids Which Benefits the Large Intestine

Resistant starch is a form of starch that is not digested and absorbed in the stomach and small intestine.  Instead it passes to the large intestine where it is fermented by the microbiota which confer numerous health benefits.  1

Resistant starch acts in similar ways to dietary fiber, yet it is not considered a dietary fiber.  It is considered more of a prebiotic substance since it serves as food for the large intestines microbiota.  Higher doses of resistant starch can cause flatulence.   2

There are five different types of resistant starch and can be viewed in the following Table.

There are a number of foods that naturally contain resistant starch.  Raw bananas and especially raw banana flour has the highest content of resistant starch.  The Table below lists those foods that contain resistant starch:

Resistant Starch in Various Foods

FoodServing sizeResistant starch (grams)
Banana flour, from green bananas1/4 cup, uncooked10.5-13.2
Banana, raw, slightly green1 medium, peeled4.7
Cold pasta1 cup1.9
Cold potato1/2" diameter0.6 - 0.8
Green peas, frozen1 cup, cooked4
High amylose RS2 corn resistant starch1 tablespoon (9.5 g)4.5
Lentils1/2 cup cooked2.5
Oatmeal1 cup cooked0.5
Oats, rolled1/4 cup, uncooked4.4
Pearl barley1/2 cup cooked1.6
White beans1/2 cup, cooked3.7
(Source: Resistant Starch Intakes in the United States)

When the three types of resistant starch, RSI, RSII and RSIII, are fermented by the large intestinal microbiota, short-chain fatty acids are produced.  There are seven short-chain fatty acids that are produced by the large intestine when it ferments dietary fiber and resistant starch.  Of these seven short-chain fatty acids, three of them are the most common:

  • acetate
  • propionate
  • butyrate

The most important short-chain fatty acid is butyrate.

Butyrate is a primary energy source for colonic cells.  3  4   Butyrate also has demonstrated anti-inflammatory properties.  5  Butyrate may also have a role in preventing certain types of colitis. A diet low in resistant starch and fiber, which will result in a low production of short-chain fatty acids in the colon, may explain the high occurrence of colonic disorders seen in the Western civilization.  6

Studies have demonstrated that butyrate has anti-carcinogenic properties:

  • It inhibits the growth and proliferation of tumor cell lines in vitro.  7
  • It induces differentiation of tumor cells, producing a phenotype similar to that of the normal mature cell.  8
  • It induces apoptosis or programmed cell death of human colorectal cancer cells.  9  10
  • It inhibits angiogenesis by inactivating Sp1 transcription factor activity and downregulating VEGF gene expression.  11

Resistant starch consistently produces more butyrate than other types of dietary fiber.   12  


Resources:

Wedo Banana Flour, 1 Pound

Bob’s Red Mill – Potato Starch, Gluten Free and Unmodified, 24 Ounces


Cover Photo by mauren veras

Polypodium leucotomos may reduce the overproduction of Interleukin 6 (IL-6) by up to 100%

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine.   1   The function of IL-6 is beyond the scope of this article.  Instead, the focus here is the excessive production of IL-6 and its implication in a variety of inflammatory disorders.   2

IL-6 stimulates the inflammatory and auto-immune processes in many diseases such as

  • Alzheimer’s Disease  3
  • Atherosclerosis  4
  • Behçet’s disease  5
  • Depression  6
  • Diabetes  7
  • Multiple myeloma  8
  • Prostate cancer  9
  • Rheumatoid arthritis  10
  • Systemic lupus erythematosus  11

A study published in the May-June 2000 edition of the Journal Anticancer Research, entitled, An extract of the fern Polypodium leucotomos (Difur) modulates Th1/Th2 cytokines balance in vitro and appears to exhibit anti-angiogenic activities in vivo: pathogenic relationships and therapeutic implications, showed that an extract of the fern Polypodium leucotomos (PLE) to partially inhibit the production of cytokines showing a Th1 pattern (IL-2, IFN-gamma and TNF-alpha) in human PHA-stimulated peripheral blood mononuclear cells.  12

The authors were surprised to find:

“that the production of the inflammatory cytokine IL-6 was completely abolished (100% inhibition) by PLE at all doses tested.”  13

Polypodium leucotomos is also known as and is an epiphytic fern native to tropical and subtropical regions of the Americas.  An extract of Polypodium leucotomos called Fernblock has proven photoimmunoprotection  properties with oral and topical application.

The extract has extensive preclinical and clinical data supporting its safety and efficacy in protecting against damage caused by solar radiation, and preventing and treating sun-related disorder.  14  15


Informational References:

Industrial Farmaceutica Cantabria. S.A. – Fernblock®


Resources:

Polypodium Leucotomos Extract 240mg ~ 200 Capsules – No Additives ~ Naturetition Supplements

Polypodium Leucotomos Extract 240mg * 200 Capsules 100 % Natural – by EarhNaturalSupplements

Shade Factor


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Oxidative DNA Damage Assessed by Concentrations of 8-Oxo-2′-deoxyguanosine in the Cell

Oxidative damage of DNA has been implicated as a fundamental cause of the physiologic changes and degenerative diseases associated with aging.  When DNA is impacted by oxidative stress, the chemical 8-Oxo-2′-deoxyguanosine (8-oxo-dG) is produced as a byproduct.

Becasue 8-oxo-dG is a major product of DNA oxidation, concentrations of 8-oxo-dG within a cell is a ubiquitous marker and measurement of oxidative stress. 

8-oxo-dG increases with age in DNA of mammalian tissues.  1   8-oxo-dG increases in both mitochonndrial DNA and nuclear DNA with age.  2  DNA is probably the most biologically significant target of oxidative attack and may be implicated in aging, carcinogenesis and other degenerative diseases.  Environmental factors, lifestyle choices such as smoking and recreational drugs, and some pharmaceuticals have also been associated with elevated urine levels of 8-oxo-dG.   For example, according to multiple regression analysis, smokers excreted 50% (31–69%; 95% confidence interval) more 8-oxo-dG than non-smokers.  The results suggest that smoking increases oxidative DNA damage by ∼50%.  3

Exposure to various environmental factors can increase 8-oxo-dG. These environmental factors include, but are not limited to:

  • ionizing radiation (such as indoor radon)
  • asbestos
  • toxic metals
  • metal fumes (such as manganese, chromium and vanadium)
  • diesel exhaust
  • benzene
  • styrene
  • toluene
  • zylenes

8-oxo-dG is the most frequently detected and studied oxidized nucleoside of DNA that is considered to be premutagenic due to its potential for initiation and promotion of carcinogenesis. 8-oxo-dG have been associated with numerous pathological processes including:

  • cystic fibrosis
  • atopic dermatitis
  • rheumatoid arthritis
  • pancreatitis
  • chronic hepatitis
  • hyperglycemia
  • inflammatory bowel disease
  • Parkinson’s disease
  • Alzheimer’s disease
  • Huntington’s disease
  • bladder cancer
  • prostate cancer

8-oxo-dG can be assessed by taking a urine test issued by a licensed medical professional and administered by a qualified medical lab.  (See Informational References)

When 8-oxo-dG levels are elevated, the identity of the sources of oxidative stress should be determined and mitigated as much as possible. 

The second step to reducing 8-oxo-dG levels is to consume foods high in antioxidants and when necessary add antioxidant supplements. 

Various research studies have identified certain natural substances that have been identified to reduce levels of 8-oxo-dG:

  • Vitamin C  4
  • Coenzyme Q10  5
  • Glutathione  6
  • Tomato juice  7 
  • Allylisothiocyanate (AITC) (found in some Brassica vegetables, including cabbage, mustard, Brussels sprouts, kale, and cauliflower)   8
  • Pomegranates  9
  • Green tea  10
  • Alpha Lipoic Acid  11
  • Olive oil  12
  • Calorie restriction  13  

Tart Cherry Demonstrates Chemoprevention Potential

Tart cherry (Prunus cerasus) is part of the species of Prunus and is native to Europe and southwest Asia.  It is also known as sour cherry or dwarf cherry. 

It is distinct from the sweet cherry (Prunus avium), which is commonly found in grocery stores.  Tart cherries are more acidic than sweet cherries and are typically used in juices and foods, rather than sold as a whole fruit.  The health benefits attributed to cherries are due to the tart cherry and not the sweet cherry.

There are a number of varieties of the tart cherry:

  • Morello cherry  (dark red)
  • Amarelle cherry  (light red)
  • Montmorency cherry (the most popular of the tart cherries)

Figure 1.   Montmorency cherry

Through numerous scientific studies, tart cherry has demonstrated a wide range of health benefits and its ability to counteract some key chronic conditions, including:

  • Reversing cardiovascular risk factors
  • Protection against oxidative stress
  • Inhibiting the early development of diabetes
  • Inhibiting the inflammatory pathway of gout
  • Regulates sleep-wake cycle in humans (due to high melatonin content)
  • Supports muscle recovery after exercise
  • Provides relief from pain associated with exercise exertion 
  • Provides anti-microbial effects 

Tart cherries are rich in anthocyanins, which are water-soluble vacuolar pigments that may appear red, purple, or blue.  They belong to the flavonoids group.  Other fruits and berries contain anthocyanins, but tart cherries are the only berry that contains all six of the key anthocyanins, including:  1

  • Cyanidin
  • Cyanidin 3-glucosylrutinoside (anthocyanin 1)
  • Cyanidin 3-rutinoside (anthocyanin 2)
  • Cyanidin sophoroside
  • Peonidin
  • Peonidin 3-glucoside

The health benefits of tart cherries can be attributed to their rich and broad anthocyanin content.  The anthocyanin content is also responsible to their anticarcinogenic effects.

Research is showing that tart cherries can exert a variety of chemopreventive effects and counteract cancer through various mechanisms by naturally switching off genes that promote cancer.  These genes activate:  2  3  4

  • inflammation
  • cell proliferation
  • angiogenesis (growth of new blood vessels)

The broad range of anthocyanins in tart cherries trigger apoptosis (programmed cell death), which effectively cleans up precancerous cells by having them self-destruct.  5  6 

Tart cherries has been shown to be effective against colon cancer.

A published study from 2003 demonstrated that mice consuming the cherry diet, anthocyanins, or cyanidin had significantly fewer and smaller cecal adenomas than mice consuming the control diet or sulindac.

Anthocyanins and cyanidin also reduced cell growth of human colon cancer cell lines HT 29 and HCT 116. The IC(50) of anthocyanins and cyanidin was 780 and 63 microM for HT 29 cells, respectively and 285 and 85 microM for HCT 116 cells, respectively.

These results suggest that tart cherry anthocyanins and cyanidin may reduce the risk of colon cancer.  7

Tart Cherries Chemoprevention Potential  8

Inhibits Inflammation Pathways

Arrests Cancerous Cell Proliferation

Inhibits Angiogenesis

Promotes and Triggers Apoptosis

 

Apigenin Demonstrates Great Promise As A Natural Molecule for Cancer Prevention

Apigenin is a flavonoid belonging to the structural class called flavones.  It is chemically known as 4’, 5’, 7-trihydroxyflavone. 

Apigenin is present in many fruits, vegetables and herbs, as follows:

    • Fruits
      • Oranges
      • Grapefruit
    • Vegetables
      • Kale
      • Lettuce (iceberg)
      • Licorice
      • Onions
      • Rutabaga
      • Cabbage
      • Celery
      • Celery Seeds
      • Globe Artichoke
      • Wheat sprouts
    • Herbs
      • Basil
      • Holy Basil
      • Chamomile
      • Feverfew
      • Balm
      • Oregano
      • Parsley
      • Peppermint
      • Perilla
      • Thyme

The highest source of apigenin is found in parsley and chamomile.

The dried flowers from Matricaria chamomilla (chamomile) contains a large quantity of apigenin, with an estimate of as much as 68% apigenin of total flavanoids.  2 

Image result for CHAMOMILE

Figure 1:  Chamomile flowers (dried)

Parsley has the largest content of Apigenin than any other vegetable, fruit or herb.  Dried parsely has considerably more apigenin content than fresh parsley:

  • Parsley (fresh)    302.0 mg per 100 grams
  • Parsley (dried)    13,506.2  mg per 100 grams *

Image result for parsley dried

Figure 2:  Parsley (dried)

Apigenin May Assist in the Prevention of Cancer

Apigenin has been shown to possess remarkable anti-carcinogenic properties.   3  There has been significant progress in studying the biological effects of apigenin at cellular and molecular levels as a chemopreventive agent.  4  

There are a number of biological effects of apigenin in numerous mammalian systems in vitro as well as in vivo, due to its  low intrinsic toxicity and because of its striking effects on normal versus cancer cells.  5    

The exact mechanism of apigenin is still being researched, but the current research demonstrates that apigenin affects several critical pathways and/or targets:

  • apigenin induces apoptosis through different cellular signaling transduction pathways:
    • NFκB  6 
    • p53   7 
    • MAPK   8 
    • PI3K/Akt   9  10  
  • apigenin has been shown to decrease tumor formation by blocking COX-2 from functioning normally  11 
  • apigenin is a strong inhibitor of ornithine decarboxylase, an enzyme that plays a major role in tumor promotion  12 
  • apigenin has been shown to increase the intracellular concentration of glutathione, enhancing the endogenous defense against oxidative stress  13 
  • apigenin blocks GLUT-1, which is elevated in head and neck cancers  14
  • apigenin inhibited enzymes that produce androgens  15  
  • apigenin suppressed tumor growth in PLC cells  16 
  • apigenin has also been shown to inhibit benzo[a]pyrene and 2-aminoanthracene-induced bacterial mutagenesis  17
  • apigenin suppresses LPS-induced cyclooxygenase-2 and nitric oxide synthase-2 activity  18 
  • apigenin treatment resulted in suppression of tumor necrosis factor (TNF)  19 
  • apigenin has been shown to inhibit the expression of casein kinase (CK)-2 in both human prostate and breast cancer cells  20 
  • apigenin has shown promise in inhibiting tumor cell invasion and metastases by regulating protease production  21 
  • exposure of endothelial cells to apigenin results in suppression of the expression of VEGF  22
  • apigenin has also been shown to inhibit the expression of HIF-1α and VEGF via the PI3K/Akt/p70S6K1 and HDM2/p53 pathways in human ovarian cancer cells  23

The Table below lists the potential targets of apigenin in various human cancers:

Apigenin as a Potential Target in Various Human Cancers

CancersReference
Adrenal cancer1
Breast cancer2
Cervical cancer3
Colon cancer4
Hematologic cancer (leukemia)5
Liver cancer6
Lung cancer7
Neuroblstoma8
Ovarian cancer9
Prostate cancer10
Skin cancer11
Stomach cancer12
Thyroid cancer13

Resources:

Swanson Health Products – Apigenin

Swanson Health Products – Chamomile Flower Extract

Parsley (dried flakes)

 

Pomegranate Peel Contains Three Times the Total Polyphenols as Pomegranate Seeds

The pomegranate is a fruit bearing deciduous shrub or small tree in the family of Lythraceae .  It is known by its botanical name Punica granatum.

The most common part of the fruit that is used by many Asian and Middle Eastern cultures is the arials or seeds.  The white pulp is sometimes used in foods as well. 

The pomegranate arials (and the juice form the arials) are abundant in phytochemicals known as polyphenols.  These polyphenols include:  1

  • tannins called ellagitannins
  • punicalagins

The peel of the pomegranate is now being recognized to contain up to three (3) times the polyphenols as the arials.  The polyphenols of the pomegranate peel includes:  2  3

  • punicalagins
  • condensed tannins
  • catechins
  • gallocatechins
  • prodelphinidins

For a more comprehensive list of the active constituents and their biological activity of Punica peel, refer to the study:  A Review on Antihyperglycemic and Antihepatoprotective Activity of Eco-Friendly Punica granatum Peel Waste

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Figure 1:  Structures of polyphenolic compounds found in pomegranate peel (Punica granatum) (Source:  A Review on Antihyperglycemic and Antihepatoprotective Activity of Eco-Friendly Punica granatum Peel Waste)

Punicalin and punicalagin are the major constituents of pericarp ranging up to 0.2% of the total amount.   4

There is great potential in the therapeutic properties of pomegranate peel.  These therapeutic properties include:

  • Alzheimer’s disease  5 
  • anti-bacterial  6
  • anti-hyperlipidemic effects  7 
  • antioxidant  8  9  10 
  • antimicrobial  11 
  • arthritis  12 
  • cancer
    • bladder cancer  13
    • breast cancer  14
    • chronic myeloid leukemia 15
    • prostate cancer  16
  • cardiovascular disease  17
  • dental conditions  18
  • dermal wounds  19
  • diabetes  20 
  • hepatoprotective  21
  • protection from ultraviolet (UV) radiation  22

An external file that holds a picture, illustration, etc. Object name is ECAM2013-656172.001.jpg

Figure 2:  Principal therapeutic effects of pomegranate peel  (Source:  A Review on Antihyperglycemic and Antihepatoprotective Activity of Eco-Friendly Punica granatum Peel Waste)


Information References:

How to make your own pomegranate peel powder

 


Resources:

eSutras Organic Pomegranate Peel Powder