Category Archives: Herbs & Spices

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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)

Puerarin from Kudzu is Chemoprotective Against Colon Cancer

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

A number of studies have showed that puerarin from Kudzu possesses anti-cancer properties.

From a study published in 2006, treatments with puerarin revealed a dose-dependent reduction of colon cancer HT-29 cellular growth through the activation of caspase-3, a key executioner of apoptosis.   1 

The findings from this 2006 study indicate that puerarin may act as a chemopreventive and/or chemotherapeutic agent in colon cancer cells by reducing cell viability and inducing apoptosis.

The Medicinal Value of Perilla (Leaf, Seeds and Oil)

Introduction to Perilla

Perilla is known by its botanical name, perilla frutescens and is a perennial plant in the mint family, Lamiaceae. The Perilla species encompasses two distinct varieties:

  • Perilla frutescens var. crispa
  • Perilla frutescens var. frutescens

Perilla frutescens var. crispa is the aromatic leafy herb.  The plant occurs in red (purple-leaved) or green-leaved forms.

Perillagreen

Green perilla leaf

PerillaRed

Red (purple) perilla leaf

In various countries and cultures it is known by different names:

  • Korean name is jasoyup, 자소엽
  • Japanese name is shiso, 紫蘇 or シソ
  • Chinese name is 紫蘇; pinyin: zĭsū; Wade–Giles: tsu-su
  • English common name is “beefsteak plant”

Perilla frutescens var. frutescens is the source of perilla oil.  The seeds contain 35 to 45 percent oil which is obtained by pressing.  Perilla oil is a very rich source of the omega-3 fatty acid alpha-linolenic acid (ALA). About 50 to 60% of the oil consists of ALA.

PerillaSeeds

Perilla seeds

PerillaOil

Perilla seed oil

How Various Cultures Use Perilla

The Asian cultures use perilla in its many forms throughout their cuisines and for its medicinal value.

Korea

In Korea, perilla is mainly cultivated in the provinces of Chungcheong, Gyeongsang, and Jeolla. In their cuisine, it is used for marinating namul (seasoned vegetable dish), coating grilled gim (Korean laver), or pan-frying jeon (pancake-like dish).  In North Korea, it is called deulkkae gireum (들깨기름). 

China

In China, perilla is called zǐsū:

  • Simplified Chinese: 紫苏
  • Traditional Chinese: 紫蘇
  • Pinyin: zǐsū

The Chinese have used perilla traditionally in Chinese medicine. 

Japan

The Japanese use the Perilla frutescens var. crispa in their cuisine and it is called shiso (紫蘇).  The Japanese name for the green type of perilla is called aojiso (青紫蘇?), or ooba (“big leaf”), and is often combined with sashimi.

Laos

The purple leaf variety are called pak maengda (ຜັກແມງດາ) in Laos.  They are usually strong in fragrance.  The people of Laos use them is a rice vermicelli dish called khao poon (ເຂົ້າປຸ້ນ).

Vietnam

The Vietnamese use a variety of perilla with greenish bronze on the top face and purple on the opposite face. The leaves are smaller and have a much stronger fragrance. In Vietnamese, it is called tía tô, derived from the characters (紫蘇) whose standard pronunciation in Vietnamese is tử tô.

India and Nepal

In Nepal and parts of India, perilla is called silam (सिलाम), thoiding (Meitei), Chhawhchhi (Mizo) and bhangira.

Components of Perilla leaf, seeds and oil

Perilla seed oil has a high lipid content, with a range as high as 38-45% lipids.

Perilla oil has one of the highest content of omega-3 (α-linolenic acid (ALA) fatty acids of any seed oil.  It also contains linoleic acid. omega-6 fatty acid.  The proportions of omega-3 and omega-6 is as follows:  1

  • Omega-3           54-64%
  • Omega-6           14%

The Japanese variety of perilla, named shiso contains a lower percentage of lipids, at approximately 25.2-25.7% lipid content.  Even though there is a lower percentage of lipids in the shiso variety, the α-linolenic acid (ALA) content is approximately 60% of the total lipids.

Perilla also contain certain essential oils, such as:  2

  • Caryophyllene
  • Farnesene
  • Limonene

Korean scientists found a number of aroma-active compounds from Korean perilla (Perilla frutescens Britton).  Thirty-three volatile compounds were identified by GC-MS.  The most important of these volatile compounds include:  3

  • I-(3-Furyl)-4-methyl-1-pentanone (perilla ketone) was found to be the most abundant volatile compound
  • (Z)-3-hexenol
  • 1-octen-3-ol

Perilla ketone comprised 81% (93 ppm), 84% (120 ppm), and 95% (490 ppm) of the volatile compounds obtained from SAFE, LLCE, and HD, respectively.

The organic acids found in perilla are:

  • Ferulic Acid   
  • Rosmarinic Acid       

The polyphenols in perilla have been identified as:

  • Chryseriol   
  • Luteolin    (17.3mg/gram)  

Health Benefits of Perilla

There are a number of research studies on the effect of perilla leaf and oil on certain health conditions.  These studies and their abstracts are listed in the Table below:

Medicinal Value of Perilla Leaf, Seed and Oil

ConditionAbstractReference
Inflammation
Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects1
Liver cancer
Growth inhibitory and apoptosis inducing effect of Perilla frutescens extract on human hepatoma HepG2 cells. The results of our study suggest that the PLE should be further investigated as a promising to treat hepatocellular carcinoma.2
Colon cancer
We have investigated the modulatory effect of dietary perilla oil which is rich in the n-3 polyunsaturated fatty acid, alpha-linolenic acid, on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) in male F344 rats. Marked increases in n-3 polyunsaturated fatty acids in membrane phospholipid fractions and decreased PGE2 levels were observed in colonic mucosa of perilla oil-fed rats. These results suggest that perilla oil, even in small amounts, suppresses the development of aberrant crypt foci, and is therefore a possible preventive agent in the early stage of colon carcinogenesis.3
Tumor necrosis factor-alpha (TNF-alpha) inhibitor
The overproduction of tumor necrosis factor-alpha (TNF-alpha) was suppressed by orally administering a perilla leaf extract (PLE). When mice were successively injected with OK-432, severe TNF-alpha was induced in the serum, but this elevated TNF-alpha level was reduced after an oral administration of PLE (400 microliters/mouse).4
Allergies
Perilla extract significantly suppressed the PCA-reaction, which was brought about by rosmarinic acid with a partial contribution from some macromolecular compounds. The anti-allergic titer of rosmarinic acid was more effective than tranilast, which is a modern anti-allergic drug. Perilla and rosmarinic acid are potentially promising agents for the treatment of allergic diseases.5
Blood clotting
As compared with high dietary linoleate safflower oil, high dietary alpha-linolenate perilla oil decreased platelet-activating factor (PAF) production by nearly half in calcium ionophore (CaI)-stimulated rat polymorphonuclear leukocytes (PMN). In the CaI-stimulated PMN from the perilla oil group, the accumulated amount of arachidonate (AA) plus eicosapentaenoate (EPA) was 30% less and that of lyso-PAF was 50% less, indicating that the decreased availability of lyso-PAF is a factor contributing to the relatively low PAF production.6
Ulcerative colitis
The DSS-treated rats were fed either a perilla oil-enriched diet (perilla group) or a soybean oil-enriched diet (soybean group). The bradykinin-stimulated DeltaIsc in the soybean and perilla groups was significantly higher than that in the control group. The mucosal level of arachidonic acid in the perilla group was significantly lower than that in the soybean group. results suggest that supplementation with alpha-linolenic acid, in combination with a lipoxygenase inhibitor, could suppress the increase in Cl- secretion in patients with ulcerative colitis (UC). 7
Learning
Donryu strain rats through two generations were fed semi-purified diets supplemented with safflower seed oil (rich in linoleic acid) or with perilla seed oil (rich in alpha-linolenic acid), or a conventional laboratory chow (normal control diet). Brightness-discrimination learning ability was determined to be the highest in the perilla oil-fed group, followed by the normal group, and then by the safflower group, extending our earlier observation in a different strain of rat that alpha-linolenic acid is a factor in maintaining high learning ability8
Asthma
Perilla seed oil (5 - 500 microg/mL) inhibited the slow reaction substance of anaphylaxis (SRS-A) release induced by antigen challenge in lung tissue of sensitized guinea pigs. It also inhibited calcium ionophore (A(23187))-induced leukotriene (LT) D4 release from the lung tissue of non-sensitized guinea pigs in a concentration-dependent manner with an IC50 (95 % CI) of 50 (36 - 69) microg/mL. These results indicate that Perilla seed oil may improve lung function in asthma by controlling eicosanoid production and suppressing LT generation.9
Fatty acid synthase suppression
This study was performed to determine the effects of dietary perilla oil, a n-3 alpha-linolenic acid (ALA) source, on hepatic lipogenesis as a possible mechanism of lowering triacylglycerol (TG) levels. The activities of hepatic lipogenic enzymes such as fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase, and malic enzyme were suppressed in the fish oil, perilla oil, and corn oil-fed groups, and the effect was the most significant in the fish oil-fed group.10


Resources:

Perilla Oil (capsules) – Source Naturals

Haepyo Korean Pure Perilla Oil 10.8 Fl Oz

Korea Premium Raw Perilla Oil 180ml Organic Edible

Perilla Liquid Extract

Zi Su Zi, Perilla frutescens seed, Herbal Powder, 500 grams

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Alzheimer’s disease is the most prevalent neurodegenerative disease in the growing population of elderly people. A hallmark of Alzheimer’s disease is the accumulation of plaques in the brain of Alzheimer’s disease patients. The plaques predominantly consist of aggregates of amyloid-beta generated in vivo by specific, proteolytic cleavage of the amyloid precursor protein. There is a growing body of evidence that amyloid-beta aggregates are ordered oligomers and the cause rather than a product of Alzheimer’s disease.

There are a number of studies that state that the accumulation of amyloid beta within the brain arises from an imbalance of the production and clearance of amyloid beta.  Most of the time in the case of Alzheimer’s disease, amyloid beta clearance is impaired.  1

The process of creating amyloid beta in the brain has multiple roles in the brain, including:  2

  • antioxidant activity
  • calcium homeostasis
  • metal ion sequestration
  • modulation of synaptic plasticity
  • neurogenesis
  • neurotrophic activity

This controlled homeostatic regulation allows for the normal functions of amyloid beta but also prevents accumulation of excess amyloid beta as a metabolic waste product. 

An imbalance in this homeostasis results in pathological and neurotoxic accumulations of cerebral amyloid beta.  3

Scientists have developed a number of therapeutic strategies as possible interventions against amyloid beta, two of which include:

  • Anti-aggregations agents
  • Clearance of amyloid beta

Anti-aggregations agents

Anti-aggregation prevent amyloid beta fragments from aggregating or clear aggregates once they are formed.  4

Clearance of amyloid beta

Impaired clearance of amyloid beta is now widely identified as a contributing factor towards Alzheimer’s disease progression.  5   In order to prevent pathological accumulations of amyloid beta in the brain, amyloid beta clearance from the cerebral milieu into periphery and out of the system is of prime importance. Improving amyloid beta clearance from the brain across the blood–brain barrier (BBB) and into blood plasma.

Clearance of amyloid beta is so important that recent evidence in humans suggests that impaired amyloid beta clearance is the main cause of pathological accumulations of cerebral amyloid beta in late onset Alzheimer’s disease and not the overproduction of amyloid beta.  6 

The purpose of this article is to examine and identify the natural compounds that act as either anti-aggregation agents or an agents for the clearance of amyloid beta, or both.  

Researchers have identified a number of natural compounds that have been effective as therapeutics for Alzheimer’s disease whether as an anti-aggregation agent and/or an agent for clearance of amyloid beta.  7 

These natural compounds include:

  • Baicalein
  • Curcumin
  • Ellagic acid
  • (−)-Epigallocatechin-3-gallate (EGCG)
  • Ferulic acid
  • Fisetin
  • Kaempferol
  • Luteolin
  • Malvidin
  • Melatonin
  • Myricetin
  • Nordihydroguaiaretic acid (NDGA)
  • Oleuropein Aglycone (OLE)
  • Proline Rich Polypeptide (Colostrinin™)
  • Quercetin
  • Resveratrol
  • Rosmarinic acid
  • Rutin
  • Vitamin A

Natural Compounds That Promote Anti-Aggregation And Clearance of Amyloid Beta

Natural CompoundAbstractReferences
BaicaleinOur data showed that baicalein inhibited the formation of α-syn oligomers in SH-SY5Y and Hela cells, and protected SH-SY5Y cells from α-syn-oligomer-induced toxicity. We also explored the effect of baicalein on amyloid-β peptide (Aβ) aggregation and toxicity. We found that baicalein can also inhibit Aβ fibrillation and oligomerisation, disaggregate pre-formed Aβ amyloid fibrils and prevent Aβ fibril-induced toxicity in PC12 cells. Our study indicates that baicalein is a good inhibitor of amyloid protein aggregation and toxicity. 1
CurcuminWhen fed to aged Tg2576 mice with advanced amyloid accumulation, curcumin labeled plaques and reduced amyloid levels and plaque burden. Hence, curcumin directly binds small beta-amyloid species to block aggregation and fibril formation in vitro and in vivo. These data suggest that low dose curcumin effectively disaggregates Abeta as well as prevents fibril and oligomer formation, supporting the rationale for curcumin use in clinical trials preventing or treating AD.2 2a
Ellagic acidHere, we tested the effects of ellagic acid (EA), a polyphenolic compound, on Abeta42 aggregation and neurotoxicity in vitro. EA promoted Abeta fibril formation and significant oligomer loss, contrary to previous results that polyphenols inhibited Abeta aggregation. 3
(−)-Epigallocatechin-3-gallate (EGCG)Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.4
The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.5
Ferulic acidFerulic acid dose-dependently inhibited fAbeta formation from amyloid beta-peptide, as well as their extension. Moreover, it destabilized preformed fAbetas. The overall activity of the molecules examined was in the order of: Cur > FA > rifampicin = tetracycline. FA could be a key molecule for the development of therapeutics for AD.6
Chronic (for 6 months from the age of 6 to 12 months) oral administration of ferulic acid at a dose of 5.3 mg/kg/day significantly enhanced the performance in novel-object recognition task, and reduced amyloid deposition and interleukin-1 beta (IL-1β) levels in the frontal cortex. These results suggest that ferulic acid at a certain dosage could be useful for prevention and treatment of AD.7
FisetinFisetin (3,3',4',7-tetrahydroxyflavone) has been found to be neuroprotective, induce neuronal differentiation, enhance memory, and inhibit the aggregation of the amyloid beta protein (Abeta) that may cause the progressive neuronal loss in Alzheimer's disease. 8
The natural flavonoid fisetin (3,3',4',7-tetrahydroxyflavone) is neurotrophic and prevents fibril formation of amyloid β protein (Aβ). It is a promising lead compound for the development of therapeutic drugs for Alzheimer's disease.  9
KaempferolKaempferol was shown to have protective effects against oxidative stress-induced cytotoxicity in PC12 cells. Administration of kaempferol also significantly reversed amyloid beta peptide (Abeta)-induced impaired performance in a Y-maze test.10
Luteolin These results indicated that luteolin from the Elsholtzia rugulosa exerted neroprotective effects through mechanisms that decrease AβPP expression, lower Aβ secretion, regulate the redox imbalance, preserve mitochondrial function, and depress the caspase family-related apoptosis.11
MalvidinWe have identified four novel polyphenols which could be efficient fibril inhibitors in Alzheimer's disease: malvidin and its glucoside and curculigosides B and D. We suggest that molecules with the particular C(6)-linkers-C(6) structure could be potent inhibitors. From the results reported for the flavan-3-ol family, their anti-amyloidogenic effects against whole peptides (1-40 and 1-42) could involve several binding sites.12
MelatoninWe report that melatonin, a hormone recently found to protect neurons against Abeta toxicity, interacts with Abeta1-40 and Abeta1-42 and inhibits the progressive formation of beta-sheets and amyloid fibrils. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.13
Inhibition of beta-sheets and fibrils could not be accomplished in control experiments when a free radical scavenger or a melatonin analog were substituted for melatonin under otherwise identical conditions. In sharp contrast with conventional anti-oxidants and available anti-amyloidogenic compounds, melatonin crosses the blood-brain barrier, is relatively devoid of toxicity, and constitutes a potential new therapeutic agent in Alzheimer's disease.14
MyricetinMyricetin was the most potent compound myricetin to the neurotoxic oligomers rather than monomers. These findings suggest that flavonoids, especially Myricetin, exert an anti-amyloidogenic effect in vitro by preferentially and reversibly binding to the amyloid fibril structure of fAbeta, rather than to Abeta monomers.15
Nordihydroguaiaretic acid (NDGA)In cell culture experiments, fAbeta disrupted by NDGA were less toxic than intact fAbeta, as demonstrated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Although the mechanisms by which NDGA inhibits fAbeta formation from Abeta, as well as breaking down pre-formed fAbetain vitro, are still unclear, NDGA could be a key molecule for the development of therapeutics for AD.16
Oleuropein Aglycone (OLE)Here we report that oleuropein aglycon also hinders amyloid aggregation of Aβ(1-42) and its cytotoxicity, suggesting a general effect of such polyphenol. We also show that oleuropein aglycon is maximally effective when is present at the beginning of the aggregation process; furthermore, when added to preformed fibrils, it does not induce the release of toxic oligomers but, rather, neutralizes any residual toxicity possibly arising from the residual presence of traces of soluble oligomers and other toxic aggregates. The possible use of this polyphenol as anti-aggregation molecule is discussed in the light of these data.17
Proline Rich Polypeptide (Colostrinin™)Colostrinin™ is a mixture of proline-rich polypeptides (PRP) from ovine (sheep) colostrums. Colostrinin inhibits amyloid beta aggregation and facilitates disassembly of existing aggregates by disrupting beta-sheets bonding.18
QuercetinQuercetin is an effective amyloid aggregation inhibitor and inhibits amyloid beta fibrillization, but not its toxic oligomerization19
ResveratrolHere we show that resveratrol (trans-3,4',5-trihydroxystilbene), a naturally occurring polyphenol mainly found in grapes and red wine, markedly lowers the levels of secreted and intracellular amyloid-beta (Abeta) peptides produced from different cell lines. Resveratrol does not inhibit Abeta production, because it has no effect on the Abeta-producing enzymes beta- and gamma-secretases, but promotes instead intracellular degradation of Abeta via a mechanism that involves the proteasome. 20
In conjunction with the concept that Abeta oligomers are linked to Abeta toxicity, we speculate that aside from potential antioxidant activities, resveratrol may directly bind to Abeta42, interfere in Abeta42 aggregation, change the Abeta42 oligomer conformation and attenuate Abeta42 oligomeric cytotoxicity. 21
Rosmarinic acidRosmarinic acid had especially strong anti-amylid beta aggregation effects in vitro22
Rosmarinic acid reduced a number of events induced by Abeta. These include reactive oxygen species formation, lipid peroxidation, DNA fragmentation, caspase-3 activation, and tau protein hyperphosphorylation. Moreover, rosmarinic acid inhibited phosphorylated p38 mitogen-activated protein kinase but not glycogen synthase kinase 3beta activation. These data show the neuroprotective effect of sage against Abeta-induced toxicity, which could validate the traditional use of this spice in the treatment of AD. Rosmarinic acid could contribute, at least in part, for sage-induced neuroprotective effect.23
RutinHere, we show that the common dietary flavonoid, rutin, can dose-dependently inhibit Aβ42 fibrillization and attenuate Aβ42-induced cytotoxicity in SH-SY5Y neuroblastoma cells. 24
Vitamin A (beta-carotene)In this study, we used fluorescence spectroscopy with thioflavin T (ThT) and electron microscopy to examine the effects of vitamin A (retinol, retinal, and retinoic acid), beta-carotene, and vitamins B2, B6, C, and E on the formation, extension, and destabilization of beta-amyloid fibrils (fAbeta) in vitro. Among them, vitamin A and beta-carotene dose-dependently inhibited formation of fAbeta from fresh Abeta, as well as their extension. Moreover, they dose-dependently destabilized preformed fAbetas.25
Withanolides (Withania somnifera)The researchers found that using Withania somnifera extracts, comprising 75% withanolides and 20% withanosides, reversed plaque pathology and reduced the amyloid beta burden in middle-aged and old APP/PS1 mice through up-regulation of liver LRPI, leading to increased clearance of amyloid beta.26

Cover Photo:  Rosemary plant and flower

Can a Spoonful of Ceylon Cinnamon Make the Parkinson’s Go Down?

Parkinson’s disease is a degenerative disorder of the central nervous system in which dopamine generating cells in the substantia nigra die.  This then affects the motor system with regards to movement related activities, such as, shaking, rigidity, difficulty in walking and slowness in walking.

Two proteins in the brain act to protect neurons in the substantia nigra from cell death.  The first is Protein deglycase DJ-1 (DJ-1) which protects neurons against oxidative stress and cell death   The second is Parkin which helps degrade one or more proteins toxic to dopaminergic neurons.  The loss of function of the Parkin protein leads to dopaminergic cell death, which then can lead to Parkinson’s disease. Parkin and DJ-1 are known to stimulate and support the survival of existing dopaminergic neurons. It has been identified that Parkin and Protein deglycase DJ-1 decrease in the brain of Parkinson’s patients.  1

An interesting article published in the Journal of Neuroimmune Pharmacology in September 2014 entitled Cinnamon Treatment Upregulates Neuroprotective Proteins Parkin and DJ-1 and Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease explored a novel use of cinnamon in upregulating Parkin and DJ-1 and protecting dopaminergic neurons in a MPTP mouse model of Parkinson’s.

The authors from Rush University Medical Center’s Department of Neurological Sciences, Kalipada Pahan and Saurabh Khasnavis found that after oral feeding, ground cinnamon (Ceylon cinnamon (Cinnamonum verum)) is metabolized into sodium benzoate, which then enters into the brain, which then:  2

  • Stops the loss of Parkin and Protein deglycase DJ-1
  • Protects neurons
  • Normalizes neurotransmitter levels
  • Improves motor functions in mice with Parkinson’s

The authors also found that the oral treatment of MPTP-intoxicated mice with cinnamon powder and sodium benzoate:  3

  • Reduces the nigral expression of iNOS
  • Blocks nigral loss of Parkin and DJ-1
  • Protects the nigrostriatal axis
  • Restores locomotor activities

They suggested that cinnamon may be used to protect dopaminergic neurons in the nigra of Parkinson’s patients.

The authors of the study used True Cinnamon or Ceylon cinnamon (Cinnamonum verum) rather than using Chinese cinnamon (Cinnamomum cassia).  They stated that “Although both types of cinnamon are metabolized into sodium benzoate, by mass spectrometric analysis, we have seen that Ceylon cinnamon is much more pure than Chinese cinnamon as the latter contains coumarin, a hepatotoxic molecule.”  4

The use of Ceylon cinnamon could potentially be one of the safest approaches to halt disease progression in Parkinson’s patients.”  5

Ceylon cinnamon contains a major compound named cinnamaldehyde, which is converted into cinnamic acid by oxidation. In the liver, this cinnamic acid is β-oxidized to benzoate that exists as sodium salt (NaB) or benzoyl-CoA.   6

The authors concluded their study by stating, “Now we need to translate this finding to the clinic and test ground cinnamon in patients with PD. If these results are replicated in PD patients, it would be a remarkable advance in the treatment of this devastating neurodegenerative disease.”  7


It is important to note that if one is to consume a teaspoon or less of Ceylon cinnamon or True cinnamon (Cinnamonum verum) daily, it should be consumed in liquid or in food, and never in its dry form directly in the mouth as this could cause choking

Also make sure that you consume Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) and not Chinese cinnamon (Cinnamomum cassia or Cinnamomum Aromaticum) or Indonesian cinammon (Cinnamomum Burmanni) or Saigon cinammon (Cinnamomum Loureiroi), as these three cassia cinnamons can be hepatotoxic (damaging to the liver) in large quantities and on a frequent basis.

A common method of consuming Ceylon cinnamon or True cinnamon (Cinnamonum verum or Cinnamomum Zeylanicum) is to mix it in a smoothie with vegetables/fruit and protein powder.


Resources:

Cinnamon Vogue – CEYLON CINNAMON POWDER USDA ORGANIC

Ceylon cinnamon or True cinnamon (Cinnamonum verum)

Flip Your AMPK switch to the “ON” position

Introduction to AMPK

AMPK (adenosine monophosphate-activated protein kinase) is an enzyme contained in every cell of the human body that serves as the body’s master regulating switch.

When the AMPK master switch is turned “ON” (by activating AMPK), it inhibits multiple damaging factors of aging and enables cells to become revitalized.  Scientists have found that activated AMPK promotes longevity factors that have been shown to extend life span in numerous organisms.  1  2 

There are various studies that show an increase in AMPK supports:

  • Reduced fat storage 3 
  • New mitochondria production  4 
  • Promotion of healthy blood glucose and lipids already within normal range  5 

dmso-7-241Fig1

Roles of AMPK in the control of whole-body energy metabolism. Notes: Activation of AMPK (green lines) stimulates the energy-generating pathways in several tissues while inhibiting the energy-consuming pathways (red lines). In skeletal muscle and heart, activation of AMPK increases glucose uptake and fatty acid oxidation. In the liver, AMPK activity inhibits fatty acid and cholesterol synthesis. Lipolysis and lipogenesis in adipose tissue are also reduced by AMPK activation. Activation of AMPK in pancreatic β-cells is associated with decreased insulin secretion. In the hypothalamus, activation of AMPK increases food intake.  Source: AMPK activation: a therapeutic target for type 2 diabetes? Kimberly A Coughlan, Rudy J Valentine, Neil B Ruderman, and Asish K Saha, Diabetes Metab Syndr Obes. 2014; 7: 241–253. Published online 2014 Jun 24. doi: 10.2147/DMSO.S43731

Activating AMPK:  Turning the Switch “ON”

The two major methods of activating AMPK is through:

  • exercise and
  • calorie restriction

When you exercise, you use up more ATP which generates higher AMP levels, which then activates AMPK.  6

The other method of activating AMPK is through calorie restriction by at least 30%.  This means cutting daily calorie consumption by 30%.  By reducing calorie consumption, the lower levels of available energy leads to rising AMP levels, which then activates AMPK.  7

In addition to exercise and calorie restriction, there are many other ways to activate AMPK, particularly through certain foods, herbs and nutraceuticals.  The Table below lists the many researched methods of activating AMPK:

AMPK Activators

CategorySubstance/ActivityReferences
Physiological
Exercise1
Fasting and Intermittant Fasting2
Cold water exposure (raise AMPK in the hypothalamus)3
Calorie Restriction4
Foods
Extra Virgin Olive Oil 5
Royal Jelly (10-Hydroxy-2-decenoic acid (10H2DA)6
Dashi kombu (Laminaria japonica Areschon)7
Bitter Orange (Citrus aurantum Linn)8
Garlic and Olives (Oleanolic acid)9
Apple Cider Vinegar10
Rose Hips (Trans-Tiliroside)11
Mulberry leaves extracts12
Fish Oil – EPA , DHA 13 14
Anthocyanins 15
Bitter melon16
Fungi
Reishi17
Herbs and Spices
Cinnamon 18
Astragalus 19 20
Marijuana (Cannabinoids)21
Green Tea/EGCG22
Rooibos23
Danshen (Chinese Red Sage)24
Gynostemma pentaphyllum (Jiagulon)25
Baicalin26 27
Hormones
Adiponectin 28 29
Thyroid hormones, especiallly T3 30
Leptin31
Nitric Oxide32 33
Immune System
Interleukin-6 (IL-6)34
Nutraceuticals
Apigenin35
Berberine36
Butyrate (Calcium/Magnesium ) or Sodium Butyrate (Short Chain Fatty-Acid)37
Carnitine38
Co-enzyme Q1039
Creatine40
Curcumin41
Fucoidan42
Genistein43
Glucosamine44 45
Hydroxytyrosol46
Oxaloacetate47
Quercetin48 49
Red yeast rice50
Resveratrol51
R-Lipoic Acid52 53
Vitamin E - gamma tocotrienol54
Pharmaceuticals
Aspirin55
Metformin56


Informational References:

Life Extension – AMPK and Aging “A Technical Review”  (November 2015)

Chinese Herbal Decoction Ge-Gen-Qin-Lian: An Effective Treatment for Type 2 Diabetes

A Traditional Chinese Medicine (TCM) herbal formula that has been used for the treatment of type-2 diabetes, and which has been documented based on clinical trials, is the Ge-Gen-Qin-Lian decoction (GGQLD).

A number of recent studies from 2011 and 2015 have showed that GGQLD had good clinical effects on type-2 diabetes and the anti-diabetic activities of GGQLD in vivo and in vitro were investigated.  1  2 

GGQLD consists of four herbs:

  • Puerariae Lobatae radix (Ge-Gen) as the principle herb
  • Scutellariae radix (Huang-Qin)
  • Coptidis rhizoma (Huang-Lian)
  • Glycyrrhizae Radix et Rhizoma Praeparata cum Melle (Gan-Cao)

Each of these 4 herbs have primary bioactive compounds that are effective in treating and reducing blood glucose level.  The primary bioactive compounds from these 4 herbs and their effect include:

Ge-Gen

Puerarin from Ge-Gen reduced blood sugar in diabetic mice, and improved insulin resistance and hyperlipidemia in rats  3 

Huang-Qin

Baicalin from Huang-Qin had antihyperglycemic effects on diabetic rats  4 

Huang-Lian

Berberine from Huang-Lian lowered blood glucose significantly by increasing insulin receptor expression  5

Gan-Cao

Amorfrutins from Gan-Cao have potent antidiabetic activity  6 

Another key component of GGQLD that has been identified called 4-Hydroxymephenytoin is involved in the antidiabetic ingredients of GGQLD stimulating endogenous insulin secretion and ameliorating insulin resistance in 3T3-L1-based insulin resistance models.  7

The Table below lists the antidibetic ingredients in Ge-Gen-Qin-Lian:  (Source) 

Potential antidiabetic ingredients in Ge-Gen-Qin-Lian formula by network target analysis.
Ingredients Herbs CID Literature evidence
4-Hydroxymephenytoin Ge-Gen 119507 /
1-OCTEN-3-OL Ge-Gen 18827 [50]
Berbericinine Huang-Lian 19009 /
Berberine bisulfate Huang-Lian 12457 [51]
Columbamine Huang-Lian 72310 [52]
Coptisine Huang-Lian 72322 [53]
Epiberberine Huang-Lian 160876 [54, 55]
Jatrorrhizine Huang-Lian 72323 [55, 56]
Oxyberberine Huang-Lian 11066 [57]
Dehydrocheilanthifoline Huang-Lian 3084708 [58]
Berberine Huang-Lian 2353 [59]
Indole Huang-Qin 798 [60]
1,3-Diphenylbenzene Huang-Qin 7076 /
2-Formylpyrrole Huang-Qin 13854 /
Guaifenesin Huang-Qin 3516 [61]
1-(1H-Pyrrol-2-yl)ethanone Gan-Cao 14079 [62]
2-Acetyl-1-methylpyrrole Gan-Cao 61240 [63]
m-Ethylphenyl acetate Gan-Cao 76462 /
5,6,7,8-Tetrahydro-4-methylquinoline Gan-Cao 185667 /
/: no evidence.

Modulating the Genetic Factors (ApoE) of Alzheimer’s Disease With Positive Behaviors and Natural Substances

Causitive Factors of Dementia and Alzheimer’s Disease

It is generally believed that the onset of dementia and Alzheimer’s disease is the consequences of complex interactions among:  1

  • genetic factors
  • environmental factors
  • lifestyle factors

The main features of dementia and Alzheimer’s disease are the presence of:

  • extracellular amyloid beta protein plaques
  • intracellular neurofibrillary tangles of tau proteins (NFTs)
  • loss of neurons and synapses in the cerebral cortex and certain subcortical regions in the brain

Image result for amyloid beta plaques

Figure 1.  Amyloid beta protein plaques and intracellular neurofibrillary tangles of tau proteins  (Source)

Image result for loss of neurons and synapses in the cerebral cortex

Figure 2.  Loss of neurons and synapses in the cerebral cortex  (Source)

This article focuses on the genetic factors as a potential cause for the late-onset of Alzheimer’s disease and what actions can be taken to modulate these genetic factors as it related to the most important genetic factor known as apolipoprotein E (ApoE).

Genetic Factors

Studies have demonstrated that Alzheimer’s disease is related to polymorphisms of at least four (4) genes:

  • amyloid precursor protein (APP)
  • presenilin (PS-1)
  • presenilin (PS-2)
  • apolipoprotein E (ApoE)

Polymorphisms in the three genes, amyloid protein precursor (APP), presenilin (PS)-1 and PS-2, is estimated to be the cause of early-onset (which is less than 60 years of age) autosomal dominant Alzheimer’s disease, which accounts for less than 1% of Alzheimer’s disease cases.  2

There are multiple genetic, environmental and lifestyle factors involved in late-onset Alzheimer’s disease, yet impairment in amyloid-beta clearance by ApoE is a major contributor to development of the disease.

Apolipoprotein E (ApoE)

Apolipoprotein E (ApoE) is a class of apolipoprotein found in the chylomicron and Intermediate-density lipoprotein (IDLs) that is essential for the normal catabolism of triglyceride-rich lipoprotein constituents. 

ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family.  ApoE is the principal cholesterol carrier in the brain and encodes for a protein that transports cholesterol, fats and fat-soluble vitamins through the blood.  

ApoE also contributes to the maintenance and repair of nerve cells.

PBB Protein APOE.jpg

Figure 3.  Apolipoprotein E (ApoE)  (Source)

There are three (3) major polymorphisms or alleles in the ApoE gene:

  • ApoE-ε2  (good one)
  • ApoE-ε3  (neutral)
  • ApoE-ε4  (problematic)

Since we carry two copies of the APOE gene, one from our mother and one from our father, the combination of alleles determines our ApoE3 genotype, for which there are six possible genotypes:

  • E2/E2
  • E3/E3
  • E4/E4
  • E2/E3
  • E2/E4
  • E3/E4

The ApoE-ε2 polymorphism, the most desirable to have, is associated with lower cholesterol levels and it actually may protect against Alzheimer’s disease in some populations and may decrease the risk.  3  

The ApoE-ε3 allele has a frequency of approximately 79 percent and is considered the “neutral” Apo E genotype. This means that for 79% of the population, a genetic polymorphism of this gene does not cause dementia or heart disease.  

The E2 allele is the one that is the most efficient in clearing and removing the amyloid-beta plaques from the brain.  The second most efficient allele is the E3 version, which does an average job of removing amyloid-beta plaques.

The E4 allele is the least efficient version in removing and clearing amyloid-beta plaques from the brain.  This results in more plaques building up and creating a much greater risk of developing Alzheimer’s disease.

The best genotype to have is E2/E2.

The worst genotype to have is E4/E4.

There are certain percentages of the population that carry certain genotypes:

  • Around 55% of the population have the E3/E3 genotype, which is the most common, equating to average risk  
  • Around 25% of the population have the E3/E4 genotype
  • Around 15% of the population have the E2/E3 genotype

ApoE-ε4 Allele

ApoE-ε4 is a major genetic risk factor for late-onset Alzheimer’s disease.  

Individuals carrying the E4 allele are at an increased risk of Alzheimer’s disease.  Having one allele of ApoE4 increases the risk of Alzheimer’s disease, and if two ApoE4 alleles are present, the risk is even higher.  15

However, many individuals with the ApoE-ε4 allele never develop the disease and many patients with Alzheimer’s disease do not have the ApoE-ε4 allele.  

With an allele frequency of approximately 14%, the ApoE-ε4 polymorphism has been implicated in the following diseases:

  • atherosclerosis  4
  • Alzheimer’s disease  5
  • impaired cognitive function  6
  • reduced hippocampal volume  7 
  • HIV  8 
  • faster disease progression in multiple sclerosis  9
  • unfavorable outcome after traumatic brain injury  10 
  • ischemic cerebrovascular disease  11 
  • sleep apnea  12
  • accelerated telomere shortening  13
  • reduced neurite outgrowth  14  

Image result for Apolipoprotein E

Figure 4.  Apolipoprotein E and Alzheimer disease  (Source)

Those patients with two ε4 alleles of the APOE gene have up to 20 times the risk of developing Alzheimer’s disease.  16  The lifetime risk estimate of developing Alzheimer’s disease for individuals with one copy of the apoE4 allele (approximately 25% of the population) is approximately 30%. 17

According to the National Institute of Health, inheriting a single copy of ApoE4 from a parent increases the risk of Alzheimer’s disease by about three-fold. Inheriting two copies, one from each parent, increases the risk by about 12-fold.

ApoE generally is an anti-inflammatory and is able to break down the amyloid beta proteins that are a cause of Alzheimer’s disease.  The ApoE-ε4 allele is limited in its ability to function as an anti-inflammatory and to break down amyloid beta proteins. 18

Increasing the Production and Function of ApoE-ε4

If a person has one E4 allele or two E4 alleles (E4/E4, which is the worst and carries the highest risk for Alzheimer’s disease), then they can and should take proactive and aggressive preventive action to increase the production and function of the ApoE-ε4 allele.

You ultimately want your ApoE working effeciently to help control and remove the harmful buildup of amyloid-beta plaques.

Since the ApoE-ε4 allele does not function as efficiently as the ApoE-ε2, there are certain behaviors that can be done and substances that can be taken to increase its production and function. 

Behavioral Actions

There are certain behavioral actions that can be taken to increase to production and function of the ApoE, such as:

  • Eat a Ketogenic diet  19
  • APOE Stabilization by Exercise  20
  • Reduce elevated total cholesterol level and blood pressure 21
  • Learning and education (allowing the brain to constantly learn new and interesting in-depth subjects)  
  • 22

Natural Substances that Increase the Production and Function of ApoE-ε4

There are also natural substances that be consumed that have shown to increase the production and function of ApoE, especially in the case of a low functioning E4 single of double allele.  

These substances are listed in the Table below:

Increasing the Production and Function of ApoE-ε4

CategorySubstanceReference
Fatty Acids
DHA Ref.
Butyrate Ref.
Polyphenols
Curcumin Ref.   Ref.
Vitamins
Vitamin A (Retinol)   Ref.
Citicoline (cytidine diphosphate-choline (CDP-Choline) Ref.

Resources:

In order to see what your genotype in the ApoE gene, especially if your have the ApoE-ε4 polymorphism, you need to order a DNA and Genetic Test.  There are a number of testing companies.  The most popular are:

23andMe

Ancestry

Genos

Once you have ordered and received your DNA and Genetic Test from the testing company, you can then download your data to one of a number of websites that will analyze your genetic data and provide information on the polymorphisms of the ApoE gene and your specific genotype. 

A number of companies will analyze your genetic data and include:

SelfDecode

Livewello

Infinome

Promethease

Codegen.eu

All of the 5 companies above will receive the 23andMe genetic data.

Another way to test for your genotype and the ApoE-ε4 polymorphism can be done by ordering the following test from Life Extension:

Life Extension – ApoE Genetic Test for Alzheimer’s and Cardiac Risk

Sample Report (PDF)

Videos:

Dr. Ben Lynch – Alzheimer’s Dirty Gene APOE4

AHS16 – Steven Gundry – Dietary Management of the Apo E 4

NutritionFacts.org – The Alzheimer’s Gene: Controlling ApoE

Apo E Gene’s connection with Alzheimer’s Disease, Heart Disease and more

Do you have Apo E 4 Dementia risk, Heart Attack diet risk; Apo(e) 4 and alcohol