Monthly Archives: March 2017

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Probiotics S. salivarius K12 and S. salivarius M18 Strengthen Oral Health

The mouth is colonized by 200 to 300 bacterial species, but only a limited number of these species participate in dental decay (caries) or periodontal disease.   An imbalance of good bacteria and bad bacteria in the mouth is considered dysbiosis in the mouth and is thought to be an important cause of periodontal disease and dental decay.

Dental decay is due to the irreversible solubilization of tooth mineral by acid produced by certain bacteria that adhere to the tooth surface in bacterial communities known as dental plaque.

The main bad bacteria associated with dental decay is Streptococcus mutans.  1 

A number of other types of bacteria, such as Actinomyces viscosus and A. naeslundii, live in the mouth, where they are part of a sticky substance called plaque.

Image result for Streptococcus mutans

Streptococcus mutans strain

Streptococcus mutans is the primary causal agent and the pathogenic species responsible for dental caries (tooth decay or cavities) specifically in the initiation and development stages.  2

Advanced periodontal disease has been linked to many chronic diseases, including:

  • Cardiovascular disease
  • Type 2 diabetes
  • Cognitive decline and Alzheimer’s disease
  • Cancer
  • Autoimmune diseases
  • Chronic kidney disease
  • Osteoporosis

Researchers have investigated the potential of probiotics to restore the good bacterial in the oral cavity.  These particular probiotic strains displace the bad bacteria, thus eliminating dysbiosis and restoring the healthy oral flora.

Certain Probiotics Strengthen Oral Health

A number of research studies have shown that two specific strains of Streptococcus salivarius, that are normally found in the mouth, may improve oral health.  These two strains are:

  • Streptococcus salivarius (S. salivarius) strain M18  (BLIS M18)
  • Streptococcus salivarius (S. salivarius) strain K12  (BLIS K12)

These two strains specifically reduce cariogenic and periodontal pathogen levels in the mouth.  This is accomplished by antimicrobial agents that the strains produce and are termed bactericon-like-inhibitory substances (BLIS), otherwise known as lantibiotics.  There are three types of BLIS that the two strains produce in the oral cavity:

  • Salivaricin A
  • Salivaricin B
  • Salivaricin 9

Streptococcus salivarius (S. salivarius) strain K12 is a potent BLIS producer, specifically Salivaricin A (bacteriostatic) and Salivaricin B (bactericidal). 

Both strains are able to produce BLIS antimicrobials in the mouth, however, BLIS K12 is more targeted to ear, nose, throat and immune health while BLIS M18 primarily supports dental health.

Streptococcus salivarius (S. salivarius) strain M18  (BLIS M18) 

Unfortunately only about two percent of the global population has the Streptococcus salivarius necessary to make the M18 peptides.  This small populace comprise people who rarely experience plaque or tooth decay.

Streptococcus salivarius (S. salivarius) strain M18 (BLIS M18) has the ability to break up plaque and neutralize acid that harms teeth and gums.  BLIS M18 produces two unique enzymes that contribute to support for dental health:

  • Urease – neutralizes that lactic acid that is produced the oral cavity by S. mutans.  3
  • Dextranase –  breaks down plaque biofilms caused by S. mutans and inhibits the development of dextrans or extracellular polysaccharides  4

BLIS M18 also corrects and maintains the oral cavity pH.  A more acidic pH oral cavity can lead to tooth demineralization.

BLIS M18 is a potent producer of BLIS or lantibiotics, which destroy disease causing bacteria in the oral cavity.  5  6

A recent study from January 2015 published in the International Journal of Pharma and Bio Sciences showed that M18 probiotic lozenges were efficacious in reducing both moderate to severe gingivitis and moderate periodontitis.  7 

Twenty eight subjects, of both sexes, were selected and divided into 4 groups (2 test groups and 2 control groups).  All 28 subjects had severe gingivitis and moderate periodontitis.  For 30 days, the Test subjects were given a M18 lozenge and the Control group did not receive a lozenge.  Clinical parameters such as plaque index, gingival index, modified sulcular bleeding index and probing pocket depth were recorded and assessed at baseline, day 15, 30, 45 and day 60.

The Test group showed significant reduction in all parameters when compared to that of Control group. After stopping probiotic administration on day 30, the test group showed a significant increase in all the clinical parameters except probing pocket depth on day 45 and day 60.

The Test subjects saw improvement in three areas:

  • less plaque
  • better gingival health
  • less bleeding on probing

Specifically, for the Test subjects, the results were promising in improving all four of these commonly used assessments of periodontal health:

  • The plaque index score decreased 44% by day 30
  • The gingival index score decreased 42% by day 30
  • The sulcular bleeding index score decreased 53% by day 30
  • The probing pocket depth decreased 20% by day 30

Even after 30 days after stopping the lozenges, the Test subjects showed good scores on the 4 indices.  This indicates that M18 has the ability to colonize the oral cavity after using the lozenges.

Streptococcus salivarius (S. salivarius) strain K12 (BLIS K12)  8

Streptococcus salivarius K12 is a strain isolated from the throat of a New Zealand child (who had evidence of exceptional throat health for several years), and is capable of producing two distinct lantibiotics bacteriocins:  9

  • salivaricin A2
  • salivaricin B

The K12 strain is not only effective against S. pyogenes but also inhibits the growth of pathogens such as:

  • Haemophilus influenzae
  • S. pneumoniae
  • Moraxella catarrhalis

These four pathogens are responsible for almost all bacterial pharyngotonsillitis cases in children and adults.  10 

BLIS K12 is a probiotic primarily used for the oral cavity (mouth) and upper respiratory tract and has now been clinically documented to reduce the incidence of strep throat infections in both adults and children.

Streptococcus salivarius: the probiotic for all ages. Diseases that may be alleviated by Streptococcus salivarius probiotics and the ages at which they generally tend to manifest.  (Source:  Developing Oral Probiotics From Streptococcus salivarius)

BLIS K12 attaches to cells in the oral cavity and colonizes the oral cavity and crowds out the bad bacteria.  This effect equalizes the flora in the oral cavity and allows room for the good bacteria to thrive.

Advantages of BLIS K12:

  • Helps maintain mouth and throat health
  • Helps maintain upper respiratory tract health
  • Naturally supports breath freshness  

Mineral Analysis of Unrefined Sea Salt Products: Potential Electrolyte Replenishment?

Electrolytes are minerals in the blood and other body fluids that carry an electric charge.

Electrolytes affect the:

  • Amount of water in the body
  • Acidity of the blood (pH)
  • Muscle function
  • Regulate function, our
  • Body’s hydration
  • Blood pressure
  • Rebuilding of damaged tissue

The primary ions of electrolytes consist of the following macrominerals:

  • Sodium (Na+)
  • Potassium (K+)
  • Calcium (Ca2+)
  • Magnesium (Mg2+)
  • Chloride (Cl−)
  • Hydrogen phosphate (HPO42−)
  • Hydrogen carbonate(HCO3−)

Electrolyte levels are kept constant by our kidneys and several hormones – even when our bodies trigger changes. When we exercise we sweat and lose electrolytes, mainly sodium and potassium.

To maintain electrolyte concentrations of our body fluids constant, these electrolytes must be replaced. Fresh fruits and vegetables are good sources of sodium and potassium and replace lost electrolytes. Excess electrolyte levels in our blood are filtered out by our kidneys.

Replenishing electrolytes by consuming sea salt can create an imbalance of certain electrolytes, typically calcium, potassium and magnesium.  Three popular sea salt products contain all the primary electrolytes (except hydrogen carbonate).  However, the percentage of sodium and chloride is much higher than the the other electrolytes.

The following Table lists the percentage of electrolytes in three popular sea salt products.  The quantities are listed in percentages per 1000 milligrams.  Therefore if sodium is calculated at 38.0%, then this would mean that there is 380mg per 1 gram of sea salt.  

Micromineral Analysis Comparison of Salt Products

Micromineral Analysis Comparison of Salt Products   
MineralRedmond Real SaltTMCeltic Sea SaltTMPink Himalayan SaltTM
Calcium.50.15.21
Phosphorus.01.04.04
Potassium.10.13.10
Sulfur.261.2.346
Sodium38.035.038.0
Chloride60.054.060.0
Magnesium.10.51.15
Silicone.14.27.15
Data based on Analysis Datasheet from each Company. PDF downloads at end of post.

For all three products, the sodium chloride content is from 89%  to 98%.  The magnesium, potassium and calcium content is quite low compared to the sodium chloride content.  For example, the potassium content is no more than 10 mg  or 50 mg per 1 gram of sea salt.  This amount of potassium is quite low per gram, especially when the RDA of potassium is 4.7 grams according to the Institute of Medicine.

The following Table list the RDA for the macrominerals (electrolytes) according to the Food and Nutrition Board of the Institute of Medicine which published the Recommended Dietary Allowances and Adequate Intakes for Elements (Minerals). 

Macrominerals (Quantity in body and RDA)

Macrominerals   
MacromineralQuantity present in average (70 kg/154.4lbs) personRDA (mg) 31-50 year MaleRDA (mg) 31-50 year Female
Calcium1.1 kg1000 mg1000 mg
Chlorine199 g2300 mg2300 mg
Magnesium35 g420 mg320 mg
Phosphorus750 g700 mg700 mg
Potassium225 g4700 mg4700 mg
Sulfur150 gNo RDANo RDA
Sodium90 g1500 mg1500 mg
Silicone30 gNo RDANo RDA

The Table below lists the RDA of the electrolytes and the percentage of each electrolyte.  It is apparent that potassium is the electrolyte with the highest percentage of 44% with sodium chloride at 36% of the total RDA.

Percentage of RDA of Electrolytes

Electrolytes  
MineralRDA (mg) 31-50 year MalePercentage of Total
Calcium1000 mg9%
Potassium4700 mg44%
Sodium1500 mg14%
Chlorine2300 mg22%
Magnesium420 mg4%
Phosphorus700 mg7%
Sodium Chloride (Salt)Combined36%
Totals10,620 mg100%


Informational References:

Recommended Dietary Allowances and Adequate Intakes, Elements (Institute of Medicine)  (PDF)

Redmond Real SaltTM Element Analysis (PDF)

Celtic Sea SaltTM Analysis (PDF)

Ancient Ocean® – Himalayan Salt Chemical Specification Analysis (PDF)

Note: PDF files require a viewer such as the free Adobe Reader


 

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.  

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

In Search of Geroprotectors: The Final Four Have Been Identified

A geroprotector is one of the five different types of senotherapeutic strategies that aims to affect the root cause of aging and age-related diseases, and thus prolong the life span of animals.  Geroprotectors utilize agents and strategies which prevent or reverse the senescent state by preventing triggers of cellular senescence, including:

  • DNA damage
  • Oxidative stress
  • Proteotoxic stress
  • Telomere shortening

Senotherapeutics refers to therapeutic agents and strategies that specifically target cellular senescence and include any of the following therapies:

  • Gene therapy
  • Geroprotectors
  • Immune clearance of senescent cells
  • SASP inhibitors
  • Senolytics  (compounds capable of identifying and eliminating senescent cells)

Senescent cells enter a stage in which they no longer properly divide and function and become dysfunctional, which utlimately leads to organ failure.  Senescent cells also generate pro-inflammatory compounds which potentially damage healthy tissues.

Senolytics and geroprotectors eliminate aging and senescent cells from the tissues which then makes room for newer more active cells.

Life Extension® has partnered with Insilico Medicine to identify nutrient cocktails that function as geroprotectors by employing artificial intelligence biomedical algorithms.  These strategic uses of high-speed computer programs accelerates the research into potential geroprotectors. 

In a study published on April 23, 2016 in the Journal Aging, the authors, including Life Extension® and Insilico Medicine, among others, used GeroScope to develop a list of geroprotectors. 1

GeroScope is a computational tool that can aid prediction of novel geroprotectors from existing human gene expression data. GeroScope maps expression differences between samples from young and old subjects to aging-related signaling pathways, then profiles pathway activation strength (PAS) for each condition.

Known substances are then screened and ranked for those most likely to target differential pathways and mimic the young signalome. 

The study identified and shortlisted ten substances, all of which have lifespan-extending effects in animal models.  These ten substances include:

  • 7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine
  • Epigallocatechin gallate (EGCG)
  • Fasudil (HA-1077)
  • HA-1004
  • Myricetin
  • N-acetyl-L-cysteine (NAC)
  • Nordihydroguaiaretic acid (NDGA)
  • PD-98059
  • Staurosporine
  • Ursolic acid
Drug Code Model Organism Lifespan (LS) Parameter % Increase Ref.
Nordihydroguaiaretic acid A D. melanogaster Median LS 23 [47]
Mus Musculus Median LS 12 [48]
Myricetin B C. elegans Mean LS 32.9 [48,49]
HA-1004 C D. melanogaster Mean LS 18 [50]
7-Cyclopentyl-5-(4-phenoxy)phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine D C. elegans Mean LS 11 [51]
Staurosporine E D. Melanogaster Mean LS 34.8 [50]
Ursolic acid F C. elegans Mean LS 39 [52]
N-acetyl-L-cysteine G Mice Max LS 40 [53]
Fasudil (HA-1077) H D. melanogaster Mean LS 14.5 [50]
PD-98059 I D. melanogaster Mean LS 27 [50]
Epigallocatechin gallate J C. elegans Mean LS 10.1 [54]
Rattus norvegicus Median LS 13.5 [55]

Table 3. Previously reported lifespan effects of test substances in animal models (compiled from geroprotectors.org [15].)  Source:  In search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state

The researchers narrowed down the list of ten substances to the final four compounds, which include:

  • Gamma tocotrienol (Vitamin E)
  • Epigallocatechin gallate (EGCG) (found in Green tea)
  • N-acetyl-L-cysteine (NAC)
  • Myricetin

These final four compounds combat numerous aging factors throughout the body by working together by influencing key anti-aging pathways. 

The researchers concluded that these four compounds reduced cellular aging and protect against the development of senescent cells by modulating a group of signaling pathways.

For a breakdown of the various pathways modulated by the final four compounds, read and review the April 2017 article from Life Extension®.

Life Extension® has combined these final four compounds into a new supplement product called GEROPROTECT™ Ageless Cell™.  Supplementing with this product may reduce the body’s burden of senescent cells.  

Sarsaparilla (Smilax Glabra Rhizome) Extract Inhibits Cancer Cell Growth by Promoting Apoptosis

Smilax glabra, commonly known as sarsaparilla or Chinaroot, is a plant species in the genus Smilax.  It is native to China, the Himalayas, and Indochina.  The genus Smilax contains about 300–350 species, and are found in temperate zones, tropics and subtropics worldwide. 

Smilax glabra is the Smilax species that is used in Chinese herbology.  The Chinese name of the plant is 土茯苓, and the pinyan name is Tu fu ling.

Smilax_glabraRhizomeDried

Dried Smilax Glabra Rhizome

Smilax glabra is oftentimes confused with two other species of Smilax:

  • Smilax officinalis
  • Smilax aristolochiifolia

Smilax aristolochiifolia is also known as:

  • Gray sarsaparilla
  • Mexican sarsaparilla
  • Sarsaparilla

It is native to Mexico and Central America.  Smilax aristolochiifolia root has a long traditional history of medicinal use.  2  

Smilax glabra contains some interesting active ingredients.  The following Dihydro-flavonol glycosides have been identified in the rhizome of Smilax glabra:   1

  • astilbin
  • neoastilbin
  • isoastilbin
  • neoisoastilbin
  • (2R, 3R)-taxifolin-3′-O-beta-D-pyranoglucoside

The following flavanonol rhamnoside has been identified in the rhizome of Smilax glabra:  

  • smitilbin

Smilax glabra has been studied in vitro and in animal studies (but it has not been studied in clinical trials) as a potent botanical plant in the following areas:

  • anticancer properties  3  4  5 
  • anti-inflammatory  6  7 
  • antioxidant  8  9
  • antiviral  10
  • hepatoprotective  11
  • immunostimulatory  12
  • renoprotective  13 

In a study published in March 2015 in the Journal Cancer Prevention Research, researchers found that Smilax Glabra Rhizome Extract Inhibits Cancer Cell Growth by S Phase Arrest, Apoptosis, and Autophagy via the Redox-Dependent ERK1/2 Pathway.  14

The researchers surmised that Sarsaparilla (Smilax Glabra Rhizome) has growth-inhibitory effects on several cancer cell lines in vitro and in vivo, with little toxicity on normal cells. What was uncertain to the researchers was the underlying functional mechanism of Smilax Glabra Rhizome against several cancer cell lines.

Their study examined the anticancer activity of the supernatant of the water-soluble extract (SW) from sarsaparilla.

Smilax Glabra Rhizome (SW) was shown to markedly inhibit the growth of a broad spectrum of cancer cell lines in the in vitro and in vivo assays. Responsible for SW-induced growth inhibition was any or all of the following:

  • apoptosis
  • autophagy
  • S phase arrest

The researchers concluded:

“Together, our results provide a molecular basis for sarsaparilla as an anticancer agent.”  15


Informational References:

Memorial Sloan Kettering Cancer Center – Smilax glabra


Resources:

Tu fu ling (Chinese smilax rhizome)

SUN TEN – Smilax Tu Fu Ling Concentrated Granules 100g S1870 by Baicao

Tu Fu Ling Liquid Extract, Tu Fu Ling, Glabrous Greenbrier (Smilax Glabra) Root Tincture Supplement 2 oz

 

The Detoxification and Biotransformation System in the Human Body

Detoxification Pathways

There are 6 main detoxification organs or systems in the human body:

  • Liver (processes and packages toxins) (70% of detoxification)
  • Lungs (gas exchange of oxygen and carbon dioxide)
  • Gastrointestinal Tract (excretes waste)
  • Skin (sweat)
  • Kidneys (urination)
  • Endothelial cells of the blood brain barrier

The intestines, liver and kidneys are the primary organs of detoxification.

Biotransformation enzymes exist in the smooth endoplasmic reticulum, cystosol (intracellular fluid) and to a lesser degree in the membranes of the mitochondria, nuclei and lysosomes (small spherical organelles) of the liver’s hepatocytes. The kidneys and lungs are the next major biotransformation sites, but only at 10 – 30% of the livers capacity. The skin, nasal mucosa and intestinal mucosa also have some biotransformation capacity.

Other sites of detoxification metabolism include epithelial cells of the gastrointestinal tract, lungs, kidneys, and the skin. These sites are usually responsible for localized toxicity reactions.

Once an unwanted compound has been completely bio transformed and removed from the cell, it will then be eliminated from the body via – kidneys, bowels, breath, sweat, saliva or hair – completing the detoxification process.

Toxins that the body is unable to eliminate build up in the tissues and typically stored in the adipose (fat) tissue.

Liver Detoxification

Almost 2 quarts of blood pass through the liver every minute for detoxification. Filtration of toxins is absolutely critical for the blood from the intestines because it is loaded with bacteria, endotoxins, antigens – and tight body complexes, and various other toxic substances.

wps_clip_image-1009

Figure 1:  Detoxification pathways

Intermediary Metabolites  and Pathological Detoxifiers

The transformation of xenobiotics into more chemically active toxins can cause several problems. A significant side effect of all this metabolic activity is the production of free radicals as xenobiotics are transformed by phase 1. Without adequate free radical defenses, every time the liver neutralizing toxins, it is damaged by the free radicals that are produced.

The most important antioxidant for neutralizing free radicals produced by phase 1 byproducts is glutathione. In the process of neutralizing free radicals glutathione is oxidized to glutathione disulfide. Glutathione is required for one of the phase 2 detoxification processes namely glutathione conjugation. When high levels of toxic exposure produces so many free radicals from phase 1, all of glutathione is used up, and glutathione conjugation stops working.

Another potential problem occurs because the toxins transformed into intermediary metabolites by phase 1 can be more toxic than the original toxin. Unless these intermediary metabolites are quickly removed from the body by phase 2 detoxification pathways, they can cause widespread problems. Therefore, the rate at which phase 1 produces intermediary metabolites must be balanced by the rate at which phase 2 finishes the process. Unfortunately, some people have a very active phase 1 detoxification system but very slow phase 2 enzymes. These people are described as “pathological detoxifiers” because they’re over active phase 1 results in a buildup of more harmful intermediate products, which phase 2 cannot detoxify quickly enough. The end result is that these people suffer severe toxic reaction to environmental poisons.

Gastrointestinal Tract Detoxification

About 25% of detoxification occurs within the cells lining the intestines, the remainder occurs in the liver.

Most literature on detoxification refers to liver enzymes, as the liver is the site of the majority of detoxification activity for both endogenous and exogenous compounds. However, the first contact the body makes with the majority of xenobiotics is the gastrointestinal tract. the gastrointestinal tract is the second major site in the body for detoxification. Detoxification enzymes such as Cyp3A4 and the antiporter  activities have been found in high concentrations at the tip of villi in the intestine.

Adequate first pass metabolism of xenobiotics by the gastrointestinal tract requires integrity of the gut mucosa. Compromised barrier function of the mucosa will easily allow xenobiotics to transit into the circulation without opportunity for detoxification. Therefore, support for healthy gut mucosa is instrumental in decreasing toxic load.

The gastrointestinal tract influences detoxification in several other ways. Gut microflora can produce compounds that either induce or inhibit detoxification activities.

Pathogenic bacteria can produce toxins that can enter circulation and increase toxic load.

Detoxification through the intestinal tract is enhanced by fasting, mono, high fiber and mucus-less diets, ingestion of substances such as charcoal, mud and grasses, and in some cases by the use of cathartics that either lubricate, increase fluidity, add bulk or stimulate peristaltic motion.

Gastrointestinal health and gut permeability also play a role in detoxification. Increased gut permeability allows for increased absorption of xenobiotics and toxins, which are processed and removed by the liver, thus increasing the demands on the liver detoxification system. Impaired gastrointestinal integrity can be improved via dietary support as well as prebiotics and probiotics.

Fiber is particularly important for supporting detoxification. Dietary fibers bind not only carcinogens, bile acids, and other potentially toxic agents, it also promotes a faster transit time and therefore less opportunity for toxin interaction with the intestinal lining and reabsorption. In addition, increased fiber intake helps positively balance the intestinal microflora, which minimizes endotoxin production from pathogenic bacteria.

Brain Detoxification: The Glymphatic System

The cytochrome P450 enzyme system is found in other parts of the body, especially the brain cells.

The glymphatic system (or glymphatic clearance pathway) is a functional waste clearance pathway for the mammalian central nervous system (CNS). The brain is not part of the body’s lymphatic system which is responsible for removing extracellular proteins, excess fluid, and metabolic waste products from peripheral tissues.

Glymphatic flow answers the long standing question of how the sensitive neural tissue of the CNS functions in the absence of a conventional lymphatic circulation. The pathway consists of a para-arterial influx route for cerebrospinal fluid (CSF) to enter the brain parenchyma, coupled to a clearance mechanism for the removal of interstitial fluid (ISF) and extracellular solutes from the interstitial compartments of the brain and spinal cord. Exchange of solutes between the CSF and the ISF is driven by arterial pulsation and regulated during sleep by the expansion and contraction of brain extracellular space.

Clearance of soluble proteins, waste products, and excess extracellular fluid is accomplished through convective bulk flow of the ISF, facilitated by astrocytic aquaporin 4 (AQP4) water channels.

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Figure 2:  Mammalian Gymphatic System

A publication by L. Xie and colleagues in 2013 explored the efficiency of the glymphatic system during slow wave sleep and provided the first direct evidence that the clearance of interstitial waste products increases during the resting state. Xia and Nedergaard demonstrated that the changes in efficiency of CSF–ISF exchange between the awake and sleeping brain were caused by expansion and contraction of the extracellular space, which increased by ~60% in the sleeping brain to promote clearance of interstitial wastes such as amyloid beta.

During the night, we experience sleep cycles that average about 90 minutes. In the first half of the night we cycle through all of the stages, N1, N2, N3, and REM sleep. Slow wave sleep or delta sleep is N3. We start at N1 and go deeper into N2, then deeper into N3, the stage where brain cleansing occurs. In the second half of the night, REM sleep increases and alternates with N1 and N2 sleep, so it appears most of the cleanup is done in the first half of the night.

The interstitial space makes up about 20% of the brain volume but that fraction varies over the course of the day and night. During sleep this space increases by up to 60% in volume. This flushing of the glymphatic system removed waste metabolic products that are potentially neurotoxins. These products include β-amyloid proteins which are strongly suspected to play a part in Alzheimer’s Disease.

This is a two part process:

  • 1. After the brain cells shrink 60 %  cerebral spinal fluid is pumped through the brain’s tissue, then 
  • 2. The waste is flushed back into the circulatory system where it enters the blood circulation system and goes to the liver

Cerebral spinal fluid quickly flows into the space, aided by the pulse of the arteries. It mixes with the interstitial fluid and washes the waste toward the veins and carries it to the liver. This process occurs during slow wave sleep, the deepest sleep.

Another startling finding was that the cells in the brain “shrink” by 60 percent during sleep. This contraction creates more space between the cells and allows CSF to wash more freely through the brain tissue. In contrast, when awake the brain’s cells are closer together, restricting the flow of CSF. 

The researchers observed that a hormone called noradrenaline is less active in sleep. This neurotransmitter is known to be released in bursts when brain needs to become alert, typically in response to fear or other external stimulus. The researchers speculate that noradrenaline may serve as a “master regulator” controlling the contraction and expansion of the brain’s cells during sleep-wake cycles.

Using these techniques, researchers were able to observe in mice – whose brains are remarkably similar to humans – what amounts to a plumbing system that piggybacks on the brain’s blood vessels and pumps cerebral spinal fluid (CSF) through the brain’s tissue, flushing waste back into the circulatory system where it eventually makes its way to the general blood circulation system and, ultimately, the liver.

Skin Detoxification

Detoxification through the skin is facilitated by the promotion of sweating. This can be accomplished by ingesting sudorific (diaphoretic) herbs like ginger, mustard and cayenne, either by themselves or in conjunction with fasting, saunas, baths and sweats.

Packs of clay, mud, salt, charcoal, seaweed, volcanic ash and castor oil have also proven useful in increasing the elimination of toxins through the skin.

Physiological Factors that Affect Detoxification

There are various physiological and pathological factors that affect the detoxification process. Physiological factors that can influence detoxification include:

  • Age
  • Genetic Factors
    • Polymorphisms (SNPs)  

Aging

The activity of phase I detoxification enzymes decreases in old age. Aging also decreases blood flow through the liver, further aggravating the problem. Lack of the physical activity necessary for good circulation, combined with the poor nutrition commonly seen in the elderly; add up to a significant impairment of detoxification capacity, which is typically found in aging individuals.

Genetic Factors

Biochemical individuality is a simple concept that states all humans differ biochemically from others. And that biochemical individuality directly affects the degree to which a chemical compound is bio-transformed from person to person. Some of the factors that determine a person’s level of biochemical individuality and therefore biotransformation capacity are:

The structure, amount of or complete lack of a specific biotransformation enzyme may differ among individuals and this can give rise to differences in rates of biotransformation.  Genetic differences in the ability of an individual to metabolize xenobiotics are related to the presence of different versions of the gene encoding that activity, or genetic polymorphism.

A Single Nucleotide Polymorphism, also known as Simple Nucleotide Polymorphism, is a DNA sequence variation occurring commonly within a population (e.g. 1%) in which a single nucleotide — A, T, C or G — in the genome (or other shared sequence) differs between members of a biological species or paired chromosomes.

Polymorphisms (SNPs) in the genes coding for a particular enzyme can increase or, more commonly, decrease the activity of that enzyme. Both increased and decreased activity may be harmful. As mentioned above, increased Phase I clearance without increased clearance in Phase II can lead to the formation of toxic intermediates that may be more toxic than the original toxin. Decreased Phase I clearance will cause toxic accumulation in the body.

Genova Diagnostics offers a comprehensive test of the Polymorphism (SNPs) in its DetoxiGenomic(TM) Profile. 

Click the link to view a Sample Report


 

Sangre de Grado: A Powerful Antioxidant

Sangre de Grado (Peruvian Spanish) or Sangre de Drago (Ecuadorian Spanish) is known by its botantical name as Croton lechleri and  is a species of flowering plant that is native to northwestern South America.  It translates to “Dragon’s Blood”.  The dragon’s blood refers to the trees thick red latex.

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Red sap (latex) of Sangre de Grado tree bark

Sangre de Grado includes a number of biologically active chemical substances:

  • Alpha-Calacorene
  • Alpha-Copaene
  • Alpha-Pinene
  • Alpha-Thujene
  • Beta-Caryophyllene
  • Beta-Elemene
  • Betaine
  • Beta-Pinene
  • Borneol
  • Calamenene
  • Camphene
  • Cuparophenol
  • Dimethylcedrusine
  • Dipentene
  • Eugenol
  • Euparophenol
  • Gamma-Terpinene
  • Gamma-Terpineol
  • Lignin
  • Limonene
  • Linalool
  • Methylthymol
  • Oligomeric Proanthocyanidins (OPC)
  • P-Cymene
  • Tannins
  • Taspine
  • Terpinen-4-ol
  • Vanillin

Purported Uses of Sangre de Grado

Taspine is an alkaloid which acts as a potent acetylcholinesterase inhibitor. [1] Taspine has also been found to be a dual topoisomerase inhibitor effective in cells overexpressing drug efflux transporters and induces wide-spread apoptosis in multicellular spheroids. [2]

Taspine promotes early phases of wound healing in a dose-dependent manner with no substantial modification due to its mechanism of action related to its chemotactic properties on fibroblasts. [3]

Taspine has also shown anti-inflammatory potential. [4]

Dimethylcedrusine, another biologically active substance in Sangre de Grado, was shown to inhibit thymidine incorporation, while protecting cells against degradation in a starvation medium. [5]

Sangre de grado exerts anti-viral effects against influenza viruses, parainfluenza viruses, herpes simplex viruses types I and II, hepatitis A virus and hepatitis B virus. [6]

Sangre de grado may also present a complementary and alternative medicine approach for the treatment of fluid loss in watery diarrhea. [7]

Sangre de grado has also been found to induce apoptosis in human gastrointestinal cancer cells. [8]

Antioxidant Activity of Sangre de Grado

Another important health benefit to Sangre de Grado is its potential as a powerful antioxidant herb.

An article published in the Nutrition Journal in 2010 entitled The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide, by Monica H Carlsen, Bente L Halvorsen, Kari Holte, Siv K Bøhn, Steinar Dragland, Laura Sampson, Carol Willey, Haruki Senoo, Yuko Umezono, Chiho Sanada, Ingrid Barikmo, Nega Berhe, Walter C Willett, Katherine M Phillips, David R Jacobs, Jr, and Rune Blomhoff, found that Sange de Grado had the highest antioxidant content of the 59 herbal products tested in the database.

Sange de Grado tested at 2897.1 mmol/100 g, much higher than the next highest herb formula Triphala at 706.25 mmol/100 g.

Other antioxidant rich products are Triphala, Amalaki and Arjuna from India and Goshuyu-tou, a traditional kampo medicine from Japan, with antioxidant values in the range of 132.6 to 706.3 mmol/100 g. [9]


References:

[1] Rollinger, JM; Schuster, D; Baier, E; Ellmerer, EP; Langer, T; Stuppner, H (2006). “Taspine: Bioactivity-guided isolation and molecular ligand-target insight of a potent acetylcholinesterase inhibitor from Magnolia x soulangiana”. Journal of Natural Products 69 (9): 1341–1346. doi:10.1021/np060268p. PMC 3526713. PMID 16989531

[2] Identification of a Novel Topoisomerase Inhibitor Effective in Cells Overexpressing Drug Efflux Transporters

[3] Porras-Reyes, B. H., et al. Enhancement of wound healing by the alkaloid taspine defining mechanism of action. Proc Soc Exp Biol Med. 203(1):18-25, 1993.

[4] Perdue, G. P., et al. South American plants II: taspine isolation and anti-inflammatory activity. J Pharm Sci. 68(1):124-126, 1979

[5] Isolation of a dihydrobenzofuran lignan from South American dragon’s blood (Croton spp.) as an inhibitor of cell proliferation

[6] Williams, J. E. Review of antiviral and immunomodulating properties of plants of the Peruvian rainforest with a particular emphasis on una de gato and sangre de grado. Alternative Medicine Review. 6(6):567-579, 2001

[7] Fischer, H., et al. A novel extract SB-300 from the stem bark latex of Croton lechleri inhibits CFTR-mediated chloride secretion in human colonic epithelial cells. Journal of Ethnopharmacology. 93(2-3):351-357, 2004.

[8] Sangre de grado Croton palanostigma induces apoptosis in human gastrointestinal cancer cells

[9] The total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwide; Nutr J. 2010; 9: 3. Published online 2010 Jan 22. doi: 10.1186/1475-2891-9-3


Informational References:

The Antioxidant Food Table, Carlsen et al. 2010 (PDF)

Memorial Sloan Kettering Cancer Center

Note: PDF files require a viewer such as the free Adobe Reader


Resources:

Herb Pharm Dragon’s Blood (Sangre de Drago) Liquid Tree Sap for Digestive Support – 1 Ounce